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A chronic treatment with CDP-choline improves functional recovery and increases neuronal plasticity after experimental stroke
Abstract
Chronic impairment of forelimb and digit movement is a common problem after stroke that is resistant to therapy. Although in the last years some studies have been performed to increase the efficacy of rehabilitative experience and training, the pharmacological approaches in this context remain poorly developed. We decided to study the effect of a chronic treatment with CDP-choline, a safe and well-tolerated drug that is known to stabilize membranes, on functional outcome and neuromorphological changes after stroke. To assess the functional recovery we have performed the staircase reaching test and the elevated body swing test (EBST), for studying sensorimotor integration and asymmetrical motor function respectively. The treatment with CDP-choline, initiated 24 h after the middle cerebral artery occlusion (MCAO) and maintained during 28 days, improved the functional outcome in both the staircase test (MCAO+CDP=87.0+/-6.6% pellets eaten vs. MCAO+SAL=40.0+/-4.5%; p<0.05) and the EBST (MCAO+CDP=70.0+/-6.8% vs. MCAO+SAL=88.0+/-5.4%; contralateral swing p<0.05). In addition, to study potential neuronal substrates of the improved function, we examined the dendritic morphology of layer V pyramidal cells in the undamaged motor cortex using a Golgi-Cox procedure. The animals treated with CDP-choline showed enhanced dendritic complexity and spine density compared with saline group. Our results suggest that a chronic treatment with CDP-choline initiated 24 h after the insult is able to increase the neuronal plasticity within noninjured and functionally connected brain regions as well as to promote functional recovery.
... Действующее вещество цитиколин (цитидин-5-дифосфохолин) относится к группе нуклеотидов; состоит из рибозы, пирофосфата, цитозина (азотистое основание) и холина. ЦДФ-холин является незаменимым предшественником фосфатидилхолина (лецитина) -основного структурного компонента всех клеточных мембран, включая нейроциты, играет важную роль в клеточном метаболизме [37,42]. Цитиколин показал положительные результаты на моделях повреж-дения ЦНС: он сохранял кардиолипин и сфингомиелин в мембранах; снижал высвобождение арахидоновой кислоты; стимулировал синтез глутатиона и активность глутатионредуктазы; ослаблял пероксидацию липидов; восстанавливал активность Na+/K+-ATФазы. ...
... Цитиколин показал положительные результаты на моделях повреж-дения ЦНС: он сохранял кардиолипин и сфингомиелин в мембранах; снижал высвобождение арахидоновой кислоты; стимулировал синтез глутатиона и активность глутатионредуктазы; ослаблял пероксидацию липидов; восстанавливал активность Na+/K+-ATФазы. Эти эффекты отчасти объясняют способность цитиколина снижать активность фосфолипазы А2 [26,28,37]. Будучи донором холина для синтеза нейротрансмиттера ацетилхолина, цитиколин стимулирует активность тирозингидроксилазы и способствует высвобождению допамина. ...
... Препарат легко проникает через гематоэнцефалический барьер и служит донором для биосинтеза нейротрансмиттера ацетилхолина в пресинаптических мембранах холинергических нейронов. Усиление метаболических процессов в головном мозге обеспечивает улучшение познавательных, психических и поведенческих функций [26,28,37,38]. ...
The article is devoted to medical support of rehabilitation measures for post-stroke motor disorders. The approach to the selection of neurocytoprotectors from the positions of the concept of neuroplasticity and multimodal action is considered. The results of our own observation of the use of citicoline (Ceraxon ®) in the complex program of medical rehabilitation of patients after ischemic stroke are presented. The high efficiency of citicoline application in complex rehabilitation of patients in the early recovery period of ischemic stroke is shown in the form of improving walking function, increasing functional independence, daily activity and quality of life.Conclusions. The use of modern neurocytoprotectors in a complex of rehabilitation programs is an important and indispensable component for achieving the maximum possible results of rehabilitation aimed at improving the functioning and quality of life of patients.
... [8] Choline precursors are exogenous agents that promote the maintenance, repair and the formation of cell membrane phospholipids as well as the neurotransmitters acetylcholine and dopamine. [9,23,24] The pharmacological characteristic of citicoline helpful in accelerating the recovery of consciousness and motor deficit facilitates the rehabilitation of the patients with the acute ischemic cerebral vascular disease. [8,[25][26][27][28][29][30][31][32][33][34] Traumatic brain injury is a major cause of death and disability. ...
... [53,68] CDP-choline has been reported to decrease infarct volume and edema to improve neurological deficits. [26,44,69] Citicoline accelerates phospholipid synthesis, neural repair, [24] also as epilepsy, [70] Alzheimer's disease, [71,72] Huntington's disease, [73] Parkinson's disease, and amyotrophic lateral sclerosis. [74,75] SOLUBILITY According to Biopharmaceutics Classification System (BCS), classification of Citicoline falls under BCS Class I, meaning it has high solubility and high permeability. ...
Citicoline is a nootropic agent. It is used in the treatment of brain insufficiency and other neurological disorders such as brain stroke, trauma, and Parkinson's disease. This review article represents summarized results of published analytical methods in the literature for the determination of citicoline in biological and pharmaceutical formulations. Various techniques such as spectrophotometry, liquid chromatography (LC), high-performance LC, ultra performance LC, gas chromatography, nuclear magnetic resonance, and hydrophilic interaction LC method were reported.
... So, the need for neuroprotective measures to decrease the damage caused by secondary brain injury in children is crucial. Phosphatidylcholine is the most important neuronal phospholipids [5]. Cytidine diphosphocholine (citicoline or CDP-choline) is an exogenous drug that is converted to cytidine and choline inside the body which helps in the repair, maintenance and synthesis of phospholipids that is degraded during cerebral ischemia to free fatty acids and free radicals [6]. ...
... Citicoline may also reduce free fatty acid release and improve the activities of membrane Na+/K+ ATPase and mitochondrial ATPase to reduce brain damage [23]. Finally, citicoline may facilitate recovery by enhancing synaptic outgrowth and increased neuroplasticity [5]. ...
Germany, part of Springer Nature 2020
Abstract
Brain hypoxia after cardiac arrest leads to damage of the neuronal cell membrane. Citicoline is necessary for the synthesis of cell membrane. We planned to assess the neuroprotective effect of citicoline in children after cardiac arrest. This randomized controlled trial was carried out at pediatric intensive care units (PICU) and surgical ICU at Tanta university hospital on 80 consecutive children surviving in-hospital cardiac arrest who were subdivided into two groups. Group I (citicoline group) included 40 children with post- cardiac arrest who received citicoline 10 mg /kg /12 h IV for 6 weeks plus other supportive measures and group II (control group) included 40 children with post-cardiac arrest who were managed with only supportive measures. All patients were evaluated for Glasgow coma score (GCS), modified Rankin scale (mRS) for children, seizures frequency, type and duration, and serum neuron- specific enolase (NSE) before and 3 months after the treatment. GCS and mRS significantly improved in citicholine group compared to the control group. Seizure frequency and duration, mortality, PICU and hospital stay significantly decreased in citicholine group compared to the control group. Serum NSE levels significantly decreased in citicholine group only. No side effects were recorded.
Conclusion: Citicoline is a promising neuroprotective drug in children with post-cardiac arrest.
... Moreover, the results of the present study also show that patients with GCI have a poorer quality of life. Apart from its neuroprotective effects, citicoline also possesses a substantial neuroregenerative potential [27][28][29][30][31][32][33][34] that may explain better its beneficial effects in post-stroke cognitive impairment and quality of life. Since experimental studies have shown that neurorepair mechanisms initiated after cerebral ischemia remain active beyond twelve months [35], the use of drugs that enhance neurorepair mechanisms as citicoline [27][28][29][30][31][32][33][34], would be indicated for periods of time longer than one year in order to improve post-stroke sequelae and prevent cognitive decline associated with age, as shown by the results of this study. ...
... Apart from its neuroprotective effects, citicoline also possesses a substantial neuroregenerative potential [27][28][29][30][31][32][33][34] that may explain better its beneficial effects in post-stroke cognitive impairment and quality of life. Since experimental studies have shown that neurorepair mechanisms initiated after cerebral ischemia remain active beyond twelve months [35], the use of drugs that enhance neurorepair mechanisms as citicoline [27][28][29][30][31][32][33][34], would be indicated for periods of time longer than one year in order to improve post-stroke sequelae and prevent cognitive decline associated with age, as shown by the results of this study. ...
Stroke, as the leading cause of physical disability and cognitive impairment, has a very significant impact on patients’ quality of life (QoL). The objective of this study is to know the effect of citicoline treatment in Qol and cognitive performance in the long-term in patients with a first ischemic stroke. This is an open-label, randomized, parallel study of citicoline vs. usual treatment. All subjects were selected 6 weeks after suffering a first ischemic stroke and randomized into parallel arms. Neuropsychological evaluation was performed at 1 month, 6 months, 1 year and 2 years after stroke, and QoL was measured using the EuroQoL-5D questionnaire at 2 years. 163 patients were followed during 2 years. The mean age was 67.5 years-old, and 50.9% were women. Age and absence of citicoline treatment were independent predictors of both utility and poor quality of life. Patients with cognitive impairment had a poorer QoL at 2 years (0.55 vs. 0.66 in utility, p = 0.015). Citicoline treatment improved significantly cognitive status during follow-up (p = 0.005). In conclusion, treatment with long-term citicoline is associated with a better QoL and improves cognitive status 2 years after a first ischemic stroke.
... [9] Additionally, citicoline shows promise in restoring dopamine turnover in ischemic brain tissue in rats and appears to improve experimental cerebral ischemia. [10] It enhances metabolic activity in the brain during ischemia, [11] increases neuronal plasticity, [12] and has a beneficial impact in relation to spatial cognition and memory in rats following focal cerebral ischemia. [13] The experimental study of citicoline in rats due to cerebral ischemia showed a prolonged onset of stroke and arrest. ...
What is expected from neuroprotection is to inhibit neuronal death and halt or decelerate the neuronal loss to lower the mortality rates, decrease disability, and improve the quality of life following an acute ischemic stroke. Several agents were described as neuroprotective up to date; however, there is still debate which to use in the neurorehabilitation of stroke patients, in terms of both efficacy and also safety. In this review, we discuss the agents, citicoline, cerebrolysin and MLC901 (NeuroAiD II), the three agents which have started to be used frequently in neurorehabilitation clinics recently in the light of the current literature.
... [50,51] Mechanisms by which citicoline is activating the "relative pathway" of EDM have been described in multiple studies like stabilization of membrane integrity in neurons, glutamate inhibition, and promoting the synthesis of various proteins and neurotransmitters after acute stroke. [52][53][54][55][56][57][58] According to our hypothesis, citicoline alone can't work alone as it is effective only in one part of defense mechanisms. ...
BACKGROUND
Stroke is a leading cause of morbidity and mortality worldwide and a leading cause of disability. None of the neuroprotective agents have been approved internationally except edaravone in Japanese guidelines in acute ischemic stroke. We here discuss that there are two types of endogenous defense mechanisms (EDMs) after acute stroke for neuromodulation and neuroregeneration, and if both can be activated simultaneously, then we can have better recovery in stroke.
AIMS AND OBJECTIVES
We aimed to study the effect of combination of neuroprotection therapies acting on the two wings of EDM in acute large-vessel middle cerebral artery (LMCA) ischemic stroke.
METHODS
Sixty patients of LMCA stroke were enrolled and randomized within 72 h into two groups of 30 patients each. The control group received standard medical care without any neuroprotective agents while the intervention group received standard medical care combined with oral citicoline with vinpocetine for 3 months with initial 1 week intravenous and edaravone and cerebrolysin injection, started within 72 h of onset of stroke. Patients were assessed on the basis of the National Institutes of Health Stroke Scale, Fugl-Meyer Assessment Score, Glasgow Coma Scale, and Mini-Mental Status Examination at admission, discharge, and after 90 days.
RESULTS
The intervention group showed significant and early improvements in motor as well as cognitive recovery.
CONCLUSION
Combination therapy for neuroprotection which is acting on two pathways of EDM can be useful in functional recovery after acute ischemic stroke.
... Inflammation, alterations in cell membrane integrity, and the impairment of phospholipid metabolism have all been implicated in the pathophysiology of TBI [5,[8][9][10]14]. Importantly, many studies have shown that citicoline has neuroprotective and neurorestorative properties, including the following: the normalization or stabilization of damaged neuronal cell membranes (i.e., phospholipid content and function, ion exchange); the restoration of some enzymatic activities; a reduction in the generation of damaging free fatty acids and free radicals; the improvement of neurotransmission and cerebral metabolism; anti-inflammatory and antioxidant properties; the enhanced integrity of the blood-brain barrier; the accelerated absorption of brain edema and the decreased volume of ischemic lesions; the inhibition of apoptosis; and the enhancement of neurorepair and neuroplasticity properties [5,[8][9][10]14,[63][64][65][66]. Thus, given its biochemical, pharmacological, and pharmacokinetic characteristics, citicoline should considered as a potentially useful drug for the treatment of patients with TBI [5,14,17]. ...
Background: Citicoline or CDP-choline is a neuroprotective/neurorestorative drug used in several countries for the treatment of traumatic brain injury (TBI). Since the publication of the controversial COBRIT, the use of citicoline has been questioned in this indication, so it was considered necessary to undertake a systematic review and meta-analysis to evaluate whether citicoline is effective in the treatment of patients with TBI. Methods: A systematic search was performed on OVID-Medline, EMBASE, Google Scholar, the Cochrane Central Register of Controlled Trials, ClinicalTrials.gov, and Ferrer databases, from inception to January 2021, to identify all published, unconfounded, comparative clinical trials of citicoline in the acute phase of head-injured patients— that is, treatment started during the first 24 h. We selected studies on complicated mild, moderate, and severe head-injured patients according to the score of the Glasgow Coma Scale (GCS). The primary efficacy measure was independence at the end of the scheduled clinical trial follow-up. Results: In total, 11 clinical studies enrolling 2771 patients were identified by the end. Under the random-effects model, treatment with citicoline was associated with a significantly higher rate of independence (RR, 1.18; 95% CI = 1.05–1.33; I2, 42.6%). The dose of citicoline or the administration route had no effect on outcomes. Additionally, no significant effects on mortality were found, and no safety concerns were noticed. Conclusions: This meta-analysis indicates some beneficial effects of citicoline’s increasing the number of independent patients with TBI. The most important limitation of our meta-analysis was the presumed heterogeneity of the studies included. Registration: PROSPERO CRD42021238998
... The same authors demonstrated that citicoline redistributes the glutamate transporter EAAT2 to lipid raft microdomains and improves glutamate uptake and this effect is also found after experimental stroke, when citicoline is administered four hours after the ischemic occlusion [199]. In another study [200], they found that a chronic treatment with citicoline, initiated 24 hours after the insult, is able to increase the neuronal plasticity as well as to promote functional recovery (Fig. 4). Zhao et al [201] also showed a positive effect of citicoline on spatial learning and memory of rats after focal cerebral ischemia. ...
