A Pitkänen

University of Eastern Finland, Kuopio, Eastern Finland Province, Finland

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Publications (278)1066.54 Total impact

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    ABSTRACT: Disease modification of epilepsy refers to the alleviation of epileptogenesis or comorbidities after genetic or acquired epileptogenic brain insults. There are currently 30 proof-of-concept experimental pharmacologic studies that have demonstrated some beneficial disease-modifying effects. None of these studies, however, has yet passed from the laboratory to the clinic. The International League Against Epilepsy and American Epilepsy Society working groups on antiepileptogenic (AEG) therapies recently released recommendations for conducting preclinical AEG studies, taking into account many of the critiques raised by previous study designs. One of the issues relates to the lack of analysis of AEG efficacy in both sexes. A review of the literature reveals that most of the preclinical studies have been performed using male rodents, whereas clinical study cohorts include both males and females. Therefore, it is important to determine whether sex differences should be taken into account to a greater extent than they have been historically at different phases of experimental studies. Here we address the following questions based on analysis of available experimental AEG studies: (a) whether sex differences should be considered when searching for novel AEG targets, (b) how sex differences can affect the preclinical AEG study designs and analysis of outcome measures, and (c) what factors should be considered when examining the effect of sex on outcome of clinical AEG trials or the clinical use of AEGs.
    Neurobiology of Disease 06/2014; · 5.62 Impact Factor
  • Noora Huusko, Asla Pitkänen
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    ABSTRACT: Traumatic brain injury (TBI) causes 10-20% of acquired epilepsy in humans, resulting in an ictogenic region that is often located in the cerebral cortex. The thalamus provides heavy projections to the cortex and the activity of thalamocortical pathways is controlled by GABAergic afferents from the reticular nucleus of the thalamus (RT). As rats with TBI induced by lateral fluid-percussion injury (FPI) undergo epileptogenesis, we hypothesized that damage to the parvalbumin (PARV)-immunoreactive (ir) neurons in the RT is associated with seizure susceptibility after lateral FPI. To address this hypothesis, adult Sprague-Dawley rats (n=13) were injured with lateral FPI. At 6 months post-TBI, each animal underwent a pentylenetetrazol (PTZ) seizure susceptibility test and two weeks of continuous video-EEG monitoring for detection of the occurrence of spontaneous seizures. Thereafter, the brain was processed for PARV immunohistochemistry. We (a) estimated the total number of PARV-ir neurons in the RT using unbiased stereology, (b) measured the volume of the ventroposteromedial (VPM) and ventroposterolateral (VPL) nuclei of the thalamus, which receive PARV-ir inputs from the RT and project to the perilesional cortex, (c) quantified the density of PARV-ir terminals in the VPM-VPL, and (d) studied the expression of GABAA receptor subunits in a separate group of rats using laser-dissection of the thalamus followed by RT-PCR array studies. At 6 months post-TBI, only 64% of PARV-ir neurons were remaining in the RT ipsilaterally (p<0.001 as compared to controls) and 84% contralaterally (p<0.05). Accordingly, the volume of the ipsilateral RT was 58% of that in controls ipsilaterally (p<0.001) and 90% contralaterally (p>0.05). Also, the volume of the VPM-VPL was only 51% of that in controls ipsilaterally (p<0.001) and 91% contralaterally (p<0.05). The density of PARV-ir axonal labeling was remarkably increased in the lateral aspects of the VPM and VPL (both p<0.001). Expression of the ε- and θ-subunits of the GABAA receptor was down-regulated (0.152, p<0.01 and 0.302, p<0.05, respectively), which could relate to the inclusion of the hypothalamus into the tissue analyzed with RT-PCR arrays. In controls, the lower the number of PARV-ir neurons in the RT, the higher the seizure susceptibility in the PTZ test. Rats with TBI showed seizure susceptibility comparable to that in controls with the lowest number of PARV-ir neurons in the RT. Our data show that the RT and VPM-VPL undergo remarkable degeneration after lateral-FPI which results in reorganization of PARV-ir terminals in the VPM-VPL. The contribution of RT damage to seizure susceptibility and post-traumatic epileptogenesis deserves further studies.
    Neuroscience 03/2014; · 3.12 Impact Factor
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    ABSTRACT: Cerebral cavernous malformations (CCMs) are well-defined, mostly singular lesions present in 0.4-0.9% of the population. Epileptic seizures are the most frequent symptom in patients with CCMs and have a great impact on social function and quality of life. However, patients with CCM-related epilepsy (CRE) who undergo surgical resection achieve postoperative seizure freedom in only about 75% of cases. This is frequently because insufficient efforts are made to adequately define and resect the epileptogenic zone. The Surgical Task Force of the Commission on Therapeutics of the International League Against Epilepsy (ILAE) and invited experts reviewed the pertinent literature on CRE. Definitions of definitive and probable CRE are suggested, and recommendations regarding the diagnostic evaluation and etiology-specific management of patients with CRE are made. Prospective trials are needed to determine when and how surgery should be done and to define the relations of the hemosiderin rim to the epileptogenic zone.
    Epilepsia 03/2014; 55(3). · 3.96 Impact Factor
  • Asla Pitkänen, Riikka Immonen
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    ABSTRACT: Post-traumatic epilepsy accounts for 10-20 % of symptomatic epilepsy in the general population and 5 % of all epilepsy. During the last decade, an increasing number of laboratories have investigated the molecular and cellular mechanisms of post-traumatic epileptogenesis in experimental models. However, identification of critical molecular, cellular, and network mechanisms that would be specific for post-traumatic epileptogenesis remains a challenge. Despite of that, 7 of 9 proof-of-concept antiepileptogenesis studies have demonstrated some effect on seizure susceptibility after experimental traumatic brain injury, even though none of them has progressed to clinic. Moreover, there has been some promise that new clinically translatable imaging approaches can identify biomarkers for post-traumatic epileptogenesis. Even though the progress in combating post-traumatic epileptogenesis happens in small steps, recent discoveries kindle hope for identification of treatment strategies to prevent post-traumatic epilepsy in at-risk patients.
    Journal of the American Society for Experimental NeuroTherapeutics 02/2014; · 5.38 Impact Factor
  • Asla Pitkänen, Jerome Engel
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    ABSTRACT: Descriptions of epileptic seizures and epilepsy date back to antiquity, and research into fundamental mechanisms of epilepsy in animal models, as well as patients, has been carried out for over a century. Studies of epileptogenesis, however, as distinct from ictogenesis, have been pursued for only a few decades, and antiepileptogenesis, the prevention of epilepsy or its progression, and the reversal of the epileptogenic process or cure, are relatively recent interests of the basic research community. The goal to develop antiepileptogenic interventions would be greatly facilitated by the identification of reliable biomarkers of epileptogenesis that could be used to create cost-effective, high-throughput screening models for potential antiepileptogenic compounds, as well as enrich patient populations and serve as surrogate endpoints for clinical trials. Without such biomarkers, the cost for clinical validation of antiepileptogenic interventions would be prohibitive. Epileptogenic mechanisms, antiepileptogenic interventions, and biomarkers are likely to be specific for the many different causes of epilepsy, which include genetic influences, cell loss and synaptic plasticity, malformations of cortical development, and autoimmune disorders, to name but a few. A high priority is currently being placed on investigations to elucidate fundamental mechanisms of epileptogenesis and identify biomarkers for specific models of human epilepsy, such as mesial temporal lobe epilepsy with hippocampal sclerosis, traumatic brain injury, and a variety of pediatric diseases, including tuberous sclerosis and West syndrome.
    Journal of the American Society for Experimental NeuroTherapeutics 02/2014; · 5.38 Impact Factor
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    ABSTRACT: Neuronal voltage-gated ion channels and ligand-gated synaptic receptors play a critical role in maintaining the delicate balance between neuronal excitation and inhibition within neuronal networks in the brain. Changes in expression of voltage-gated ion channels, in particular sodium, hyperpolarization-activated cyclic nucleotide-gated (HCN) and calcium channels, and ligand-gated synaptic receptors, in particular GABA and glutamate receptors, have been reported in many types of both genetic and acquired epilepsies, in animal models and in humans. In this chapter we review these and discuss the potential pathogenic role they may play in the epilepsies.