This review is based on the previous one published in 2016 (Secades JJ. Citicoline: pharmacological and clinical
review, 2016 update. Rev Neurol 2016; 63 (Supl 3): S1-S73), incorporating 176 new references, having all the information
available in the same document to facilitate the access to the information in one document. This review is focused on the
main indications of the drug, as acute stroke and its sequelae, including the cognitive impairment, and traumatic brain
injury and its sequelae. There are retrieved the most important experimental and clinical data in both indications.
... The same authors demonstrated that citicoline redistributes the glutamate transporter EAAT2 to lipid raft microdomains and improves glutamate uptake and this effect is also found after experimental stroke, when citicoline is administered four hours after the ischemic occlusion [199]. In another study [200], they found that a chronic treatment with citicoline, initiated 24 hours after the insult, is able to increase the neuronal plasticity as well as to promote functional recovery (Fig. 4). Zhao et al [201] also showed a positive effect of citicoline on spatial learning and memory of rats after focal cerebral ischemia. ...
This review is based on the previous one published in 2016 (Secades JJ. Citicoline: pharmacological and clinical review, 2016 update. Rev Neurol 2016; 63 (Supl 3): S1-S73), incorporating 176 new references, having all the information available in the same document to facilitate the access to the information in one document. This review is focused on the main indications of the drug, as acute stroke and its sequelae, including the cognitive impairment, and traumatic brain injury and its sequelae. There are retrieved the most important experimental and clinical data in both indications.
... Although central axons have no regenerative capacity in adults, mechanical damage can stimulate the formation of new structural connections [26]. Studies have shown that reconstructing damaged axons and dendrites after brain injury can partially restore neurological function [27]. Therefore, an effective therapeutic strategy for ICH that restores axonal structure and function is needed. ...
Intracerebral hemorrhage (ICH) is a devastating event with high disability and fatality rates. However, there is a lack of effective treatments for this condition. We aimed to investigate the neuroprotective and axonal regenerative effects of progesterone after ICH. For this purpose, an ICH model was established in adult mice by injecting type VII collagenase into the striatum; the mice were then treated with progesterone (8 mg/kg). Hematoma absorption, neurological scores, and brain water content were evaluated on days one, three, and seven after the ICH. The effect of progesterone on inflammation and axonal regeneration was examined on day three after the ICH using western blotting, immunohistochemistry, immunofluorescence, as well as hematoxylin-eosin, Nissl, and Luxol fast blue staining. In addition, we combined progesterone with the phosphoinositide 3-kinase/serine/threonine-specific protein kinase (PI3K/AKT) inhibitor, LY294002, to explore its potential neuroprotective mechanisms. Administration of progesterone attenuated the neurological deficits and expression of inflammatory cytokines and promoted axonal regeneration after ICH, this effect was blocked by LY294002. Collectively, these results suggest that progesterone could reduce axonal damage and produced partial neuroprotective effects after ICH through the PI3K/AKT/mTOR pathway, providing a new therapeutic target and basis for the treatment of ICH.
... Citicoline (CDP-choline or cytidinediphosphate choline; cytidine 5′-diphosphocholine) is a complex organic molecule composed of ribose, pyrophosphate, cytosine and choline [1]. Citicoline has been suggested to provide beneficial recovery and neuroprotective effects in brain traumatic injuries, stroke, brain ageing and neurodegenerative diseases [2,3], although the exact mechanisms through which it operates are not fully understood. ...
Background and purposes - Citicoline is neuroprotective agent used in stroke patients. Citicoline induces angiogenesis i n vitro ; however, the molecular mechanisms induced by citicoline have not been fully investigated. The present study was designed to investigate the key signalling mechanisms through which citicoline modulates angiogenesis-associated with stroke recovery.
Methods - In vitro angiogenesis assays: migration (Bodyen chamber, a chemotaxis assay and wound recovery), proliferation and differentiation into tube-like structures in Matrigel TM as well as spheroid development assays were carried out using human brain microvessel endothelial cells (HBMECs). Western blotting was performed on the protein extraction from HBMEC stimulated with citicoline. Citicoline signalling pathway was studied using a phospho-protein screening array performed by Kinexus. A Staurosporin/calcium ionophore-induced apoptosis assay was performed by seeding HBMEC on the glass coverslips. Cells were pre-incubated with citicoline and the apoptosis was induced by addition of the ionophore or staurosporin. Cells were examined by microscoy and/or stained using propidium iodide and Hoechst stain solution and then counted under fluorescence microscope. Transient MCAO was carried out on Sprague Dawley rats (n=4 per group) with and without citicoline treatment (1000mg/Kg) applied at the time of occlusion and subsequently every 3 days until euthanasia (21 days). Vascularity of the stroke-affected regions was examined with antibodies recognising the microvessels (CD34) and active cells (CD105).
Results - Citicoline presented no mitogenic and chemotactic effects on HBMEC; however, it significantly increased wound recovery, the formation of tube-like structures in Matrigel TM -with a stronger effect than FGF-2, and enhanced spheroid development and sprouting. Citicoline induced the expression of ERK-1/2, known to be involved in last step of signalling pathways of angiogenesis. Kinexus results showed an over-expression of ASK-1, HER2, IRS-1 and Jun and inhibition of Hsp27, Integrin alpha4, MEK1 (MAP2K1) and Histone H2B proteins. Knock-down of IRS-1 with targeted siRNA inhibited the pro-angiogenic effects (sprouting and tube-formation) of citicoline in HBMECs. The percentage of surviving cells was higher in the presence of citicoline after inducing apoptosis. Histology of infarcted regions showed that citicoline significantly increased the numbers of new active (CD105-positive) microvessels.
Conclusion - The findings demonstrate both a pro-angiogenic and protective effect of citicoline on HBMECs in vitro and following MCAO in vitro. Additionally, this molecule may play a key role in the modulation of angiogenesis thereby and ultimately, improving tissue function, revascularisation and neuronal survival after ischaemic stroke.
... Therefore, PLA2 inhibitors (Fig. 4e) have been assessed for stroke treatment in several studies. Chronic treatment of cytidine-5'diphosphocholine (CDP-choline) for 28 days improved neuronal plasticity and promoted functional recovery in MCAO rats [100]. A random clinical trial involving 1652 patients showed that oral citicoline administration for 6 weeks increased global stroke recovery by 33% at 3 months compared with placebo in patient subgroups with moderate to severe ischemic stroke. ...
Stroke ranks as the second leading cause of death across the globe. Despite advances in stroke therapeutics, no US Food and Drug Administration (FDA)-approved drugs that can minimize neuronal injury and restore neurological function are clinically available. Ferroptosis, a regulated iron-dependent form of nonapoptotic cell death, has been shown to contribute to stroke-mediated neuronal damage. Inhibitors of ferroptosis have also been validated in several stroke models of ischemia or intracerebral hemorrhage. Herein, we review the therapeutic activity of inhibitors of ferroptosis in stroke models. We further summarize previously reported neuroprotectants that show protective effects in stroke models that have been recently validated as ferroptosis inhibitors. These findings reveal new mechanisms for neuroprotection and highlight the importance of ferroptosis during stroke processes.
... Citicoline can decrease the free radical and delayed the ischemic brain injury process 17 . It can also increase synaptic outgrowth and neuroplasticity 18 . These several mechanisms of citicoline can allow the improvement of motoric functional in ischemic stroke patients. ...
Background: According to WHO, stroke is the leading cause of morbidity and the second cause of death with a mortality rate of around 5.54 million. Stroke, based on its etiology, consists of ischemic and hemorrhagic. Ischemic stroke is caused by a blockage in the blood-brain, whereas hemorrhagic stroke occurs due to the rupture of brain blood vessels. Based on the pathophysiology of ischemic stroke, its therapy consists of thrombolytic in thrombus for brain reperfusion and anticoagulants or antiplatelet in strokes due to embolization because it is grown in a collateral-containing lavatory and neuroprotectant assistance to trace cytotoxic nerves. Neuroprotectants that are often used are piracetam and citicoline. Citicoline improves neuronal cell membranes by increasing synthesis of the main component of cell membranes, phosphatidylcholine, then repaired neuronal cell membranes.
Objective: To find out motor improvement in stroke patients at Siti Khodijah Sepanjang Hospital by giving 500mg of citicoline per day orally for 5 days.
Methods: A case-control observational analytic study using medical record data. Consists of a group with standard therapy, antiplatelets, and another group with 500mg/day antiplatelet and citicoline therapy for 5 days. Patients were examined for MRC motor on the first day and the fifth day.
Results: The statistical test used the Chi-Square test and wilcoxon test with a significance value of 0.00 and 0,01 (
... По данным многих отечественных и зарубежных клинических исследований, прием цитиколина способствует восстановлению неврологических функций и снижению инвалидизации больных после инсульта. Это обусловлено тем, что цитиколин стимулирует процессы нейропластичности, ингибируя апоптоз, вызванный глутаматной эксайтотоксичностью, и обеспечивает нормализацию функционирования митохондриальной АТФазы и мембранной Na + -K + -АТФазы, в результате чего происходит уменьшение высвобождения жирных кислот [11]. ...
Objective : to investigate the efficacy and safety of citicoline (Ceresil ® Canon) in patients with post-stroke cognitive impairment.
Patients and methods . Examinations were made in 33 patients aged 45 years and older who had experienced primary ischemic hemispheric stroke with complaints of a decline in memory or other cognitive functions. The cognitive status was assessed using the Mini-Mental State Examination (MMSE) and the Montreal Cognitive Assessment (MoCA). The presence of anxiety-depressive spectrum disorders was determined on the Hospital Anxiety and Depression Scale. All the patients received citicoline (Ceresil ® Canon) oral solution at a dose of 1000 mg/day for 3 months.
Results and discussion . Citicoline administration showed a statistically significant reduction in the severity of cognitive impairment (p<0.001). The time course of positive changes in the cognitive status of patients was reflected by an increase in the median score on the MMSE from 26 [25; 27.5] to 28 [26.5; 29] and on MoCA from 23 [21; 25] to 25 [22; 26]. There was a decline in the number of patients with anxiety-depressive disorders. No adverse events or side effects were found in the patients.
Conclusion . The findings suggest that citicoline (Ceresil ® Canon) produced as an oral solution is well tolerated and improves cognitive functions and affective sphere in patients in the recovery period of ischemic stroke.
... The same authors demonstrated that citicoline redistributes the glutamate transporter EAAT2 to lipid raft microdomains and improves glutamate uptake and this effect is also found after experimental stroke, when citicoline is administered 4 h after the ischemic occlusion [185]. In another study [186], they found that a chronic treatment with citicoline, initiated 24 h after the insult, is able to increase the neuronal plasticity within noninjured and functionally connected brain regions as well as to promote functional recovery. To assess the functional recovery they have performed the staircase reaching test and the elevated body swing test (EBST), for studying sensorimotor integration and asymmetrical motor function respectively. ...
Summary. This review is based on the previous one published in 2006 –Secades JJ, Lorenzo JL. Citicoline: pharmacological
and clinical review, 2006 update. Methods Find Exp Clin Pharmacol 2006; 28 (Suppl B): S1-56–, incorporating the new
references until now, having all the information available to facilitate the access to the información in one document. This
review is focused on the main indications of the drug, as acute stroke and its sequelae, including the cognitive impairment,
and traumatic brain injury and its sequelae. There are retrieved the most important experimental and clinical data in both
indications.
Key words. Alcoholism. Alzheimer disease. Amblyopia. Apoptosis. CDP-choline. Cerebral edema. Cerebral ischemia. Citicoline.
Cognitive disorder. Drug addiction. Glaucoma. Head injury. Memory. Neuronal membrane. Neuroplasticity. Neuroprotection.
Neurorepair. Neurotransmission. Parkinson disease. Phosphatidylcholine. Phospholipase. Senile dementia. Stroke. Structural
phospholipids. Traumatic brain injury.
... Posteriormente, estos mismos autores [185] han demostrado el efecto de la citicolina sobre el transportador de glutamato EAAT2, incluso cuando se administra a las cuatro horas de la oclusión de la arteria cerebral media del animal de experimentación. En otro estudio [186], han demostrado que el tratamiento crónico con citicolina, iniciado 24 horas después de la isquemia, es capaz de mejorar la plasticidad neuronal y promover la recuperación funcional (Fig. 4). Zhao et al [168] también han demostrado un efecto beneficioso de la citicolina en aprendizaje espacial y memoria en un modelo de isquemia cerebral focal en ratas. ...
This review is based on the previous one published in 2010 -Secades JJ. Citicoline: pharmacological and clinical review, 2010 update. Rev Neurol 2011; 52 (Suppl 2): S1-62-, incorporating 183 new references, having all the information available to facilitate the access to the information in one document. This review is focused on the main indications of the drug, as acute stroke and its sequelae, including the cognitive impairment, and traumatic brain injury and its sequelae. There are retrieved the most important experimental and clinical data in both indications.
... 128 Preclinical studies of citicoline treatment showed lower infarct volumes and improved animal behavior, but a variety of different treatment protocols have been evaluated with less success. 68 Four clinical trials of citicoline have shown no differences in their primary outcome measures. [19][20][21]153 Although a pooled analysis of 1372 participants with baseline NIHSS scores ≥ 8 showed a statistically significant effect of citicoline on 3-month global outcome incorporating NIHSS, mRS, and Barthel Index scores at 3 months (25.2% vs 20.2%; p = 0.0034), these trials were limited by multiple design flaws. ...
OBJECTIVE
Various strategies have been proposed to reduce the incidence of external ventricular drain (EVD)–related infections. The authors retrospectively studied the impact of EVD care management on EVD-related infections at 3 French university hospital intensive care units.
METHODS
Between 2010 and 2014, 462 consecutive adult patients with no evidence of a preexisting CSF infection received EVDs as part of their care at one of the following sites: Grenoble (221 patients), Saint-Etienne (130 patients), and Marseille (111 patients). Written protocols describing the EVD placement procedure, management, and removal were implemented at the 3 sites. Daily CSF sampling and intraventricular administration of antibiotics prior to EVD removal were performed at the Grenoble site only. EVD-related infection was considered for any confirmed ventriculostomy-related infection (VRI) and ventriculitis. VRI was defined as one or more positive CSF cultures or Gram stain with CSF pleocytosis and biochemical abnormalities. Ventriculitis was defined as CSF pleocytosis and biochemical abnormalities with degradation of neurological status and fever.
RESULTS
A total of 6945 EVD days were observed in the entire population. In the Grenoble cohort, the mean cumulative incidence of EVD-related infections was significantly lower than that in the 2 other cohorts: 1.4% (95% CI 0.0%–2.9%) versus 9.2% (95% CI 4.2%–14.2%) and 7.2% (95% CI 2.4%–12.0%) at Saint-Etienne and Marseille, respectively (p < 0.01). Accounting for the duration of external ventricular drainage at each site, the risk for EVD-related CSF infections was significantly higher at Saint-Etienne and Marseille than at Grenoble, with ORs of 15.9 (95% CI 3.6–71.4, p < 0.001) and 10.0 (95% CI 2.2–45.5, p = 0.003), respectively.