    Advances in experimental medicine and biology 01/2014; 813:211-29. · 1.83 Impact Factor
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    ABSTRACT: Traumatic brain injury (TBI) can cause a myriad of sequelae depending on its type, severity, and location of injured structures. These can include mood disorders, posttraumatic stress disorder and other anxiety disorders, personality disorders, aggressive disorders, cognitive changes, chronic pain, sleep problems, motor or sensory impairments, endocrine dysfunction, gastrointestinal disturbances, increased risk of infections, pulmonary disturbances, parkinsonism, posttraumatic epilepsy, or their combinations. The progression of individual pathologies leading to a given phenotype is variable, and some progress for months. Consequently, the different post-TBI phenotypes appear within different time windows. In parallel with morbidogenesis, spontaneous recovery occurs both in experimental models and in human TBI. A great challenge remains; how can we dissect the specific mechanisms that lead to the different endophenotypes, such as posttraumatic epileptogenesis, in order to identify treatment approaches that would not compromise recovery? This article is part of a Special Issue entitled “NEWroscience 2013”.
    Epilepsy & Behavior 01/2014; · 1.84 Impact Factor
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    ABSTRACT: Traumatic brain injury (TBI) contributes to about 10% of acquired epilepsy. Even though the mechanisms of post-traumatic epileptogenesis are poorly known, a disruption of neuronal networks predisposing to altered neuronal synchrony remains a viable candidate mechanism. We tested a hypothesis that resting state BOLD-fMRI functional connectivity can reveal network abnormalities in brain regions that are connected to the lesioned cortex, and that these changes associate with functional impairment, particularly epileptogenesis. TBI was induced using lateral fluid-percussion injury in seven adult male Sprague-Dawley rats followed by functional imaging at 9.4T 4 months later. As controls we used six sham-operated animals that underwent all surgical operations but were not injured. Electroencephalogram (EEG)-functional magnetic resonance imaging (fMRI) was performed to measure resting functional connectivity. A week after functional imaging, rats were implanted with bipolar skull electrodes. After recovery, rats underwent pentyleneterazol (PTZ) seizure-susceptibility test under EEG. For image analysis, four pairs of regions of interests were analyzed in each hemisphere: ipsilateral and contralateral frontal and parietal cortex, hippocampus, and thalamus. High-pass and low-pass filters were applied to functional imaging data. Group statistics comparing injured and sham-operated rats and correlations over time between each region were calculated. In the end, rats were perfused for histology. None of the rats had epileptiform discharges during functional imaging. PTZ-test, however revealed increased seizure susceptibility in injured rats as compared to controls. Group statistics revealed decreased connectivity between the ipsilateral and contralateral parietal cortex and between the parietal cortex and hippocampus on the side of injury as compared to sham-operated animals. Injured animals also had abnormal negative connectivity between the ipsilateral and contralateral parietal cortex and other regions. Our data provide the first evidence on abnormal functional connectivity after experimental TBI assessed with resting state BOLD-fMRI.
    PLoS ONE 01/2014; 9(4):e95280. · 3.73 Impact Factor
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    ABSTRACT: In a subgroup of patients, traumatic brain injury (TBI) results in the occurrence of acute epileptic seizures or even status epilepticus, which are treated with antiepileptic drugs (AEDs). Recent experimental data, however, suggest that administration of AEDs at the early post-injury phase can compromise the recovery process. The present study was designed to assess the profile of a novel anticonvulsant, lacosamide (Vimpat®) on post-TBI structural, motor and cognitive outcomes. Moderate TBI was induced by lateral fluid-percussion injury in adult rats. Treatment with 0.9% saline or lacosamide (30 mg/kg, i.p.) was started at 30 min post-injury and continued at 8 h intervals for 3 d (total daily dose 90 mg/kg/d). Rats were randomly assigned to 4 treatment groups: sham-operated controls treated with vehicle (Sham-Veh) or lacosamide (Sham-LCM) and injured animals treated with vehicle (TBI-Veh) or lacosamide (TBI-LCM). As functional outcomes we tested motor recovery with composite neuroscore and beam-walking at 2, 7, and 15 d post-injury. Cognitive recovery was tested with the Morris water-maze at 12-14 d post-TBI. To assess the structural outcome, animals underwent magnetic resonance imaging (MRI) at 2 d post-TBI. At 16 d post-TBI, rats were perfused for histology to analyze cortical and hippocampal neurodegeneration and axonal damage. Our data show that at 2 d post-TBI, both the TBI-Veh and TBI-LCM groups were equally impaired in neuroscore. Thereafter, motor recovery occurred similarly during the first week. At 2 wk post-TBI, recovery of the TBI-LCM group lagged behind that in the TBI-VEH group (p < 0.05). Performance in beam-walking did not differ between the TBI-Veh and TBI-LCM groups. Both TBI groups were similarly impaired in the Morris water-maze at 2 wk post-TBI. MRI and histology did not reveal any differences in the cortical or hippocampal damage between the TBI-Veh and TBI-LCM groups. Taken together, acute treatment with LCM had no protective effects on post-TBI structural or functional impairment. Composite neuroscore in the TBI-LCM group lagged behind that in the TBI-Veh group at 15 d post-injury, but no compromise was found in other indices of post-TBI recovery in the LCM treated animals.