CONCLUSIONS
These findings indicate that it is possible to attain a low incidence of EVD-related infections, provided that an EVD care bundle, which can include routine daily CSF sampling, is implemented and strongly adhered to.
... These studies were remarkable because they showed that citicoline is safe and effective in neuroprotection and neurodegeneration through a number of different mechanisms, including the activation of a group of important proteins, called sirtuins [14,15]. ...
... The same authors demonstrated that citicoline redistributes the glutamate transporter EAAT2 to lipid raft microdomains and improves glutamate uptake and this effect is also found after experimental stroke, when citicoline is administered 4 h after the ischemic occlusion [185]. In another study [186], they found that a chronic treatment with citicoline, initiated 24 h after the insult, is able to increase the neuronal plasticity within noninjured and functionally connected brain regions as well as to promote functional recovery. To assess the functional recovery they have performed the staircase reaching test and the elevated body swing test (EBST), for studying sensorimotor integration and asymmetrical motor function respectively. ...
This review is based on the previous one published in 2010 -Secades JJ. Citicoline: pharmacological and clinical review, 2010 update. Rev Neurol 2011; 52 (Suppl 2): S1-62-, incorporating 183 new references, having all the information available to facilitate the access to the information in one document. This review is focused on the main indications of the drug, as acute stroke and its sequelae, including the cognitive impairment, and traumatic brain injury and its sequelae. There are retrieved the most important experimental and clinical data in both indications.
... Так, в экспериментальных работах было продемонстрировано, что длительное лечение цитиколином приводит к улучшению функционального восстановления после экспериментального инсульта и что потенциальным нейрональным субстратом для улучшения функций может быть повышение ветвистости дендритов и плотности отростков по сравнению с таковой в контрольной группе, получавшей физиологический раствор. В связи с этим лечение цитиколином может повышать нейрональную пластичность, что может быть связано с клиническим улучшением после инсульта [5]. ...
The article is dedicated to the diagnosis, classification, and rehabilitation of various forms of speech disorders in poststroke patients. It is considered the most common types of expressive and impressive speech disorders. The main diagnostic signs of most frequent forms of aphasia and dysarthria are given. A plan for the rehabilitation program with the inclusion of a medication (Ceraxon®) and non-pharmacological methods of correcting speech disorders after stroke is offered.
... Folate and choline metabolism are tightly linked in the brain (Caudill, 2009) and we have previously shown that there is a significant reduction in choline in brain tissue of mice that are folate deficient (Jadavji et al., 2012;Jadavji et al., 2015a). Furthermore, choline has also been shown to be neuroprotective after stroke (Hurtado et al., 2007). The dosage of each vitamin and nutrient reflected doses from studies that previously reported beneficial effects (Agte et al., 1998;Craciunescu et al., 2003;Wolff et al., 1998). ...
Folates are B-vitamins that play an important role in brain function. Dietary and genetic deficiencies in folate metabolism result in elevated levels of homocysteine which have been linked to increased risk of developing a stroke. Reducing levels of homocysteine before or after a stroke through B-vitamin supplementation has been a focus of many clinical studies, however, the results remain inconsistent. Animal model systems provide a powerful mechanism to study and understand functional impact and mechanisms through which supplementation affects stroke recovery. The aim of this study was to understand the role of B-vitamins in stroke pathology using in vivo and in vitro mouse models. The first objective assessed the impact of folate deficiency prior to ischemic damage followed by B-vitamins and choline supplementation. Ischemic damage targeted the sensorimotor cortex. C57Bl/6 wild-type mice were maintained on a folic acid deficient diet for 4 weeks prior to ischemic damage to increased levels of plasma homocysteine, a risk factor for stroke. Post-operatively mice were placed on a B-vitamin and choline supplemented diet for a period of four weeks, after which motor function was assessed in mice using the rotarod, ladder beam and forepaw asymmetry tasks. The second objective was to determine how a genetic deficiency in methylenetetrahydrofolate reductase (MTHFR), an enzyme involved in folate metabolism, increases vulnerability to stroke. Primary cortical neurons were isolated from Mthfr+/+, Mthfr+/− and Mthfr−/− embryos and were exposed to in vitro models of stroke which include hypoxia or oxygen glucose deprivation. Cell viability was measured 24-h after exposure stroke like conditions in vitro. In supplemented diet mice, we report improved motor function after ischemic damage compared to mice fed a control diet after ischemic damage. Within the perilesional cortex, we show enhanced proliferation, neuroplasticity and anti-oxidant activity in mice fed the supplemented diet. A genetic MTHFR deficiency resulted in neurodegeneration after exposure to in vitro models of stroke, by activating apoptosis promoting p53-dependent mechanisms. These results suggest that one-carbon metabolism plays a significant role in recovery after stroke and MTHFR deficiency contributes to poor recovery from stroke.
... 128 Preclinical studies of citicoline treatment showed lower infarct volumes and improved animal behavior, but a variety of different treatment protocols have been evaluated with less success. 68 Four clinical trials of citicoline have shown no differences in their primary outcome measures. [19][20][21]153 Although a pooled analysis of 1372 participants with baseline NIHSS scores ≥ 8 showed a statistically significant effect of citicoline on 3-month global outcome incorporating NIHSS, mRS, and Barthel Index scores at 3 months (25.2% vs 20.2%; p = 0.0034), these trials were limited by multiple design flaws. ...
Stroke is a leading cause of disability in the US. Although there has been significant progress in the area of medical and surgical thrombolytic technologies, neuroprotective agents to prevent secondary cerebral injury and to minimize disability remain limited. Only limited success has been reported in preclinical and clinical trials evaluating a variety of compounds. In this review, the authors discuss the most up-to-date information regarding the underlying molecular biology of stroke as well as strategies that aim to mitigate this complex signaling cascade. Results of historical research trials involving N-methyl-d-aspartate and α-amino-3-hydroxy-5-methyl-4-isoxazole propionate receptor antagonists, clomethiazole, antioxidants, citicoline, nitric oxide, and immune regulators have laid the groundwork for current progress. In addition, more recent studies involving therapeutic hypothermia, magnesium, albumin, glyburide, uric acid, and a variety of other treatments have provided more options. The use of neuroprotective agents in combination or with existing thrombolytic treatments may be one of many exciting areas of further development. Although past trials of neuroprotective agents in ischemic stroke have been limited, significant insights into mechanisms of stroke, animal models, and trial design have incrementally improved approaches for future therapies.
... У пациентов пожилого возраста прием цитиколина в течение 6 недель приводил к значительному повышению содержания в лобной доле (передней части поясной извилины коры головного мозга) фосфокреатинина (+17 %), бета-нуклеозидтрифосфатов, в основном АТФ, в головном мозге (+14 %) и увеличению отношения фосфокреатинина к неорганическому фосфату (+32 %) по данным фосфорной магнитно-резонансной спектроскопии [9,14,18]. ...
Стаття присвячена веденню пацієнтів iз хронічними порушеннями мозкового кровообігу. Показано місце цитиколіну в комплексному лікуванні хронічних цереброваскулярних захворювань. Проведено комплексний аналіз курсового впливу цитиколіну на емоційно-мнестичні функції, мозковий кровообіг, біоелектричну активність головного мозку, морфофункціональний стан серця і міжсистемні взаємозв’язки у хворих похилого віку з церебральним атеросклерозом. У комплексному клініко-неврологічному дослідженні із застосуванням препарату цитиколіну Кванiл (табл. 500 мг № 30, «КУСУМ ХЕЛТХКЕР ПВТ. ЛТД») взяли участь 30 хворих з атеросклеротичною дисциркуляторною енцефалопатією 1–2-ї ст. Було показано, що під впливом курсового прийому препарату Кванiл (табл. 500 мг № 30, «КУСУМ ХЕЛТХКЕР ПВТ. ЛТД») активізуються когнітивні функції (підвищується увага, покращується короткострокова і довгострокова пам’ять) та поліпшується емоційна сфера (знижується рівень реактивної та особистісної тривожності), відбувається позитивна реорганізація біоелектричної активності головного мозку. Препарат має вазоактивну дію на церебральну гемодинаміку, гармонізує симпато-парасимпатичне відношення.
... A number of experimental studies utilizing PLA2 inhibitors have shown benefit in acute CNS injury models. Examples include Cytidine-5'-diphosphocholine (CDP-choline) in TBI and stroke (Hurtado et al., 2007;Jacotte-Simancas et al., 2015;Secades and Frontera, 1995), quinacrine in middle cerebral artery occlusion (MCAO) (Estevez and Phillis, 1997), and arachidonyl trifluoromethyl ketone in SCI (Huang et al., 2009). CDP-choline is also investigated for its neuroprotective potential in clinical TBI (Adibhatla, 2013;Zafonte et al., 2009). ...
Lipid peroxidation can be broadly defined as the process of inserting a hydroperoxy group into a lipid. Polyunsaturated fatty acids present in the phospholipids are often the targets for peroxidation. Phospholipids are indispensable for normal structure of membranes. The other important function of phospholipids stems from their role as a source of lipid mediators – oxygenated free fatty acids that are derived from lipid peroxidation. In the CNS, excessive accumulation of either oxidized phospholipids or oxygenated free fatty acids may be associated with damage occurring during acute brain injury and subsequent inflammatory responses. There is a growing body of evidence that lipid peroxidation occurs after severe traumatic brain injury in humans and correlates with the injury severity and mortality. Identification of the products and sources of lipid peroxidation and its enzymatic or non-enzymatic nature is essential for the design of mechanism-based therapies. Recent progress in mass spectrometry-based lipidomics/oxidative lipidomics offers remarkable opportunities for quantitative characterization of lipid peroxidation products, providing guidance for targeted development of specific therapeutic modalities. In this review, we critically evaluate previous attempts to use non-specific antioxidants as neuroprotectors and emphasize new approaches based on recent breakthroughs in understanding of enzymatic mechanisms of lipid peroxidation associated with specific death pathways, particularly apoptosis. We also emphasize the role of different phospholipases (calcium-dependent and -independent) in hydrolysis of peroxidized phospholipids and generation of pro- and anti-inflammatory lipid mediators.
The primary and secondary injuries are the phases of the pathophysiology of traumatic brain injury (TBI). Primary injury happens when the brain is subjected to an external force that directly affects the vascular system, glial cells, and neuronal tissue according to their physical properties. The development of biological processes brought on by the first damage leads to secondary injuries. These may include cellular malfunction, resulting in apoptosis, ischemia, glutamate toxicity, neuroinflammation, edema, and increased blood–brain barrier (BBB) permeability. Choline acts as a modulator of the inflammatory response, a neuroprotective agent.
In addition, nanomaterials associated with choline and their strong loading capacity could play an important role in the treatment of TBI.
Despite rapid and recent progress in our understanding of numerous new mechanisms regulating neuronal cell physiology and responses to ischemia, no neuroprotective agents have been developed as an adjunctive treatment for acute ischemic stroke. However, with the widespread deployment of acute tissue perfusion-based stroke imaging and endovascular thrombectomy, there is a great therapeutic opportunity to identify patients with salvageable ischemic tissue and provide neuroprotective treatment along with recanalization that significantly improves stroke outcome. In this chapter, we review seminal and recent developments in our understanding of the mechanisms underlying ischemic large vessel stroke injury including bioenergetic failure, excitotoxicity, oxidative stress, regulated cell death, and inflammation. Exciting developments in collaborative translational research efforts will provide investigators with a blueprint for systematically testing the most promising therapies preclinically analogous to clinical trials. Together, these basic, translational, and clinical advances hold the promise of developing novel neuroprotective therapies and greatly improving stroke patient outcomes.
Objective
To compare selective serotonin reuptake inhibitors (SSRIs) and nootropic drugs in the reduction of anxiety and depressive symptoms in post-stroke patients.
Methods
This retrospective cohort study included patients diagnosed with post-stroke depression that were treated with either SSRIs or nootropic drugs (i.e. citicoline or choline alphoscerate). Depression and anxiety were assessed using the Hamilton Rating Scales. Statistical associations between the use of nootropic drugs and mood disorder improvements were determined by measuring assessment scores at 6-months.
Results
A total of 44 post-stroke patients with depression (aged 45–75 years) were enrolled in the study: 20 were treated with SSRIs and 24 received nootropic drugs. From baseline to follow-up, the SSRI group showed a large effect size with regard depression (success rate difference [SRD] 0.57; 95% confidence interval [CI] 0.21, 0.79) and anxiety (SRD 0.49; 95% CI 0.14, 0.74), whereas the nootropic group showed a small effect size for depression (SRD 0.16; 95% CI –0.17, 0.46) and a small effect size for anxiety (SRD 0.36; 95% CI –0.03, 0.62).
Conclusion
The administration of nootropic drugs could be a valid therapeutic strategy to manage post-stroke patients suffering from mild–moderate anxiety or anxious-depressive syndrome, but this requires further research.
Background
Cytidine-5′-diphosphate choline (CDP-choline) has been suggested to exert neuroprotective and neuroreparative effects and may be beneficial for patients with stimulant dependence. This randomized, double-blind, placebo-controlled study in methamphetamine (MA) dependence investigated effects of CDP-choline on the brain structures and their associations with craving and MA use.
Methods
MA users (n = 44) were randomized to receive 2 g/day of CDP-choline (n = 22) or placebo (n = 22) for 8 weeks. Patients underwent brain magnetic resonance imaging (MRI) at baseline and 8-week follow-up. Healthy individuals (n = 27) were also examined using brain MRI at the same interval. Voxel-based morphometry analysis was conducted to examine changes in gray matter (GM) volumes and their associations with craving and MA use.
Results
Craving for MA was significantly reduced after the 8 week-treatment with CDP-choline (p = 0.01), but not with the placebo treatment (p = 0.10). There was no significant difference in the total number of MA-negative urine samples between the two groups (p = 0.19). With CDP-choline treatment, GM volumes in the left middle frontal gyrus (p = 0.001), right hippocampus (p = 0.009), and left precuneus (p = 0.001) were significantly increased compared to the placebo and control groups. Increased GM volumes in the left middle frontal gyrus with CDP-choline treatment were associated with reduced craving for MA (Spearman's ρ = −0.56, p = 0.03). In addition, the right hippocampal volume increases were positively associated with the total number of MA-negative urine results in the CDP-choline group (Spearman's ρ = 0.67, p = 0.006).
Conclusion
Our findings suggest that CDP-choline may increase GM volumes of MA-dependent patients, which may be related to decreases in MA use and craving.
Pharmacological intervention for the augmentation of brain function in healthy individuals and for recovery after neurological conditions has reached new horizons. The advent of neuro-technologies, such as advanced functional imaging techniques and neurostimulation methods, offers valuable new data about the multiple levels of organization within the brain, uncovering crucial insights about the dynamic cross talk between cerebral networks. From nutritional components and traditional natural remedies to synthetic psychostimulants or multimodal agents, a wide range of interventions are currently used to enhance brain function. Of these, some have raised questions concerning safety, efficacy, and overall effectiveness. In response to increasing demands for cognitive performance or to an internal insult, the nervous system relies on the endogenous defense activity: a process of continuous modulation of neurobiological processes of neurotrophicity, neuroprotection, neuroplasticity, and neurogenesis. In this chapter, several pharmacological brain enhancers are reviewed to assess their capacity to support the brain’s anticorrelated endogenous defense mechanisms.
The incidence of all acute cerebrovascular events in COVID-19 patients ranges between 0.2 and 1.3 %, while ischemic stroke (IS) is more common – 1.1 %, the proportion of hemorrhagic stroke is about 0.2 %. The presence of COVID-19 is associated with 3.58 times increased risk of IS and 5.60 times risk of in-hospital mortality. COVID-19 infection increases the risk of different subtypes of IS, especially cryptogenic stroke, which is characterized by the most severe course. The pathogenesis of stroke in COVID-19 is complex and includes a number of pathophysiological mechanisms: coagulopathy, thromboembolism, vasculitis, direct neuronal damage. The main pathophysiological mechanisms in COVID-19 stroke are yet to be established and need further investigation. Strokes in patients with COVID-19 are often characterized by a more severe course and high mortality. The stroke onset in COVID-19 patients is relatively common in younger age groups and in people without any traditional stroke risk factors. Due to the coagulopathy in COVID-19, the effectiveness of reperfusion therapy (thrombolysis and thromboextraction) is potentially reduced. Thus, early initiation of secondary prevention and active rehabilitation, which includes the drugs with cytoprotective and neuroprotective properties, are needed. When choosing a specific neuroprotective drug, special attention should be paid to the drug’s evidence base confirming its efficacy and safety, especially in stroke, it is equally important that the drug has a multimodal mechanism of action to affect the maximum possible diverse pathophysiological mechanisms of stroke development in patients with COVID-19. Citicoline appears to be a promising drug for stroke patients with COVID-19, since its effectiveness in acute ischemia is due to several mechanisms of action, in addition, the drug has a large evidence base in the treatment of stroke.
Improvements in neuronal plasticity are considered to be conducive to recovery from neuropathic pain. Electroacupuncture (EA) is regarded as an effective rehabilitation method for neuropathic pain. However, the effects and potential mechanism associated with EA-induced repair of hyperesthesia are not fully understood. Evidence has suggested that the adenosine A2A receptor (A2AR) and the cyclic adenosine monophosphate (cAMP)/protein kinase A (PKA) pathway play an important role in improving neuropathic pain. Here, we examined the function of EA in promoting neuronal plasticity in spinal nerve ligation (SNL) rats. The A2AR antagonist SCH5 8261, A2AR agonist 2-p-(2-carboxyethyl)phenethylamino-50-N-ethylcarboxamido adenosine HCl (CGS21680) and A2AR siRNA were used to confirm the relationship between A2AR and the cAMP/PKA pathway as well as the effects of A2AR on EA-induced improvements in neurobehavioral state and neuronal plasticity. Mechanical withdrawal threshold (MWT), thermal withdrawal latency (TWL), HE staining, Western blotting, RT-PCR, immunofluorescence, enzyme-linked immunosorbent assay, Nissl staining, silver staining, Golgi-Cox staining and transmission electron microscopy were used to evaluate the changes in neurobehavioral performance, protein expression, neuronal structure and dendrites/synapses. The results showed that EA and CGS21680 improved the behavioral performance, neuronal structure and dendritic/synaptic morphology of SNL rats, consistent with higher expression levels of A2AR, cAMP and PKA. In contrast to the positive effects of EA, SCH5 8261 inhibited dendritic growth and promoted dendritic spine/synaptic remodeling. In addition, the EA-induced improvement in neuronal plasticity was inhibited by SCH5 8261 and A2AR siRNA, consistent with lower expression levels of A2AR, cAMP and PKA, and worse behavioral performance. These results indicate that EA suppresses SNL-induced neuropathic pain by improving neuronal plasticity via upregulating the A2AR/cAMP/PKA signaling pathway.
Background:
Citicoline is a drug used both in degenerative and in vascular cognitive decline; memantine is a drug used for the treatment of mild to moderate Alzheimer’s disease (AD). Our hypothesis is that their combined use could have an enhanced action in patients affected with AD and mixed dementia (MD) too. We report the main tips from a recent study on the use of these drugs, the CITIMEM study.
Methods:
The study was retrospective and was performed on 126 patients aged 65 years old or older affected with AD or MD (mean age 80.7 ± 5.2 years old) who had been visited between 2015 and 2017 in four different centers for dementia all over Italy. Neuropsychological and functional tests were administered at baseline (T0), after 6 (T1), and 12 months (T2). The effects of combined treatment versus memantine alone on cognitive functions assessed by Mini Mental State Examination (MMSE) and the possible onset of side effects or adverse events, as well as the influence on daily life functions and behavioral symptoms were investigated.
Results:
Patients undergoing combined treatment showed a significant increase in MMSE vs memantine alone, both at T1 (p=0.003) and T2 (p =0.000).
Conclusions:
The CITIMEM study confirms our hypothesis that combined administration of memantine plus citicoline is safe and more effective than memantine alone on cognition in patients suffering from AD or MD.
One-carbon (1C) metabolism is a metabolic network that is centered on folate, a B vitamin; it integrates nutritional signals with biosynthesis, redox homeostasis, and epigenetics. This metabolic pathway also reduces levels of homocysteine, a non-protein amino acid. High levels of homocysteine are linked to increased risk of hypoxic events, such as stroke. Several preclinical studies have suggested that 1C metabolism can impact stroke outcome, but the clinical data are unclear. The objective of this paper was to review preclinical and clinical research to determine whether 1C metabolism has an antioxidant role on stroke. To accomplish the objective, we searched for publications using the following medical subject headings (MeSH) keywords: antioxidants, hypoxia, stroke, homocysteine, one-carbon metabolism, folate, methionine, and dietary supplementation of one-carbon metabolism. Both pre-clinical and clinical studies were retrieved and reviewed. Our review of the literature suggests that deficiencies in 1C play an important role in the onset and outcome of stroke. Dietary supplementation of 1C provides beneficial effects on stroke outcome. For stroke-affected patients or individuals at high risk for stroke, the data suggest that nutritional modifications in addition to other therapies could be incorporated into a treatment plan.
In recent years, significant successes have been achieved in the treatment of acute ischemic stroke. Given the trend towards an increase in the proportion of patients undergoing intravenous thrombolysis and / or mechanical thrombectomy, the question justifies: is there place for neuroprotective therapy (NT) in the era of active introduction of reperfusion treatment? The review discusses the main mechanisms of brain damage in ischemia / reperfusion and the leading neuroprotective strategies studied in clinical trials. Neuroprotective approaches to suppress excitotoxicity, oxidative and nitrosative stress are presented. The clinical efficacy of magnesium sulfate, uric acid, and edaravone is discussed. Non-pharmacological methods of neuroprotection have been characterized, including remote ischemic conditioning, therapeutic hypothermia and neurostimulation. NT in a situation of impossibility of cerebral reperfusion is discussed. The results of randomized clinical trials and meta-analyzes on citicoline (ceraxon) are analyzed. A clinical case is presented illustrating the management of a patient for whom reperfusion therapy was not feasible due to the course of the disease. In the era of the active development of reperfusion methods for the treatment of ischemic stroke, the goal-setting of NT has changed: it is intended to expand the possibilities of application and increase the effectiveness of intravenous thrombolysis and/or mechanical thrombectome, as well as neutralize their negative reperfusion effects. The main targets for NT remain excitotoxicity, oxidative and nitrosative stress. On the other hand, the real clinical situation associated with the low frequency of reperfusion technology in our country necessitates the use of neuroprotectors effective in this category of patients. In this regard, the administration of ceraxon increases the chances of achieving functional independence. The most effective use of the drug from the first day of the disease at a dose of 2000 mg per day intravenously for at least 4-6 weeks with further long-term oral administration at a dose of 1000 mg per day.
The clinical example in this article shows the successful experience of using the neuroprotective agent citicoline (Noocyl) in a comorbid patient after an ischemic stroke with motor and cognitive impairment in combination with antihypertensive, hypolipidemic, and antiplatelet therapy. High efficiency and good tolerance of this drug, the ability to improve cognitive and motor processes are shown.
Introduction
Citicoline can have beneficial effects both in degenerative and in vascular cognitive decline; it works through an increase in acetylcholine intrasynaptic levels and promoting phospholipid synthesis, (chiefly phosphatidylcholine), cellular function, and neuronal repair. Memantine is an N-methyl-D-aspartate (NMDA) receptor antagonist used for the treatment of mild to moderate Alzheimer’s disease (AD). When co-administered they could have a synergistic action in patients affected with AD and mixed dementia (MD) too.
Scope
The aim of the present study was to show the effectiveness of oral citicoline plus memantine in patients affected with AD and MD.
Patients and methods
This was a retrospective study between 2015 and 2017 on 126 patients aged 65 years old or older affected with AD or MD (mean age 80.7 ± 5.2 years old). The study involved four different centers for dementia all over Italy. Diagnosis of AD was made according to clinical symptoms, neuropsychological tests and brain imaging. Diagnosis of MD was made when symptoms typical of AD such as memory loss were associated to symptoms due to cerebrovascular deficits, i.e., impaired judgement, ability to make decisions, plan or organize, and brain imaging. 58 patients were treated with memantine (group A), 68 patients with memantine plus citicoline 1 g/day given orally (group B). In both groups memantine dosage was 10-20 mg/day according to its tolerability. 24 patients of group A and 29 patients of group B were affected with MD. Cognitive functions were assessed by MMSE, daily life functions by ADL and IADL, behavioral symptoms by NPI, comorbidities by CIRS, and mood by GDS-short form. Tests were administered at baseline (T0), after 6 (T1), and 12 months (T2). The primary outcomes were the effects of combined treatment versus memantine alone on cognitive functions assessed by MMSE. The secondary outcomes were the possible side effects or adverse events of combination therapy versus memantine alone, influence on daily life functions and behavioral symptoms.
Results and conclusions
Patients treated with citicoline plus memantine showed an increase in MMSE between T0 and T1 (16.6 ± 2.9 vs 17,4 ± 2.7) and between T1 and T2 (17.4 ± 2.7 vs 17.7 ± 2.8).
The difference in MMSE score was significant when comparing the two groups, both at T1 (p = 0.003) and T2 (p = 0.000).
Since it is important to maximize the pharmacological means in AD and MD, the present study encourages the role of combined administration of memantine plus citicoline in disease management and in slowing down the progression of disease.
Spinal cord injury (SCI) is a serious neurological disease without efficacious drugs. Anti-apoptosis and suppressing dendritic/synaptic degeneration in the anterior horn are essential targets after SCI. Previous studies found that hyperbaric oxygen therapy (HBOT) significantly protected rats after SCI. However, its potential effects and mechanisms remain unknown. The BDNF/TrkB signaling pathways evidently contribute to the SCI recovery. Currently, we mainly investigate the potential effects and mechanism of HBOT on anti-apoptosis and ameliorating impaired dendrites, dendritic spines and synapses after SCI. Establish SCI model and randomly divide rats into 5 groups. After SCI, rats were subjected to HBOT. ANA-12 is the specific inhibitor of BDNF/TrkB signal pathway. Changes in neurological deficit, neuronal morphology, apoptosis, protein expression and dendrite/synapse were examined by Basso–Beattie–Bresnahan (BBB) locomotor rating scale, Hematoxylin-eosin (HE) and Nissl staining, TUNEL staining, RT-PCR, Western blot, immunofluorescence and Golgi-Cox staining. We found HBOT suppressed dendritic/synaptic degeneration and alleviated apoptosis, consistent with the increase of BDNF and TrkB expression and improved neurological recovery. In contrast to the positive effects of HBOT, inhibitor increased degeneration and apoptosis. Moreover, we observed that these HBOT-mediated protective effects were significantly inhibited by inhibitor, consistent with the lower expression of BDNF/TrkB and worse neurobehavioral state. These findings suggest that hyperbaric oxygen therapy ameliorates spinal cord injury-induced neurological impairment by anti-apoptosis and suppressing dendritic/synaptic degeneration via upregulating the BDNF/TrkB signaling pathways.
Stroke is a leading cause of mortality and the main cause of severe and long-term disability in adults. Following
treatment during the acute phase, there is a need to continue the treatment of the patients in the rehabilitation phase, in
order to improve the outcome and daily life activities. This is the role of rehabilitation programs. Rehabilitation is focused
on increasing brain plasticity to recover some of the lost functions, based on different methodologies, including pharmacotherapy.
In this context, the role of citicoline in the rehabilitation of patients with stroke is reviewed.
Key words. Citicoline. Neuroprotection. Neurorepair. Rehabilitation. Sequelae. Stroke. Treatment.
Oxidative stress and inflammation are implicated as cardinal mechanisms of neuronal death following stroke. In the present study citalopram (Cit) was investigated in a 2 h middle cerebral artery occlusion (MCAo) model of stroke in male Wistar rats. Pretreatment, posttreatment (Post Cit) and pre plus posttreatment (Pre + Post Cit) with Cit were evaluated for its neuroprotective effect. In pretreatment protocol, effect of Cit at three doses (2, 4, and 8 mg/kg) administered i.p., 1 h prior to MCAo was evaluated using neurological deficit score (NDS), motor deficit paradigms, and cerebral infarction 24 h post‐MCAo. In posttreatment and pre plus posttreatment protocol, the effective dose of Cit (4 mg/kg) was administered i.p., 0.5 h post‐reperfusion (Post Cit) only, and 1 h prior to MCAo and again at 0.5 h post‐reperfusion (Pre + Post Cit), respectively. These two groups were assessed for NDS and cerebral infarction. Though NDS was significantly reduced in both Post Cit and Pre + Post Cit groups, significant reduction in cerebral infarction was evident only in Pre + Post Cit group. Infarct volume assessed by magnetic resonance imaging was significantly attenuated in Pre + Post Cit group (10.6 ± 1.1%) compared to MCAo control group (18.5 ± 3.0%). Further, Pre + Post Cit treatment significantly altered 17 metabolites along with attenuation of malondialdehyde, reduced glutathione, matrix metalloproteinases, and apoptotic markers as compared to MCAo control. These results support the neuroprotective effect of Cit, mediated through amelioration of oxidative stress, inflammation, apoptosis, and altered metabolic profile.