    Epilepsy research 01/2014; · 2.48 Impact Factor
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    ABSTRACT: Diffusion tensor imaging (DTI) has become a valuable tool to investigate white matter integrity in the brain. DTI also gives contrast in gray matter, which has been relatively little explored in studies assessing post-injury structural abnormalities. The present study was designed to compare white and gray matter reorganization in the rat hippocampus after two epileptogenic brain injuries, status epilepticus (SE) and traumatic brain injury (TBI), using ex vivo high-resolution DTI. Imaging was performed at 6-12 months post-injury and findings were compared to histological analyses of Nissl, myelin, and Timm-stained preparations from the same animals. In agreement with the severity of histological damage, fractional anisotropy (FA), axial (D ||) and radial (D ⊥) diffusivities, and mean diffusivity (MD) measurements were altered in the order SE > TBI ipsilaterally > TBI contralaterally. After SE, the most severe abnormalities were found in the dentate gyrus and CA3b-c subfields, in which the mean FA was increased to 125 % (p < 0.001) and 143 % (p < 0.001) of that in controls, respectively. In both subfields, the change in FA was associated with an increase in D || (p < 0.01). In the stratum radiatum of the CA1, FA was decreased to 81 % of that in controls (p < 0.05) which was associated with an increase in D ⊥ (p < 0.01). After TBI, DTI did not reveal any major abnormalities in the dentate gyrus. In the ipsilateral CA3b-c, however, FA was increased to 126 % of that in controls (p < 0.01) and associated with a mild decrease in D ⊥ (p < 0.05). In the stratum radiatum of the ipsilateral CA1, FA was decreased to 88 % of that in controls (p < 0.05). Our data demonstrate that DTI reveals subfield-specific abnormalities in the hippocampus with remarkable qualitative and quantitative differences between the two epileptogenic etiologies, suggesting that DTI could be a valuable tool for follow-up of focal circuitry reorganization during the post-injury aftermath.
    Brain Structure and Function 12/2013; · 7.84 Impact Factor
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    ABSTRACT: Reduced hippocampal GABAergic inhibition is acknowledged to be associated with epilepsy. However, there are no studies that had quantitatively compared the loss of various interneuron populations in different models of epilepsy. We tested a hypothesis that the more severe the loss of hippocampal interneurons, the more severe was the epilepsy. Epileptogenesis was triggered in adult rats by status epilepticus (SE) (56 SE, 24 controls) or by traumatic brain injury (TBI) (45 TBI, 23 controls). The total number of hippocampal parvalbumin (PARV), cholecystokinin (CCK), calretinin (CR), somatostatin (SOM), or neuropeptide Y (NPY) positive neurons was estimated using unbiased stereology at 1 or 6 months post-insult. The rats with TBI had no spontaneous seizures but showed increased seizure susceptibility. Eleven of the 28 rats (39 %) in the SE group had spontaneous seizures. The most affected hippocampal area after TBI was the ipsilateral dentate gyrus, where 62 % of PARV-immunoreactive (ir) (p < 0.001 compared to controls), 77 % of CR-ir (p < 0.05), 46 % of SOM-ir (p < 0.001), and 59 % of NPY-ir (p < 0.001) cells remained at 1 month after TBI. At 6 months post-TBI, only 35 % of PARV-ir (p < 0.001 compared to controls), 63 % of CCK-ir (p < 0.01), 74 % of CR-ir (p < 0.001), 55 % of SOM-ir (p < 0.001), and 51 % of NPY-ir (p < 0.001) cells were remaining. Moreover, the reduction in PARV-ir, CCK-ir, and CR-ir neurons was bilateral (all p < 0.05). Substantial reductions in different neuronal populations were also found in subfields of the CA3 and CA1. In rats with epilepsy after SE, the number of PARV-ir neurons was reduced in the ipsilateral CA1 (80 % remaining, p < 0.05) and the number of NPY-ir neurons bilaterally in the dentate gyrus (33-37 %, p < 0.01) and the CA3 (54-57 %, p < 0.05). Taken together, interneuron loss was substantially more severe, widespread, progressive, and included more interneuron subclasses after TBI than after SE. Interneurons responsible for perisomatic inhibition were more vulnerable to TBI than those providing dendritic inhibition. Unlike expected, we could not demonstrate any etiology-independent link between the severity of hippocampal interneuron loss and the overall risk of spontaneous seizures.