Stroke is the clinical manifestation of the occlusion (ischemic stroke) or rupture of a blood vessel to the brain (hemorrhagic stroke). Neurotoxicity is triggered in stroke by the failure of oxygen delivery and the buildup of metabolites resulting in a cascade of harmful physiological events. Here, we review and contrast neurotoxicity and its corollary - neuroprotection - in the context of preclinical (animal) and clinical (patient) drug trials. Preclinical tests are distinguished by greater homogeneity, earlier time windows for treatment, and greater probability of success. Many of the same processes have been targeted in preclinical and clinical trials - such as excitotoxicity, oxidation, inflammation, and trophic factors - however, it is not a seamless flow from bench to bedside and back. Current trends in stroke neuroprotection include combination neuroprotection and improved trial designs. Areas where drug development in stroke could be improved include better target identification, development of lead drug candidates prior to preclinical testing and use of computational tool for prediction of toxicity based on biochemical pathway and drug characteristics. © Springer Science+Business Media New York 2014. All rights reserved.
The article presents data from a study evaluating the comparative efficacy and tolerability of Neurocitin, solution for infusions, manufactured by «Yuria-Farm» Ltd. and Ceraxon, solution for injections, manufactured by «Ferrer Internacional S.A.» in patients with acute ischemic stroke. The objective of this work — the evaluation of therapeutic equivalence of the drugs Neurocitin and Ceraxon. Materials and methods. The clinical study included 108 patients with acute ischemic stroke, who, based on the method of simple randomization in the ratio 1: 1, were divided in the study (n = 54) and control (n = 54) groups. Patients of the study group received Neurocitin, solution for infusions, patients from the control group — reference product Ceraxon, solution for injections. The course of treatment was 3 weeks, followed by a 3-week observation. Treatment efficacy was determined by the main variable — reduction in the score on the NIHSS, the severity of stroke scale, compared with baseline. Safety of the drug was evaluated based on monitoring the patient’s condition, the incidence and nature of adverse events, the data of laboratory examination, assessment of the subjective condition of the patient. Results. The study shows that Neurocitin is highly effective and on its properties is therapeutically equivalent to foreign analogue — the drug Ceraxon. During the treatment, no severe or unexpected adverse events were detected, laboratory parameters did not undergo negative changes that allowed to consider the tolerability in both groups as good one. Conclusions. Based on these findings, Neurocitin, solution for infusions, manufactured by «Yuria-Pharm» Ltd. can be recommended as an effective and safe drug in patients with acute ischemic stroke.
The review presents data on the evaluation of the efficacy of citicoline in ischemic stroke. It presents research findings about the effect of citicoline to reduce infarct volume in animal models of cerebral ischemia. Long-term treatment of CDP-choline initiated 24 hours after stroke contributes to the increased plasticity of neurons in intact brain areas (functionally associated with the damaged areas) and accelerated functional recovery. The oral administration of citicoline within the first 24 hours after the onset of symptoms in moderate and severe stroke increases the probability of complete recovery in 3 months. A neuroprotective effect of citicoline in acute and early restorative stages of stroke accompanied by cognitive impairment was shown. According to the results of clinical trials of the dosage regimen, citicoline administered in the dose of 1000 mg/day for 8 weeks accelerates the regression of hemiplegia; the intravenous injection in the dose of 750 mg/day for 10 days, starting with the first 48 hours of stroke onset symptoms, promotes the recovery of motor and cognitive functions; the intravenous injection in the dose of 1 g within 14 days improves the recovery of consciousness, general condition and functional status.
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Aim: To observe the effects of catalpol on the axon sprouting and synaptogenesis within the periinfarct cortex(PIC) in rats with focal cerebral ischemia, so as to explore the morphological bases for catalpol promoting neurorepairment after stroke. Methods: 36 adult Sprague-Dawley rats were randomized into 7 groups, including sham operation group, model group, normal saline group, low dose, middle dose and high dose of catalpol treatment group (1, 5 and 10 mg·kg-1, respectively) and citicoline treatment group (0.5 g·kg-1). Rats were subjected to permanent occlusions of the right middle cerebral artery (pMCAO) and were intraperitoneally administered with either catalpol, citcoline or saline 24 h after pMCAO and daily for 7 days. The immunohistochemical double staining technique was employed to detect the co-localisation of growth associated protein 43 (GAP-43) with synaptophysin (P38) protein in PIC, and stereological methods and transmission electron microscopy were then used to quantify synaptic density in PIC. Results: The distribution of P38 and GAP-43 in PIC region were determined with double immunofluorescence. P38 was labeled with FITC and shown in green, GAP-43 was labeled with cy3 and shown in red, and the co-localisation of P38/GAP-43 was shown in yellow. The Pearson's correlation coefficient of GAP-43 with P38 was calculated. The more the Pearson's correlation coefficient was, the more new presynaptic terminus was formed. It was shown that the Pearson's correlation coefficient was significantly higher in the model group than in the sham operation group (P < 0.05), indicating spontaneous axon sprouting and new synapse connection formed after cerebral ischemic stroke. The Pearson's correlation coefficient in the catalpol group increased remarkably, compared with the model group and the citicoline group (P < 0.05). It showed that catalpol promoted the new axon sprouting to form new synapse connection effectively. Synaptic ultrastructural analysis showed that catalpol at dose of 5 mg·kg-1 increased the synaptic number density and the surface density in the neuropil within the PIC obviously (P < 0.05), when compared with the model group and the normal saline group, but there was no difference between the catalpol and citicoline group (P > 0.05). It demonstrated that catalpol could enhance the synaptic reorganization after cerebral ischemia. Conclusion: Catalpol can promote CNS axonal sprouting and increase synaptic structure plasticity by synaptogenesis.
Aim: To investigate the possible mechanisms underlying the observed functional recovery and to observe the effects of catalpol on the dendritic outgrowth and the expression of synaptophysin in the periinfarct cortex(PIC) in rats with focal permenant cerebral ischemia. Methods: Sprague Dawley rats were randomly divided into 7 groups, including sham operation group, permenant middle cerebral artery occlusion (pMCAO ) model group, normal saline group, low, middle and high doses of catalpol treatment groups (1, 5 and 10mg·kg -1, respectively) and citicoline treatment group (0.5g·kg -1). A permenant focal cerebral ischemia model was established by pMCAO with modified craniectomy electric-coagulation method, and then 24h after pMCAO treated with catalpol once a day for 7days. The corner tests were performed to evaluate the sensorimotor integration functional status before operation (baseline) and at 1d, 4d, 7d and 15d after pMCAO by a blinded investigator. Lesion volume was measured with magnetic resonance imaging (MRI) at 1d (before treatment) and 15d after pMCAO. Rats were sacrificed 15days after pMCAO and brains were removed to detect the expression of synaptophysin by immunofluorescence staining and Western blot. In addition, brains were processed for Golgi-Cox staining procedure to show the changes of dendritic branches and spine density of pyramidal neurons in the peri-infarct cortex. Results: The neurological functions in different doses of catalpol treated groups and citicoline group were better on 7d and 15d after pMCAO as compared with those in the pMCAO model group and the normal saline group (P<0.05). However, there was no significant difference in lesion volume among the control and different treatment groups. Animals treated with catalpol in dose of 5mg·kg -1 showed an increase in the number of dendritic branches and spine density compared with either pMCAO model group, normal saline group or citicoline group (P<0.05). The expression of synaptophysin was significantly up-regulated in groups treated with different doses of catalpol in comparison with either model group, saline group or citicoline group (P<0.05 ), as revealed by both immunofluoresence staining and Western blot. Conclusion: Catalpol can promote functional recovery after focal ischemic stroke in association with up-regulation of the synaptophysin protein expression and improve the neuronal dendritic plasticity in the peri-infarct cortex.
CDP-choline is an essential element of the cell membrane-phospholipid biosynthesis, and hereby important for membrane regeneration after stroke or other neurological diseases. Recent studies showed, that CDP-choline exerts additional multimodal mechanisms of action after stroke such as anti-excitotoxic, anti-apoptotic and anti-oxidant effects. CDP-choline improves the neurological deficits and decreases the infarct volume in a number of preclinical studies. Due to its very good tolerability CDP-choline has been used used for the treatment of stroke in Europe, Latin America and Asia for more than 30 years. Controlled clinical studies recently showed first signs of improvement of the neurological deficits of stroke patients after treatment with this substance. CDP-choline may therefore be an alternative for the treatment of stroke, especially when considering the very good benefit-risk ratio.
Unilateral damage to the forelimb representation area of the sensorimotor cortex in adult rats increases dendritic arborization of layer V pyramidal neurons of the contralateral homotopic cortex. Arbor size was maximum at approximately 18 d postlesion, following which there was a partial elimination, or pruning, of dendritic processes. These neural changes were closely associated with behavioral events. The overgrowth of dendrites was related in time to disuse of the contralateral (to the lesion) forelimb and over-reliance on the ipsilateral forelimb for postural and exploratory movements. The pruning of dendrites was related to a return to more symmetrical use of the forelimbs. To investigate the possibility that lesion-induced asymmetries in motor behavior contributed to dendritic arborization changes, movements of the forelimb ipsilateral to the lesion were restricted during the period of dendritic overgrowth through the use of one-holed vests. This interfered with the increase in dendritic arborization. In contrast, animals that were allowed to use both forelimbs, or only the forelimb ipsilateral to the lesion, showed the expected increases. When sham-operated rats were forced to use only one forelimb, no significant increases in arborization were found. Therefore, neither a lesion nor asymmetrical limb use alone could account for the dendritic overgrowth--it depended on a lesion-behavior interaction. Furthermore, greater sensorimotor impairments were found when the dendritic growth was blocked, suggesting that the neural growth and/or associated limb-use behavior were related to functional recovery from the cortical damage. Finally, in a second experiment, immobilization of the impaired limb during the pruning period did not prevent the elimination of processes. Thus, the pruning of neural processes was not related simply to the recovery of more symmetrical forelimb use. There may be a period early after brain damage during which marked neural structural changes can occur in the presence of adequate behavioral demand.
In conclusion, the rat primary motor cortex appears to be organized into irregularly shaped patches of cortex devoted to particular movements. The location of major subdivisions such as the forelimb or hindlimb areas is somatotopic and is consistent from animal to animal, but the internal organization of the pattern of movements represented within major subdivisions varies significantly between animals. The motor cortex includes both agranular primary motor cortex (AgL) and, in addition, a significant amount of the bordering granular somatic sensory cortex (Gr(SI)), as well as the rostral portion of the taste sensory insular or claustrocortex (Cl). The rat frontal cortex also contains a second, rostral motor representation of the forelimb, trunk and hindlimb, which is somatotopically organized and may be the rat's supplementary motor area. Both of these motor representations give rise to direct corticospinal projections, some of which may make monosynaptic connections with cervical enlargement motoneurons. Medial to the primary motor cortex, in cytoarchitectonic field AgM, is what appears to be part of the rat's frontal eye fields, a region which also includes the vibrissae motor representation. The somatic motor cortical output organization pattern in the rat is remarkably similar to that seen in the primate, whose primary, supplementary and frontal eye field cortical motor regions have been extensively studied.
Parkinson's disease is characterized by a depletion of dopamine (DA) neurons in the nigrostriatal pathway. Stereotaxic injections of 6-hydroxydopamine (6-OHDA), a selective neurotoxin, into either the medial forebrain bundle or the substantia nigra result in a massive DA denervation of the nigrostriatal pathway. Following unilateral nigrostriatal DA depletion, hemiparkinsonian animals develop a stereotypical rotational behavior when challenged with DA agonists such as apomorphine. The drug-induced rotational behavior has been widely used as the behavioral index of hemiparkinsonian animals, but it has some limitations. Although asymmetries in the rotational behavior may indicate an imbalance of DA contents and release capacity in the bilateral nigrostriatal pathway, the behavior is a pharmacological reaction. Accordingly, the drug-induced rotation test is subject to sensitization effects. The present study proposes the elevated body swing test (EBST) as a measure of asymmetrical motor behavior of hemiparkinsonian animals in a drug-free state. The EBST simply involves elevating the animal by handling its tail and recording the frequency and direction of the swing behavior. Unilateral nigral 6-OHDA-lesioned rats exhibited significant biased swing activity with the direction contralateral to the lesioned side, corresponding to the direction of apomorphine-induced rotations. A 30 sec EBST was noted as the peak time for biased swing activity. At 7 d postlesion (the start of testing), and every week thereafter for a period of 2 months, a fairly stable biased swing activity level was observed. At 1 and 2 months postlesion, the same animals were also challenged with apomorphine.(ABSTRACT TRUNCATED AT 250 WORDS)
Unilateral damage to the forelimb representation area of the sensorimotor cortex in adult rats increases dendritic arborization of layer V pyramidal neurons of the contralateral homotopic cortex. Arbor size was maximum at approximately 18 d postlesion, following which there was a partial elimination, or pruning, of dendritic processes. These neural changes were closely associated with behavioral events. The overgrowth of dendrites was related in time to disuse of the contralateral (to the lesion) forelimb and over-reliance on the ipsilateral forelimb for postural and exploratory movements. The pruning of dendrites was related to a return to more symmetrical use of the forelimbs. To investigate the possibility that lesion-induced asymmetries in motor behavior contributed to dendritic arborization changes, movements of the forelimb ipsilateral to the lesion were restricted during the period of dendritic overgrowth through the use of one-holed vests. This interfered with the increase in dendritic arborization. In contrast, animals that were allowed to use both forelimbs, or only the forelimb ipsilateral to the lesion, showed the expected increases. When sham-operated rats were forced to use only one forelimb, no significant increases in arborization were found. Therefore, neither a lesion nor asymmetrical limb use alone could account for the dendritic overgrowth--it depended on a lesion-behavior interaction. Furthermore, greater sensorimotor impairments were found when the dendritic growth was blocked, suggesting that the neural growth and/or associated limb-use behavior were related to functional recovery from the cortical damage. Finally, in a second experiment, immobilization of the impaired limb during the pruning period did not prevent the elimination of processes. Thus, the pruning of neural processes was not related simply to the recovery of more symmetrical forelimb use. There may be a period early after brain damage during which marked neural structural changes can occur in the presence of adequate behavioral demand.
This article reviews recent evidence from animal experiments indicating that there is considerable potential for reorganization of representations and functions in in sensory and motor cortex following localized lesions or various manipulations of peripheral target structures. Three major mechanisms for this plastic reorganization are considered: unmasking of existing but functionally inactive pathways, sprouting of fibers from surviving neurons and formation of new synapses, and redundancy of CNS circuitry allowing alternative pathways to take over functions. Studies using positron emission tomography or transcranial magnetic stimulation suggest that similar forms of neuroplasticity may occur in the human brain and could contribute to functional recovery following stroke. The potential therapeutic implications are discussed.
Restoration of motor function is relatively common in humans and non-human primates. Studies of the behavioral aspects of recovery indicate that responses re-emerge in a fixed sequence that resembles initial acquisition. The extent to which this occurs depends on factors unique to the subject. Research suggests that the traditional view of a hierarchically organized brain is inaccurate. Instead, the brain is comprised of parallel circuits which may be disinhibited and/or recruited when damage occurs. In some cases, damage leads to reorganization of cerebral cortical maps. Available data point to the utility of interventions to promote recovery. Research suggests that recovery from other forms of impairment (e.g., non-vascular lesions or impairment in language) involves similar processes.
To assess behavioral experience effects on synaptic plasticity after brain damage, the present study examined the effects of complex motor skills training (the acrobatic task) on synaptic changes in layer V of the motor cortex opposite unilateral damage to the forelimb sensorimotor cortex (FLsmc). Adult male rats were given lesions or sham operations followed by 28 d of training on the acrobatic task [acrobat condition (AC)]. As a motor activity control [motor control (MC)], lesion and sham animals were given simple repetitive exercise. Previously, FLsmc lesions and acrobatic training have independently been found to result in increases in synapse to neuron ratios in the intact motor cortex relative to controls, and both of these effects were replicated in the present study. In addition, acrobat training after lesions significantly increased layer V synapses per neuron relative to sham-AC and lesion-MC rats. Thus, the combination of acrobatic training and lesions resulted in an enhanced synaptogenic response. Synapse subtypes were also differentially affected by the conditions. Lesion-MC and sham-AC primarily had increases in the number of synapses per neuron formed by multiple synaptic boutons in comparison to sham-MC. In contrast, lesion-AC had increases in both multiple and single synapses. Multiple synaptic spines and perforated synapses were also differentially affected by training versus lesions. On tests of coordinated forelimb use, lesion-AC rats performed better than lesion-MC rats. In addition to supporting a link between behavioral experience and structural plasticity after brain damage, these findings suggest that adaptive neural plasticity may be enhanced using behavioral manipulations as "therapy."
Chronic impairment of forelimb and digit movement is a common problem after stroke that is resistant to therapy. Previous studies have demonstrated that enrichment improves behavioral outcome after focal ischemia; however, postischemic enrichment alone is not capable of enhancing fine digit and forelimb function. Therefore, we combined environmental enrichment with daily skilled-reach training to assess the effect of intensive task-specific rehabilitation on long-term functional outcome. Rats were subjected to either endothelin-1-induced focal ischemia or sham surgery and subsequently designated to enriched-rehabilitation or standard-housing treatment groups starting 15 d after ischemia. Functional assessment of the affected forelimb at 4 and 9 weeks after treatment revealed that ischemic plus enrichment (IE) animals had improved approximately 30% on the staircase-reaching task and were indistinguishable from sham animals for both latency and foot faults in a beam-traversing task. In contrast, ischemic plus standard (IS) animals remained significantly impaired on both tasks. Interestingly, both ischemic groups (IE and IS) relied on the nonaffected forelimb during upright weight-bearing movements, a pattern that persisted for the duration of the experiment. Dendritic arborization of layer V pyramidal cells within the undamaged motor cortex was examined using a Golgi-Cox procedure. IE animals showed enhanced dendritic complexity and length compared with both IS and sham groups. These results suggest that enrichment combined with task-specific rehabilitative therapy is capable of augmenting intrinsic neuronal plasticity within noninjured, functionally connected brain regions, as well as promoting enhanced functional outcome.
Cytidine-5'-diphosphocholine (citicoline or CDP-choline) is an essential intermediate in the biosynthesis of phosphatidylcholine, an important component of the neural cell membrane. Citicoline provided significant neuroprotection after transient forebrain ischemia in gerbils. This study was undertaken to examine changes and effects of citicoline on phospholipids and glutathione synthesis after transient cerebral ischemia and reperfusion.
Ten-minute transient forebrain ischemia was induced by bilateral carotid artery occlusion in male Mongolian gerbils with reperfusion up to 6 days. Citicoline (500 mg/kg IP in saline) was given to gerbils just after the end of ischemia, at 3-hour reperfusion, and daily thereafter until 1 day before euthanasia. Hippocampal lipids were extracted and analyzed by thin-layer and gas chromatography. Glutathione was measured by using an enzymatic recycling assay. Glutathione reductase activity was determined by measuring NADPH oxidation.
Significant decreases in phospholipids occurred at 1-day reperfusion. Citicoline significantly restored the phosphatidylcholine, sphingomyelin, and cardiolipin levels but did not affect phosphatidylinositol and phosphatidylserine at 1 day. The phospholipids returned to sham levels over days 2 to 6 and were unaffected by citicoline. Ceramide levels significantly increased by 3 and 6 days of reperfusion and were unaltered by citicoline. Ischemia resulted in significant decreases in glutathione and glutathione reductase activity over 3 days of reperfusion. Citicoline significantly increased total glutathione and glutathione reductase activity and decreased the glutathione oxidation ratio, an indicator of glutathione redox status.
Our data indicated that the effects of citicoline on phospholipids occurred primarily during the first day of reperfusion, with effects on glutathione being important over the 3-day reperfusion period.
Functional recovery after stroke has been associated with brain plasticity; however, the exact relationship is unknown. We performed behavioral tests, functional MRI, and histology in a rat stroke model to assess the correlation between temporal changes in sensorimotor function, brain activation patterns, cerebral ischemic damage, and cerebrovascular reactivity. Unilateral stroke induced a large ipsilateral infarct and acute dysfunction of the contralateral forelimb, which significantly recovered at later stages. Forelimb impairment was accompanied by loss of stimulus-induced activation in the ipsilesional sensorimotor cortex; however, local tissue and perfusion were only moderately affected and cerebrovascular reactivity was preserved in this area. At 3 days after stroke, extensive activation-induced responses were detected in the contralesional hemisphere. After 14 days, we found reduced involvement of the contralesional hemisphere, and significant responses in the infarction periphery. Our data suggest that limb dysfunction is related to loss of brain activation in the ipsilesional sensorimotor cortex and that restoration of function is associated with biphasic recruitment of peri- and contralesional functional fields in the brain.
Acid-sensing ion channel 3 (ASIC3), a proton-gated ion channel of the degenerins/epithelial sodium channel (DEG/ENaC) receptor family is expressed predominantly in sensory neurons including nociceptive neurons responding to protons. To study the role of ASIC3 in pain signaling, we generated ASIC3 knockout mice. Mutant animals were healthy and responded normally to most sensory stimuli. However, in behavioral assays for pain responses, ASIC3 null mutant mice displayed a reduced latency to the onset of pain responses, or more pain-related behaviors, when stimuli of moderate to high intensity were used. This unexpected effect seemed independent of the modality of the stimulus and was observed in the acetic acid-induced writhing test (0.6 vs. 0.1-0.5%), in the hot-plate test (52.5 and 55 vs. 50 degrees C), and in tests for mechanically induced pain (tail-pinch vs. von Frey filaments). We postulate that ASIC3 is involved in modulating moderate- to high-intensity pain sensation.
No single neuroprotective agent has been shown to influence outcome after acute stroke. Citicoline has been studied worldwide in many clinical trials with positive findings, but only 1 trial has obtained significant results in the primary efficacy variables. Our objective was to evaluate the effects of oral citicoline in patients with acute ischemic stroke by a data pooling analysis of clinical trials. The primary efficacy end point chosen was the common evaluation of recovery, combining National Institutes of Health Stroke Scale </=1, modified Rankin Scale score </=1, and Barthel Index >/=95 at 3 months using the generalized estimating equations analysis.
A systematic search of all prospective, randomized, placebo-controlled, double-blind clinical trials with oral citicoline (MEDLINE, Cochrane, and Ferrer Group bibliographic databases) was undertaken. Individual patient data were extracted from each study and pooled in a single data file. The main inclusion criteria included compatible neuroimaging with ischemic stroke, National Institutes of Health Stroke Scale >/=8, and prior modified Rankin Scale score </=1. Four clinical trials using various doses of oral citicoline (500, 1000, and 2000 mg) were identified.
Of 1652 randomized patients, 1372 fulfilled the inclusion criteria (583 received placebo, 789 received citicoline). Recovery at 3 months was 25.2% in citicoline-treated patients and 20.2% in placebo-treated patients (odds ratio [OR], 1.33; 95% CI, 1.10 to 1.62; P=0.0034). The dose showing the largest difference with placebo was 2000 mg, with 27.9% of patients achieving recovery (OR, 1.38; 95% CI, 1.10 to 1.72; P=0.0043). The overall safety of citicoline was similar to placebo.
Treatment with oral citicoline within the first 24 hours after onset in patients with moderate to severe stroke increases the probability of complete recovery at 3 months.
The pattern and role of brain plasticity in stroke recovery has been incompletely characterized. Both ipsilesional and contralesional changes have been described, but it remains unclear how these relate to functional recovery. Our goal was to correlate brain activation patterns with tissue damage, hemodynamics, and neurologic status after temporary stroke, using functional magnetic resonance imaging (fMRI). Transverse relaxation time (T2)-weighted, diffusion-weighted, and perfusion MRI were performed at days 1 (n = 7), 3 (n = 7), and 14 (n = 7) after 2 hr unilateral middle cerebral artery occlusion in rats. Functional activation and cerebrovascular reactivity maps were generated from contrast-enhanced fMRI during forelimb stimulation and hypercapnia, respectively. Before MRI, rats were examined neurologically. We detected loss of activation responses in the ipsilesional sensorimotor cortex, which was related to T2 lesion size (r = -0.858 on day 3, r = -0.979 on day 14; p < 0.05). Significant activation responses in the contralesional hemisphere were detected at days 1 and 3. The degree of shift in balance of activation between the ipsilesional and contralesional hemispheres, characterized by the laterality index, was linked to the T2 and apparent diffusion coefficient in the ipsilesional contralesional forelimb region of the primary somatosensory cortex and primary motor cortex at day 1 (r = -0.807 and 0.782, respectively; p < 0.05) and day 14 (r = -0.898 and -0.970, respectively; p < 0.05). There was no correlation between activation parameters and perfusion status or cerebrovascular reactivity. Finally, we found that the laterality index and neurologic status changed in parallel over time after stroke, so that when all time points were grouped together, neurologic status was inversely correlated with the laterality index (r = -0.571; p = 0.016). This study suggests that the degree of shift of activation balance toward the contralesional hemisphere early after stroke increases with the extent of tissue injury and that functional recovery is associated mainly with preservation or restoration of activation in the ipsilesional hemisphere.
Since the area was first described by Fritsch and Hitzig,¹ the function of the electrostimulable cortex of the cerebrum has been the subject of almost continuous controversy. The experiments were immediately called in question through criticisms of the technic by Dupuy,² Sanderson,³ Carville and Duret,⁴ and others, or by abstruse metaphysical deductions such as were advanced by Hermann⁵ who objected to the motor area as violating the "unity of mind." The work of Ferrier,⁶ Carville and Duret and Hitzig soon established the fact of the electrical excitability of limited areas of the cortex, but immediately a new question arose. Fritsch and Hitzig had considered the excitable zone as motor, if we may translate the expression, "entry of single psychic functions into material" by such a term. In this they were followed by Carville and Duret, who described the motor disturbances following lesions in the
Animal and human studies have shown that motor and somatosensory cortex are capable of reorganization throughout adult life. Cortical reorganization has been associated with functional recovery in experimental and human stroke. Retraining after experimental cortical infarction has been shown to extend cortical representation of the infarcted area and improve skilled motor performance.
Exceptionally clear Golgi—Nissl sections of 300 μm thickness have been morphometrically studied by light microscopy using oil immersion objectives. The clarity results from a new variation of a staining procedure that combines Golgi and Nissl images in one section. A viewing technique has been developed that permits a histologic preparation to be examined from its obverse (or normally viewed) side and its reverse (or under) side. The technique was designed for use with a computer microscope but can be employed with any light microscope whose stage position can be measured within 100 μm. Sections thicker than 300 μm can be studied dependent on the working distance of the objective lens, provided that the clarity of the material permits it.
A method for impregnating the whole rat brain with Golgi-Cox stain and sectioning with the vibratome is described. The method is simple, inexpensive and provides good resolution of dendrites and spines.
The purpose of this study was to analyze recovery of motor function in a cohort of patients presenting with an acute occlusion in the carotid distribution. Analysis of recovery patterns is important for estimating patient care needs, establishing therapeutic plans, and estimating sample sizes for clinical intervention trials.
We prospectively measured the motor deficits of 104 stroke patients over a 6-month period to identify earliest measures that would predict subsequent motor recovery. Motor function was measured with the Fugl-Meyer Assessment. Fifty-four patients were randomly assigned to a training set for model development; 50 patients were assigned to a test set for model validation. In a second analysis, patients were stratified on basis of time and stroke severity. The sample size required to detect a 50% improvement in residual motor function was calculated for each level of impairment and at three points in time.
At baseline the initial Fugl-Meyer motor scores accounted for only half the variance in 6-month motor function (r2 = 0.53, p less than 0.001). After 5 days, both the 5-day motor and sensory scores explained 74% of the variance (p less than 0.001). After 30 days, the 30-day motor score explained 86% of the variance (p less than 0.001). Application of these best models to the test set confirmed the results obtained with the training set. Sample-size calculations revealed that as severity and time since stroke increased, sample sizes required to detect a 50% improvement in residual motor deficits decreased.
Most of the variability in motor recovery can be explained by 30 days after stroke. These findings have important implications for clinical practice and research.
The role of chronic exogenous intracerebroventricular administration of nerve growth factor (NGF) on the morphology of layer V pyramidal cell dendrites in aging rats was quantified using Golgi impregnations. Both dendritic branching and dendritic spines from the basilar tree of randomly selected pyramidal neurons of the frontal cortex were evaluated in young control (4-month-old) Fischer 344 rats, in old controls (24-month-old), and in 24-month-old rats administered NGF for 4 weeks. Sholl analysis of basilar dendritic trees showed that neuronal branching in older rats was significantly greater than that in young rats (probably due to compensatory dendritic hypertrophy). The extent of dendritic material in aged rats receiving NGF, however, was identical to that in young rats, that is, the dendritic tree had regressed in size. Dendritic spine response to NGF treatment depended on the region of the dendritic tree sampled. Normal aging resulted in spine loss. However, NGF treatment restored dendritic spine densities to those seen in young controls on terminal tip segments ("plastic" regions). Internal branch segments ("nonplastic" regions) showed no response to NGF. As dendritic spines are thought to represent the neuroanatomic basis of learning and memory, results suggest that NGF can influence the morphology of cortical neurons (probably indirectly via the basal forebrain projections) and therefore may play an efficacious role in the treatment of geriatric cognitive dysfunction and even perhaps in Alzheimer's disease.
A novel reaching test for the rat has been developed to assess the independent use of forelimbs in skilled reaching and grasping tasks. The apparatus is a plexiglas box with a removable baited double staircase. Food pellets are placed on the staircase and presented bilaterally at 7 graded stages of reaching difficulty to provide objective measures of side bias, maximum forelimb extension and grasping skill. In the present experiment, the apparatus was used to assess the reaching performance of rats following unilateral lesions of the sensorimotor cortex, unilateral lesions of the posterior cortex or bilateral lesions of the olfactory bulbs. The task has the advantage of objective over rating measurement, and the simplicity of the apparatus permits many animals to be tested concurrently.