    Brain Structure and Function 10/2013; · 7.84 Impact Factor
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    ABSTRACT: The search for new treatments for seizures, epilepsies, and their comorbidities faces considerable challenges. This is due in part to gaps in our understanding of the etiology and pathophysiology of most forms of epilepsy. An additional challenge is the difficulty in predicting the efficacy, tolerability, and impact of potential new treatments on epilepsies and comorbidities in humans, using the available resources. Herein we provide a summary of the discussions and proposals of the Working Group 2 as presented in the Joint American Epilepsy Society and International League Against Epilepsy Translational Workshop in London (September 2012). We propose methodologic and reporting practices that will enhance the uniformity, reliability, and reporting of early stage preclinical studies with animal seizure and epilepsy models that aim to develop and evaluate new therapies for seizures or epilepsies, using multidisciplinary approaches. The topics considered include the following: (1) implementation of better study design and reporting practices; (2) incorporation in the study design and analysis of covariants that may influence outcomes (including species, age, sex); (3) utilization of approaches to document target relevance, exposure, and engagement by the tested treatment; (4) utilization of clinically relevant treatment protocols; (5) optimization of the use of video-electroencephalography (EEG) recordings to best meet the study goals; and (6) inclusion of outcome measures that address the tolerability of the treatment or study end points apart from seizures. We further discuss the different expectations for studies aiming to meet regulatory requirements to obtain approval for clinical testing in humans. Implementation of the rigorous practices discussed in this report will require considerable investment in time, funds, and other research resources, which may create challenges for academic researchers seeking to contribute to epilepsy therapy discovery and development. We propose several infrastructure initiatives to overcome these barriers.
    Epilepsia 08/2013; 54 Suppl 4:13-23. · 3.96 Impact Factor
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    ABSTRACT: Several preclinical proof-of-concept studies have provided evidence for positive treatment effects on epileptogenesis. However, none of these hypothetical treatments has advanced to the clinic. The experience in other fields of neurology such as stroke, Alzheimer's disease, or amyotrophic lateral sclerosis has indicated several problems in the design of preclinical studies, which likely contribute to failures in translating the positive preclinical data to the clinic. The Working Group on "Issues related to development of antiepileptogenic therapies" of the International League Against Epilepsy (ILAE) and the American Epilepsy Society (AES) has considered the possible problems that arise when moving from proof-of-concept antiepileptogenesis (AEG) studies to preclinical AEG trials, and eventually to clinical AEG trials. This article summarizes the discussions and provides recommendations on how to design a preclinical AEG monotherapy trial in adult animals. We specifically address study design, animal and model selection, number of studies needed, issues related to administration of the treatment, outcome measures, statistics, and reporting. In addition, we give recommendations for future actions to advance the preclinical AEG testing.
    Epilepsia 08/2013; 54 Suppl 4:35-43. · 3.96 Impact Factor
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    ABSTRACT: A biomarker is defined as an objectively measured characteristic of a normal or pathologic biologic process. Identification and proper validation of biomarkers of epileptogenesis (the development of epilepsy) and ictogenesis (the propensity to generate spontaneous seizures) might predict the development of an epilepsy condition; identify the presence and severity of tissue capable of generating spontaneous seizures; measure progression after the condition is established; and determine pharmacoresistance. Such biomarkers could be used to create animal models for more cost-effective screening of potential antiepileptogenic and antiseizure drugs and devices, and to reduce the cost of clinical trials by enriching the trial population, and acting as surrogate markers to shorten trial duration. The objectives of the biomarker subgroup for the London Workshop were to define approaches for identifying possible biomarkers for these purposes. Research to identify reliable biomarkers may also reveal underlying mechanisms that could serve as therapeutic targets for the development of new antiepileptogenic and antiseizure compounds.
    Epilepsia 08/2013; 54 Suppl 4:61-9. · 3.96 Impact Factor
  • Xavier Ekolle Ndode-Ekane, Asla Pitkänen
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    ABSTRACT: Mutation in Plaur gene encoding urokinase-type plasminogen activator receptor (uPAR) results in epilepsy and autistic phenotype in mice. In humans, a single nucleotide polymorphism in PLAUR gene represents a risk for autism spectrum disorders. Importantly, the expression of uPAR is elevated in the brain after various epileptogenic insults like traumatic brain injury and status epilepticus. So far, the consequences of altered uPAR expression on brain networks are poorly known. We tested a hypothesis that uPAR regulates post-injury neuronal reorganization and consequent functional outcome, particularly epileptogenesis. Epileptogenesis was induced by intrahippocampal injection of kainate in adult male wild type (Wt) or uPAR knockout (uPAR-/-) mice, and animals were monitored with continuous (24/7) video-electroencephalogram for 30 days. The severity of status epilepticus did not differ between the genotypes. The spontaneous electrographic seizures which developed were, however, longer and their behavioral manifestations were more severe in uPAR-/- than Wt mice. The more severe epilepsy phenotype in uPAR-/- mice was associated with delayed but augmented inflammatory response and more severe neurodegeneration in the hippocampus. Also, the distribution of newly born cells in the dentate gyrus was more scattered, and the recovery of hippocampal blood vessel length from status epilepticus-induced damage was compromised in uPAR-/- mice as compared to Wt mice. Our data demonstrate that a deficiency in uPAR represents a mechanisms which results in the development of a more severe epilepsy phenotype and progressive brain pathology after status epilepticus. We suggest that uPAR represents a rational target for disease-modifying treatments after epileptogenic brain insults.
    Molecular Neurobiology 12/2012; · 5.47 Impact Factor
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    ABSTRACT: Deficient energy metabolism and network hyperactivity are the early symptoms of Alzheimer's disease (AD). In this study, we show that administration of exogenous oxidative energy substrates (OES) corrects neuronal energy supply deficiency that reduces the amyloid-beta-induced abnormal neuronal activity in vitro and the epileptic phenotype in AD model in vivo. In vitro, acute application of protofibrillar amyloid-β(1-42) (Aβ(1-42) ) induced aberrant network activity in wild-type hippocampal slices that was underlain by depolarization of both the neuronal resting membrane potential and GABA-mediated current reversal potential. Aβ(1-42) also impaired synaptic function and long-term potentiation. These changes were paralleled by clear indications of impaired energy metabolism, as indicated by abnormal NAD(P)H signaling induced by network activity. However, when glucose was supplemented with OES pyruvate and 3-beta-hydroxybutyrate, Aβ(1-42) failed to induce detrimental changes in any of the above parameters. We administered the same OES as chronic supplementation to a standard diet to APPswe/PS1dE9 transgenic mice displaying AD-related epilepsy phenotype. In the ex-vivo slices we found neuronal sub-populations with significantly depolarized resting and GABA-mediated current reversal potentials, mirroring abnormalities we observed under acute Aβ(1-42) application. Ex-vivo cortex of transgenic mice fed with standard diet displayed signs of impaired energy metabolism, such as abnormal NAD(P)H signaling and strongly reduced tolerance to hypoglycemia. Transgenic mice also possessed brain glycogen levels twofold lower than those of wild-type mice. However, none of the above neuronal and metabolic dysfunctions were observed in transgenic mice fed with the OES-enriched diet. In vivo, dietary OES supplementation abated neuronal hyperexcitability, as the frequency of both epileptiform discharges and spikes was strongly decreased in the APPswe/PS1dE9 mice placed on the diet. Altogether, our results suggest that early AD-related neuronal malfunctions underlying hyperexcitability and energy metabolism deficiency can be prevented by dietary supplementation with native energy substrates. © 2012 International Society for Neurochemistry, J. Neurochem. (2012) 10.1111/jnc.12127.