Generally accepted features of alcoholic fetopathy are delayed maturation and retarded dendritic development of neocortex, hippocampus and cerebellum. The present study investigates the effects of a membrane stabilizing agent (CDP-choline) on Purkinje cells of chronically alcohol intoxicated newborn rat pups, employing a Golgi impregnation technique. Both quantitative and qualitative data indicate that CDP-choline modifies the alcohol induced lesion.
The basal ganglia, of which the striatum is the major component, process inputs from virtually all cerebral cortical areas to affect motor, emotional, and cognitive behaviors. Insights into how these seemingly disparate functions may be integrated have emerged from studies that have demonstrated that the mammalian striatum is composed of two compartments arranged as a mosaic, the patches and the matrix, which differ in their neurochemical and neuroanatomical properties. In this study, projections from prefrontal, cingulate, and motor cortical areas to the striatal compartments were examined with the Phaseolus vulgaris-leucoagglutinin (PHA-L) anterograde axonal tracer in rats. Each cortical area projects to both the patches and the matrix of the striatum; however, deep layer V and layer VI corticostriatal neurons project principally to the patches, whereas superficial layer V and layer III and II corticostriatal neurons project principally to the matrix. The relative contribution of patch and matrix corticostriatal projections varies among the cortical areas examined such that allocortical areas provide a greater number of inputs to the patches than to the matrix, whereas the reverse obtains for neocortical areas. These results demonstrate that the compartmental organization of corticostriatal inputs is related to their laminar origin and secondarily to the cytoarchitectonic area of origin.
This article describes a 3-year experience with focal neocortical ischemia in three rat strains. Multiple groups of adult Wistar (n = 50), Fisher 344 (n = 31), and spontaneously hypertensive (n = 72) rats were subjected to permanent occlusion of the distal middle cerebral (MCA) and ipsilateral common carotid arteries (CCA). Twenty-four hours later the animals were killed, and frozen brain sections were stained with hematoxylin and eosin to demarcate infarcted tissue. The infarct volume for each section was quantified with an image analyzer, and the total infarct volume was calculated with an iterative program that summed all interval volumes. Neocortical infarct volume was the largest and most reproducible in the spontaneously hypertensive rats (SHR). Statistical power analysis to project the numbers of animals necessary to detect a 25 or 50% change in infarct volume with alpha = 0.05 and beta = 0.2 revealed that only the SHR model was practical in terms of requisite animals: i.e., less than 10 animals per group. Tandem occlusion of the distal MCA and ipsilateral CCA in the SHR strain provides a surgically simple method for causing large neocortical infarcts with reproducible topography and volume. The interanimal variability in infarct volume that occurs even in the SHR strain dictates that randomized, concomitant controls are necessary in each study to ensure the accurate assessment of experimental manipulations or pharmacologic therapies.
Double-labeled cytidine, with a 3H/14C isotope ratio of 20.00, has been intraventricularly injected into the brain of young rats, and its fate followed up to 90 min from administration together time-course of labeling. The injected nucleoside enters the brain as an intact molecule and is immediately utilized without prior degradation. Cytidine is actively converted into uridine and CMP, the latter being then transformed by a stepwise mechanism into CDP and CTP, and finally into CDP-choline and CDP-ethanolamine. The results indicate that administered cytidine represents a compound likely to enter metabolic events, which lead to CDP-choline and CDP-ethanolamine synthesis, and presumably to phospholipid production.
Neuroanatomical plasticity is well described in lesions of the hippocampus but remains a subject of some controversy in the neocortex. The purpose of the present study was to measure the neocortical distribution and density of expression of proteins known to be involved in neurite growth or synaptogenesis and to correlate the neocortical expression with behavioral recovery after a focal neocortical infarction. Focal neocortical infarction creates a circumscribed lesion in the neocortex that provides a denervation stimulus for neurite growth and synaptogenesis.
Unilateral neocortical ischemia was induced in male spontaneously hypertensive Wistar rats (n = 4 per time point) by permanent occlusion of the distal middle cerebral artery and ipsilateral common carotid artery. To determine the spatial and temporal distribution of neurite growth and/or synaptogenesis, GAP-43, a growth-associated protein expressed on axonal growth cones, and synaptophysin, a calcium-binding protein found on synaptic vesicles, were examined by immunohistochemical techniques. The reaction product was measured, and the distribution was recorded. Since the resulting infarction included a portion of the forelimb neocortex, behavioral assessments of forelimb function that used the foot-fault test of Hernandez and Schallert were performed on the same rats used for immunohistochemical studies. Recovery times were 3, 7, 14, 30, and 60 days after surgery.
Both GAP-43 and synaptophysin proteins demonstrated statistically significant increases in the density of immunoreaction product as determined by optical density measurements in the neocortex of infarcted rats compared with sham controls. The GAP-43 was elevated to statistically significant levels in forelimb, hindlimb, and parietal neocortical regions medial and lateral to the infarction only at days 3, 7, and 14. In contrast, synaptophysin demonstrated no statistically significant changes in expression at 3 or 7 days but demonstrated statistically significant increases at 14, 30, and 60 days in the forelimb, hindlimb, and parietal neocortical regions medial and lateral to the infarction as well as in the contralateral parietal neocortex. Behavioral assessment of forelimb function indicated impairment of forelimb placement on the side contralateral to the infarction that trended toward control values at 14 days and was not significantly different from controls by 30 days.
These data support the occurrence of neurite growth followed by synaptogenesis in the neocortex, ipsilateral and contralateral to neocortical ischemia, in a pattern that corresponds both spatially and temporally with behavioral recovery. Thus, neuroanatomical remodeling in the neocortex provides a mechanism for recovery of function.
We evaluated the effect of chronic administration of CDP-choline, an intermediate of phospholipid synthesis, on outcome from middle cerebral artery occlusion, ranging from 30 to 120 min in duration in spontaneously hypertensive rats. Rats were randomly assigned to either CDP-choline 500 mg kg-1 or saline. CDP-choline treatment was initiated by intraperitoneal injection 15 min after the onset of ischemia and continued once a day for 14 days. Morphologic damage and behavioral dysfunction (motor and sensorimotor performance) were evaluated, and the maximal morphologic damage (Volmax), maximal behavioral dysfunction (BDmax) as well as the duration of ischemia producing half-maximal morphologic damage (T50) or behavioral dysfunction (BD50) were calculated using a curve-fitting program (ALLFIT). Ischemia in control animals produced a Volmax of 103.3 +/- 13.6 mm3. CDP-choline did not affect this value (Volmax of 101.6 +/- 11.4 mm3). However, CDP-choline significantly extended the T50 from 38.3 +/- 5.9 to 60.5 +/- 4.3 min (p < 0.05). Similar to the morphologic outcome, CDP-choline had no effect on BDmax but significantly extended BD50 from 41.9 +/- 4.6 to 72.9 +/- 24.5 min (p < 0.05). Our results suggest that the effectiveness of CDP-choline is greater in animals demonstrating submaximal ischemic injury which in this model is produced by 30-75 min of ischemia (effect on T50 and BD50), than in animals suffering maximal ischemic injury produced by ischemia longer than 75 min (no effect on Volmax and BDmax). These results may reflect a threshold of biological membrane damage within which CDP-choline is able to restore phospholipid content/arrangement and retain membrane integrity.
This study examined the behavioural and anatomical effects of intraventricular injections of nerve growth factor in rats with unilateral damage that included Zilles' areas Frl, FL, HL, ParI and the anterior portion of Oc2. Nerve growth factor-treated lesion rats showed attenuation of behavioural symptoms in measures of forelimb function (Whishaw reaching task) and hindlimb function (beam traversing task) as well as a measure of spatial navigation (Morris water task). Analysis of dendritic arborization using a modified Golgi. Cox procedure also showed a complete reversal of lesion-induced atrophy of dendritic fields in pyramidal neurons in motor (Zilles' Fr2) and cingulate (Zilles' Cgl) cortex. In addition, there was a reversal of a lesion-induced reduction in spine density. These results demonstrate that nerve growth factor treatment can facilitate functional recovery from cortical injury. This recovery may be mediated by a reorganization of intrinsic cortical circuitry that is reflected in changes in dendritic arborization and spine density of pyramidal neurons.
Animal and human studies have shown that motor and somatosensory cortex are capable of reorganization throughout adult life. Cortical reorganization has been associated with functional recovery in experimental and human stroke. Retraining after experimental cortical infarction has been shown to extend cortical representation of the infarcted area and improve skilled motor performance.
Rats were given medial frontal lesions at 7 days of age and were tested as adults on tests of forelimb use, forelimb tactile sensitivity, tongue use, hindleg use, and in a spatial navigation task. The brains were processed with a modified Golgi-Cox procedure and dendritic arborization and spine density was measured. The animals showed recovery only on the spatial task and this was associated with an increase in the number of spines per unit length of dendrite. We also reanalyzed Golgi-Cox stained material from an experiment in which animals were depleted of cortical noradrenaline (NA) in infancy and then given frontal lesions on day 7. The NA depletion blocked the recovery from frontal lesions. Analysis of dendritic morphology showed that in otherwise intact rats, NA depletion decreased dendritic arbor but increased spine density to the level of frontal operates. Depleted frontal-operates showed no additional increase in spine density and also showed a decrease in dendritic arborization. These results suggest that recovery from neonatal cortical injury and from neonatal noradrenaline depletion may be supported by changes in both the dendritic arborization and the spine density in the remaining cortex.
Oxyradicals attack double bonds of unsaturated fatty acids in cell membranes in a process called membrane lipid peroxidation (MLP).This process occurs in many different acute and chronic neurodegenerative conditions, and to a lesser extent during normal physiological activity in neuronal circuits. It can modify neurotransmitter release and uptake, ion-channel activity, the function of ion-motive ATPases and glucose transporters,and the coupling of cell-surface receptors to GTP-binding proteins. MLP can also impair mitochondrial function and promote a cascade of events that culminates in apoptotic cell death. The lipid peroxidation product 4-hydroxynonenal might play a central role in MLP-induced alterations in plasma membrane and mitochondrial protein functions. The modification of processes such as outgrowth of neurites and long-term potentiation of synaptic transmission by agents that suppress or promote MLP suggests roles for subtoxic levels of MLP in neuronal plasticity.
Osteogenic protein-1 (OP-1, BMP-7) is a member of the transforming growth factor-beta (TGF-beta) superfamily that selectively induces dendritic outgrowth from cultured neurons. We injected human recombinant OP-1 (1 or 10 micrograms) or vehicle into the cisterna magna of mature male Sprague-Dawley rats 1 and 4 days after focal cerebral infarction induced by middle cerebral artery (MCA) occlusion. OP-1 treatment was associated with a marked enhancement of recovery of sensorimotor function of the impaired forelimb and hindlimb (contralateral to infarcts) as assessed by limb placing tests. This effect appeared to be dose dependent. There was no difference in infarct volume between OP-1 and vehicle-treated rats. The mechanisms of enhanced recovery by intracisternal OP-1 may include promotion of dendritic sprouting in the intact uninjured brain.
D-Amphetamine administration increases behavioral recovery after various cortical lesions including cortical ablations, contusions, and focal ischemia in animals and after stroke in humans. The purpose of the present study was to test the enhanced behavioral recovery and increased expression of proteins involved in neurite growth and synaptogenesis in D-amphetamine-treated rats compared with vehicle-treated controls after a focal neocortical infarct.
Unilateral neocortical ischemia was induced in male spontaneously hypertensive Wistar rats (n=8 per time point per group) by permanently occluding the distal middle cerebral artery and ipsilateral common carotid artery in 2 groups of rats: D-amphetamine treated (2 mg/kg IP injections) and vehicle treated (saline IP injections). To determine the spatial and temporal distribution of neurite growth and/or synaptogenesis, growth-associated protein (GAP-43), a protein expressed on axonal growth cones, and synaptophysin, a calcium-binding protein found on synaptic vesicles, were examined by immunohistochemical techniques, and both density and distribution of reaction product were measured. Since the resulting infarction included a portion of the forelimb neocortex, behavioral assessments of forelimb function using the foot-fault test of Hernandez and Schallert were performed on the same rats used for immunohistochemical studies during the period of drug action and 24 hours later. A Morris water maze and other indices of behavioral assays were also measured similarly. Recovery times were 3, 7, 14, 30, and 60 days postoperatively.
Both GAP-43 and synaptophysin proteins demonstrated statistically significant increases in density and distribution of immunoreaction product as determined by optical density measurements in the neocortex of the infarcted group treated with D-amphetamines compared with vehicle-treated infarcted controls. The GAP-43 was elevated to statistically significant levels in forelimb, hindlimb, and parietal neocortical regions ipsilateral to the infarction only at days 3, 7, and 14. By contrast, the synaptophysin demonstrated no statistically significant changes in expression at 3 or 7 days but demonstrated statistically significant increases at 14, 30, and 60 days in the forelimb, hindlimb, and parietal neocortical regions ipsilateral to the infarction as well as increased distribution in the contralateral parietal neocortex. Behavioral assessment of forelimb function indicated that improved recovery of forelimb placement on the side contralateral to the infarction was statistically significant in the D-amphetamine-treated group compared with the vehicle-treated group (P<0.025). Spatial memory, as measured with the Morris water maze, worsened in the vehicle-treated group compared with the D-amphetamine-treated group at 60 days (P<0.025).
These data support the occurrence of neurite growth followed by synaptogenesis in the neocortex in a pattern that corresponds both spatially and temporally with behavioral recovery that is accelerated by D-amphetamine treatment. While the specific mechanisms responsible for D-amphetamine-promoted expression of proteins involved in neurite growth and synaptogenesis and of enhanced behavioral recovery are not known, it is suggested that protein upregulation occurs as a result of functional activation of pathways able to remodel in response to active behavioral performance.
Cortical reorganization of motor systems has been found in recovered stroke patients. Reorganization in nonrecovered hemiplegic stroke patients early after stroke, however, is less well described. We used positron emission tomography to study the functional reorganization of motor and sensory systems in hemiplegic stroke patients before motor recovery.
Regional cerebral blood flow (rCBF) was measured in 6 hemiplegic stroke patients with a single, subcortical infarct and 3 normal subjects with the [(15)O]H(2)O injection technique. Brain activation was achieved by passive elbow movements driven by a torque motor. Increases of rCBF comparing passive movements and rest were assessed with statistical parametric mapping. Significant differences were defined at P<0.01.
In normal subjects, significant increases of rCBF were found in the contralateral sensorimotor cortex, supplementary motor area, cingulate cortex, and bilaterally in the inferior parietal cortex. In stroke patients, significant activation was observed bilaterally in the inferior parietal cortex and in the contralateral sensorimotor cortex, ipsilateral prefrontal cortex, supplementary motor area, and cingulate cortex. Significantly larger increases of rCBF in patients compared with normal subjects were found bilaterally in the sensorimotor cortex, stronger in the ipsilateral, unaffected hemisphere, and in both parietal lobes, including the ipsilateral precuneus.
Passive movements in hemiplegic stroke patients before clinical recovery elicit some of the brain activation patterns that have been described during active movements after substantial motor recovery. Changes of cerebral activation in sensory and motor systems occur early after stroke and may be a first step toward restoration of motor function after stroke.
Both cerebral hemispheres seem to contribute to motor recovery after stroke. We studied the effect of motor activity on cerebral blood flow in both hemispheres at different stages of stroke evolution.
Thirty patients with hemiplegic stroke and 30 controls were included. Patients were examined within the first week (T1), 1 month (T2) and 6 months after stroke (T3). All subjects performed a 2-min sequential thumb-to-finger opposition task while blood flow velocities in both middle cerebral arteries were measured with transcranial Doppler ultrasonography (TCD).
Contralateral movement caused a higher increase in blood flow velocity than ipsilateral movement in controls (p < 0.0001). On the healthy side, patients showed a striking increase with ipsilateral movement (affected hand), which was similar to the increase with contralateral movement (normal hand) at all stages. On the damaged side, the increase with contralateral movement (affected hand) was low and was similar to the increase with ipsilateral movement (normal hand) at T1 and T2; however, at T3 the increase with contralateral movement was higher and the pattern of response was similar to that found in controls.
TCD can trace the evolution of brain motor output following stroke. Compensatory activation of the healthy side of the brain may be already present soon after stroke, whereas function of the damaged side may improve during several months.
Neuronal connections and cortical maps are continuously remodeled by our experience. Knowledge of the potential capabilityof the brain to compensate for lesions is a prerequisite for optimal stroke rehabilitation strategies. Experimental focal cortical lesions induce changes in adjacent cortex and in the contralateral hemisphere. Neuroimaging studies in stroke patients indicate altered poststroke activation patterns, which suggest some functional reorganization. To what extent functional imaging data correspond to outcome data needs to be evaluated. Reorganization may be the principle process responsible for recovery of function after stroke, but what are the limits, and to what extent can postischemic intervention facilitate such changes? Postoperative housing of animals in an enriched environment can significantly enhance functional outcome and can also interact with other interventions, including neocortical grafting. What role will neuronal progenitor cells play in future rehabilitation-stimulated in situ or as neural replacement? And what is the future for blocking neural growth inhibitory factors? Better knowledge of postischemic molecular and neurophysiological events, and close interaction between basic and applied research, will hopefully enable us to design rehabilitation strategies based on neurobiological principles in a not-too-distant future.
Recovery from hemiparesis due to corticospinal tract infarction is well documented, but the mechanism of recovery is unknown. Functional MRI (fMRI) provides a means of identifying focal brain activity related to movement of a paretic hand. Although prior studies have suggested that supplementary motor regions in the ipsilesional and contralesional hemisphere play a role in recovery, little is known about the time course of cortical activation in these regions as recovery proceeds.
Eight patients with first-ever corticospinal tract lacunes causing hemiparesis had serial fMRIs within the first few days after stroke and at 3 to 6 months. Six healthy subjects were used as controls. Statistically significant voxels during a finger-thumb opposition task were identified with an automated image processing program. An index of ipsilateral versus contralateral activity was used to compare relative contributions of the 2 hemispheres to motor function in the acute and chronic phases after stroke.
Controls showed expected activation in the contralateral sensorimotor cortex (SMC), premotor, and supplementary motor areas. Stroke patients differed from control patients in showing greater activation in the ipsilateral SMC, ipsilateral posterior parietal, and bilateral prefrontal regions. Compared with the nonparetic hand, the ratio of contralateral to ipsilateral SMC activity during movement of the paretic hand increased significantly over time as the paretic hand regained function.
The evolution of activation in the SMC from early contralesional activity to late ipsilesional activity suggests that a dynamic bihemispheric reorganization of motor networks occurs during recovery from hemiparesis.
Long-term potentiation (LTP) is a sustained increase in the efficacy of synaptic transmission, based on functional changes involving pre- and postsynaptic mechanisms, and has been considered a cellular model for learning and memory. The sulphurated tripeptide glutathione acts as a powerful antioxidant agent within the nervous system. Recent in vitro studies suggest that the cellular redox status might influence the mechanisms involved in synaptic plasticity. It is not known, however, how glutathione depletion might affect LTP. In the present study, we evaluated the input-output relationships, LTP, and paired-pulse interactions in rats with low glutathione levels induced by systemic injection of diethylmaleate. Our results in anesthetized rats show that the basic synaptic transmission between the perforant pathway and the dentate gyrus granule cells was not affected by glutathione depletion. However, in the same synapses it was not possible to induce prolonged changes in synaptic efficacy (LTP). Paired-pulse facilitation was also absent in the treated animals, suggesting an impairment of short-term synaptic interactions. These findings indicate that low content of glutathione can impair short-term and long-term mechanisms of synaptic plasticity and stress the importance of the redox balance in the normal function of brain circuitry.
The "staircase" test has become established for measurement of side-specific deficits in coordinated paw reaching in rats, and has been shown to reveal impairments on the contralateral side following unilateral lesions in a wide range of motor structures of the brain. As mice become more widely used in behavioural neuroscience, we have scaled down the staircase reaching test for application to this latter species. We here validate the test in C57BL/6J mice by (a) establishing the optimal dimensions of the apparatus, (b) comparing the effects of test parameters including sex, test duration, levels of deprivation and alternative reward pellets, and (c) demonstrating contralateral deficits after aspirative lesions of the motor cortex. Differences between mice and rats in normal performance of the task are noted. The staircase test provides a simple objective test of skilled motor function that allows measurement of lateralised effects without unduly constraining the animal, and which may prove as useful for mice as has previously been demonstrated in rats.
Behavioral recovery takes place even after permanent damage to the entire brain region normally controlling sensorimotor hind limb function in the rat. In our study, 2 weeks after full behavioral recovery from an experimental unilateral permanent brain damage, the topographic representation of the previous paretic hindlimb was investigated by fMRI. The analysis showed that during electrical stimulation of the previously paretic hindlimb, two normally inactive brain regions were now being activated. One region was the non-damaged contralateral sensori-motor cortex and the other region was located lateral to the lesion. These results suggest that behavioral recovery can be explained by functional reorganization and neuromodulation of the brain.
Unlabelled:
The effects of citicoline and/or low dose of MK-801 (sufficient to prevent the development of seizures) on survival, neurological and behavioral recovery following transient hyperglycemic-oligemic-hypoxic insult have been evaluated in mice. Neurological recovery was assessed semi-quantitatively on the third and the 10th day after the insult, and behavioral tests evaluating spontaneous locomotor activity, motor coordination and spontaneous alternation performance were performed on day 10. Neither drug given alone did influence survival rate, but the combination of MK-801 and higher citicoline dose decreased mortality on day 10. Behavioral performance was markedly compromised by the insult. Citicoline, but not MK-801, slightly but significantly improved behavioral outcome in all three tests.
Conclusion:
when brain ischemic insult is complicated with acute hyperglycemia, post-treatment with citicoline combined with MK-801 in low anti-convulsive dose improves survival and neurological recovery, and citicoline but not MK-801 enhances behavioral recovery.
By a variety of mechanisms, the human brain is constantly undergoing plastic changes. Plasticity can be studied with phenomena such as peripheral deafferentation and motor learning. Spontaneous recovery from stroke in the chronic stag likely comes about because of plasticity, and the best recovery seems to result from reorganization in the damaged hemisphere. Knowledge about the physiology of brain plasticity has led to the development of new techniques for rehabilitation. Published by Elsevier Science BY.
Few reliable estimates of the long-term functional outcome after stroke are available. This population-based study aimed to describe disability, dependency, and related independent prognostic factors at 5 years after a first-ever stroke in patients in Perth, Western Australia.
All individuals with a suspected acute stroke who were resident in a geographically defined region (population, 138 708) of Perth, Western Australia, were registered prospectively and assessed according to standardized diagnostic criteria over a period of 18 months in 1989 to 1990. Patients were followed up prospectively at 4 and 12 months and 5 years after the index event.
There were 370 cases of first-ever stroke, and 277 patients survived to 30 days. Of these early survivors, 152 (55%) were alive at 5 years, and among those who were neither institutionalized (n=146) nor disabled (n=129) at the time of their stroke, 21 (14%) were institutionalized in a nursing home, and 47 (36%) were disabled. The most important predictors of death or disability at 5 years were increasing age, baseline disability defined by a Barthel Index score of <20/20 (odds ratio [OR], 6.3; 95% confidence interval [CI], 2.7 to 14), moderate hemiparesis (OR, 2.7; 95% CI, 1.1 to 6.2), severe hemiparesis (OR, 4.5; 95% CI, 1.1 to 19), and recurrent stroke (OR, 9.4; 95% CI, 3.0 to 30). A low level of activity before the stroke was a significant predictor of institutionalization, and subsequent recurrent stroke was a consistent, independent predictor of institutionalization, disability, and death or institutionalization, increasing the odds of each of these 3 adverse outcomes by 5- to 15-fold.
Among 30-day survivors of first-ever stroke, about half survive 5 years; of survivors, one third remain disabled, and 1 in 7 are in permanent institutional care. The major modifiable predictors of poor long-term outcome are a low level of activity before the stroke and subsequent recurrent stroke. Efforts to increase physical activity among the elderly and to prevent recurrent stroke in survivors of a first stroke are likely to reduce the long-term burden of cerebrovascular disease.
The goal of this study was to characterize cortical reorganization after stroke and its relation with the site of the stroke-induced lesion and degree of motor recovery using functional MRI (fMRI).
Fourteen stroke patients with an affected upper limb were studied longitudinally. Three fMRI sessions were performed over a period of 1 to 6 months after stroke. Upper limb recovery, Wallerian degeneration of the pyramidal tract, and responses to transcranial magnetic stimulation were assessed.
Two main patterns of cortical reorganization were found. Pattern 1 was focusing, in which, after initial recruitment of additional ipsilateral and contralateral areas, activation gradually developed toward a pattern of activation restricted to the contralateral sensorimotor cortex in 9 patients. Five patients were found to have pattern 2, persistent recruitment, in which there was an initial and sustained recruitment of ipsilateral activity. Occurrence of recruitment or focusing seemed to depend mainly on whether the primary motor cortex (M1) was lesioned; persistent recruitment was observed in 3 of 4 patients with M1 injury, and focusing was seen in 8 of 10 patients with spared M1. These patterns had no relation to the degree of recovery; in particular, focusing did not imply recovery. However, there was a clear relation between the degree of recovery and the degree of Wallerian degeneration.
These results suggest that ipsilateral recruitment after stroke corresponds to a compensatory corticocortical process related to the lesion of the contralateral M1 and that the process of compensatory recruitment will persist if M1 is lesioned; otherwise, it will be transient.
There is increasing evidence that brain-derived neurotrophic factor (BDNF) modulates synaptic and morphological plasticity in the developing and mature nervous system. Plasticity may be modulated partially by BDNF's effects on dendritic structure. Utilizing transgenic mice where BDNF overexpression was controlled by the beta-actin promoter, we evaluated the effects of long-term overexpression of BDNF on the dendritic structure of granule cells in the hippocampal dentate gyrus. BDNF transgenic mice provided the opportunity to investigate the effects of modestly increased BDNF levels on dendrite structure in the complex in vivo environment. While the elevated BDNF levels were insufficient to change levels of TrkB receptor isoforms or downstream TrkB signaling, they did increase dendrite complexity of dentate granule cells. These cells showed an increased number of first order dendrites, of total dendritic length and of total number of branch points. These results suggest that dendrite structure of granule cells is tightly regulated and is sensitive to modest increases in levels of BDNF. This is the first study to evaluate the effects of BDNF overexpression on dendrite morphology in the intact hippocampus and extends previous in vitro observations that BDNF influences synaptic plasticity by increasing complexity of dendritic arbors.
In humans and other animals, sufficient unilateral damage to the sensorimotor cortex can cause impairments in the opposite forelimb and the development of a hyper-reliance on the nonimpaired limb. This hyper-reliance is adaptive to the extent that it contributes to functional compensation for lesion-induced impairments. We have found that unilateral lesions of the forelimb region of the sensorimotor cortex (FLsmc) in rats, or callosal transections, cause neurons of the opposite motor cortex to become exceptionally responsive to changes in forelimb behavior. This enhanced responsiveness might facilitate learning of compensatory strategies with the nonimpaired forelimb after unilateral FLsmc lesions. The possibility that these lesions facilitate learning with the nonimpaired forelimb was addressed in this study. Rats were required to learn a skilled forelimb reaching task after either unilateral FLsmc lesions or sham operations. The trained limb in animals with lesions was the nonimpaired limb. Compared with shams, rats with unilateral lesions had a greater rate of acquisition and asymptotic performance level on the task, which was especially evident on more difficult trials. Quantitative measures of microtubule associated protein-2 (MAP2) immunostained dendrites indicated an enhancement of training-induced dendritic cytoskeletal changes in the motor cortex opposite lesions. Thus, unilateral FLsmc lesions facilitate learning of at least some types of motor skills using the nonimpaired forelimb as well as some of the neuronal changes associated with this learning. This facilitation could be a substrate underlying behavioral compensation for unilateral FLsmc damage and may contribute to the phenomenon of learned nonuse of the impaired limb.
A short ischemic event (ischemic preconditioning [IPC]) can result in a subsequent resistance to severe ischemic injury (ischemic tolerance [IT]). Although tumor necrosis factor-alpha (TNF-alpha) contributes to the brain damage, its expression and neuroprotective role in models of IPC have also been described. However, the role of TNF-alpha convertase (TACE) in IPC and IT is not known. Using in vitro models, the authors previously demonstrated that TACE is upregulated after ischemic brain damage. In the present study, the authors used a rat model of transient middle cerebral artery occlusion as IPC to investigate TACE expression, its involvement in TNF-alpha release, and its role in IT. Western blot analysis showed that TACE expression is increased after IPC. Ischemic preconditioning caused TNF-alpha release, an effect that was blocked by the selective TACE inhibitor BB-1101 (10 mg. kg(-1). day(-1); SHAM, 1,050 +/- 180; IPC, 1,870 +/- 290; IPC + BB, 1,320 +/- 260 ng/mg; n = 4, < 0.05). Finally, IPC produced a reduction in infarct volume, which was inhibited by treatment with BB-1101 and with anti-TNF-alpha (10 microg/5 doses; SHAM + permanent middle cerebral artery occlusion [pMCAO], 335 +/- 20; IPC + pMCAO, 244 +/- 14; IPC + BB + pMCAO, 300 +/- 6; IPC + anti-TNF + pMCAO, 348 +/- 22 mm3; n = 6-10, < 0.05). Taken together, these data demonstrate that TACE is upregulated after IPC, plays a major role in TNF-alpha shedding in IPC, and has a neuroprotective role in IT.