    Journal of Neurochemistry 12/2012; · 3.97 Impact Factor
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    ABSTRACT: For several decades, both in vitro and in vivo models of seizures and epilepsy have been employed to unravel the molecular and cellular mechanisms underlying the occurrence of spontaneous recurrent seizures (SRS)-the defining hallmark of the epileptic brain. However, despite great advances in our understanding of seizure genesis, investigators have yet to develop reliable biomarkers and surrogate markers of the epileptogenic process. Sadly, the pathogenic mechanisms that produce the epileptic condition, especially after precipitating events such as head trauma, inflammation, or prolonged febrile convulsions, are poorly understood. A major challenge has been the inherent complexity and heterogeneity of known epileptic syndromes and the differential genetic susceptibilities exhibited by patients at risk. Therefore, it is unlikely that there is only one fundamental pathophysiologic mechanism shared by all the epilepsies. Identification of antiepileptogenesis targets has been an overarching goal over the last decade, as current anticonvulsant medications appear to influence only the acute process of ictogenesis. Clearly, there is an urgent need to develop novel therapeutic interventions that are disease modifying-therapies that either completely or partially prevent the emergence of SRS. An important secondary goal is to develop new treatments that can also lessen the burden of epilepsy comorbidities (e.g., cognitive impairment, mood disorders) by preventing or reducing the deleterious changes during the epileptogenic process. This review summarizes novel antiepileptogenesis targets that were critically discussed at the XIth Workshop on the Neurobiology of Epilepsy (WONOEP XI) meeting in Grottaferrata, Italy. Further, emerging neurometabolic links among several target mechanisms and highlights of the panel discussion are presented.
    Epilepsia 10/2012; · 3.96 Impact Factor
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    ABSTRACT: To investigate how kainic acid-induced epileptiform activity is related to hemodynamic changes probed by blood oxygenation level-dependent functional magnetic resonance imaging (BOLD fMRI). Epileptiform activity was induced with kainic acid (KA) (10 mg/kg, i.p.), and simultaneous fMRI at 7 Tesla, and deep electrode local field potential (LFP) recordings were performed from the right hippocampus in awake and medetomidine-sedated adult Wistar rats. Recurrent seizure activity induced by KA was detected in LFP both in medetomidine-sedated and awake rats, even though medetomidine sedation reduced the mean duration of individual seizures as compared to awake rats (33 ± 24 and 46 ± 34 s, respectively, mean ± SD p < 0.01). KA administration also triggered robust positive BOLD responses bilaterally in the hippocampus both in awake and medetomidine-sedated rats; however, in both animal groups some of the seizures detected in LFP recording did not cause detectable BOLD signal change. Our data suggest that medetomidine sedation can be used for simultaneous fMRI and electrophysiologic studies of normal and epileptic brain function, even though seizure duration after medetomidine administration was shorter than that in awake animals. The results also indicate that neuronal activity and BOLD response can become decoupled during recurrent kainic acid-induced seizures, which may have implications to interpretation of fMRI data obtained during prolonged epileptiform activity.
    Epilepsia 06/2012; 53(7):1245-53. · 3.96 Impact Factor
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    ABSTRACT: Calcifications represent one component of pathology in many brain diseases. With MRI, they are most often detected by exploiting negative contrast in magnitude images. Calcifications are more diamagnetic than tissue, leading to a magnetic field disturbance that can be seen in phase MR images. Most phase imaging studies use gradient recalled echo based pulse sequences. Here, the phase component of SWIFT, a virtually zero acquisition delay sequence, was used to detect calcifications ex vivo and in vivo in rat models of status epilepticus and traumatic brain injury. Calcifications were detected in phase and imaginary SWIFT images based on their dipole like magnetic field disturbances. In magnitude SWIFT images, calcifications were distinguished as hypointense and hyperintense. Hypointense calcifications showed large crystallized granules with few surrounding inflammatory cells, while hyperintense calcifications contained small granules with the presence of more inflammatory cells. The size of the calcifications in SWIFT magnitude images correlated with that in Alizarin stained histological sections. Our data indicate that SWIFT is likely to better preserve signal in the proximity of a calcification or other field perturber in comparison to gradient echo due to its short acquisition delay and broad excitation bandwidth. Furthermore, a quantitative description for the phase contrast near dipole magnetic field inhomogeneities for the SWIFT pulse sequence is given. In vivo detection of calcifications provides a tool to probe the progression of pathology in neurodegenerative diseases. In particular, it appears to provide a surrogate marker for inflammatory cells around the calcifications after brain injury.
    NeuroImage 03/2012; 61(4):761-72. · 6.25 Impact Factor
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    ABSTRACT: Preclinical research has facilitated the discovery of valuable drugs for the symptomatic treatment of epilepsy. Yet, despite these therapies, seizures are not adequately controlled in a third of all affected individuals, and comorbidities still impose a major burden on quality of life. The introduction of multiple new therapies into clinical use over the past two decades has done little to change this. There is an urgent demand to address the unmet clinical needs for: (1) new symptomatic antiseizure treatments for drug-resistant seizures with improved efficacy/tolerability profiles, (2) disease-modifying treatments that prevent or ameliorate the process of epileptogenesis, and (3) treatments for the common comorbidities that contribute to disability in people with epilepsy. New therapies also need to address the special needs of certain subpopulations, that is, age- or gender-specific treatments. Preclinical development in these treatment areas is complex due to heterogeneity in presentation and etiology, and may need to be formulated with a specific seizure, epilepsy syndrome, or comorbidity in mind. The aim of this report is to provide a framework that will help define future guidelines that improve and standardize the design, reporting, and validation of data across preclinical antiepilepsy therapy development studies targeting drug-resistant seizures, epileptogenesis, and comorbidities.
    Epilepsia 03/2012; 53(3):571-82. · 3.96 Impact Factor

Publication Stats

8k Citations
1,066.54 Total Impact Points

Institutions

  • 2010–2014
    • University of Eastern Finland
      • • A.I. Virtanen Institute for Molecular Sciences
      • • Department of Neurobiology
      • • Department of Neurology
      Kuopio, Eastern Finland Province, Finland
  • 2013
    • University of California, Los Angeles
      • Department of Neurology
      Los Angeles, CA, United States
  • 2004–2012
    • Nencki Institute of Experimental Biology
      • Department of Molecular and Cellular Neurobiology
      Warsaw, Masovian Voivodeship, Poland
  • 2001–2012
    • Academy of Sciences of the Czech Republic
      • Institute of Physiology
      Praha, Praha, Czech Republic
  • 2011
    • L'Institut du Cerveau et de la Moelle Épinière
      Lutetia Parisorum, Île-de-France, France
  • 1984–2010
    • University of Kuopio
      • Department of Neurology
      Kuopio, Eastern Finland Province, Finland
  • 2009
    • University of California, San Francisco
      • Department of Neurology
      San Francisco, CA, United States
  • 2007–2009
    • Mario Negri Institute for Pharmacological Research
      • Department of Neuroscience
      Milano, Lombardy, Italy
    • University of Pennsylvania
      • Department of Neurosurgery
      Philadelphia, PA, United States
    • University of Leuven
      Louvain, Flanders, Belgium
  • 2006–2007
    • Polish Academy of Sciences
      • Instytut Biologii Doświadczalnej im. Marcelego Nenckiego
      Warsaw, Masovian Voivodeship, Poland
  • 2005
    • Hospital Pedro Hispano
      Senhora da Hora, Porto, Portugal
    • University of Castilla-La Mancha
      • Laboratorio de Neuroanatomía Humana
      Ciudad Real, Castille-La Mancha, Spain
  • 2003
    • University of Wisconsin, Madison
      • Department of Neurology
      Madison, MS, United States
  • 2002
    • Institute for Molecular Medicine, Finland
      Helsinki, Southern Finland Province, Finland
  • 1989–2001
    • Kuopio University Hospital
      • Department of Neurology
      Kuopio, Province of Eastern Finland, Finland
  • 1999
    • University of California, Davis
      • Center for Neuroscience
      Davis, CA, United States
  • 1998
    • Universidad de Navarra
      • Department of Anatomy
      Pamplona, Navarre, Spain
  • 1992
    • University of California, San Diego
      • Department of Neurosciences
      San Diego, CA, United States
    • Hungarian Academy of Sciences
      Budapeŝto, Budapest, Hungary