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A chronic low dose of Δ(9)-tetrahydrocannabinol (THC) restores cognitive function in old mice

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Abstract

The balance between detrimental, pro-aging, often stochastic processes and counteracting homeostatic mechanisms largely determines the progression of aging. There is substantial evidence suggesting that the endocannabinoid system (ECS) is part of the latter system because it modulates the physiological processes underlying aging. The activity of the ECS declines during aging, as CB1 receptor expression and coupling to G proteins are reduced in the brain tissues of older animals and the levels of the major endocannabinoid 2-arachidonoylglycerol (2-AG) are lower. However, a direct link between endocannabinoid tone and aging symptoms has not been demonstrated. Here we show that a low dose of Δ(9)-tetrahydrocannabinol (THC) reversed the age-related decline in cognitive performance of mice aged 12 and 18 months. This behavioral effect was accompanied by enhanced expression of synaptic marker proteins and increased hippocampal spine density. THC treatment restored hippocampal gene transcription patterns such that the expression profiles of THC-treated mice aged 12 months closely resembled those of THC-free animals aged 2 months. The transcriptional effects of THC were critically dependent on glutamatergic CB1 receptors and histone acetylation, as their inhibition blocked the beneficial effects of THC. Thus, restoration of CB1 signaling in old individuals could be an effective strategy to treat age-related cognitive impairments.

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... Animal studies, however, have found opposing effects of cannabis in hippocampal volume and memory loss. For example, it was found that chronic (defined as 28 days of use) but low-dose exposure (3 mg/kg or lower) of THC increased the number of synapses in hippocampus and facilitated memory and learning functions in mature to older (12 and 18 months old) mice (Bilkei-Gorzo et al., 2017) and that a single injection of ultra-low-dose THC (0.002 mg/kg) to elderly mice (24 months old) achieves the same functional improvement (Sarne, Toledano, Rachmany, Sasson, & Doron, 2018). The difference between human and animal studies may be due to the potency of THC being examined, where higher doses may have led to the effects described in the human literature. ...
... Recent studies using old rodents reported that long-term low-dose exposure to THC (3 mg/kg for 28 days) enhances the synaptogenesis and the level of dendritic spine density in hippocampal neurons of 12-to 18-month-old mice (Bilkei-Gorzo et al., 2017), and even a single injection of the low-dose THC (0.002 mg/kg) may normalize memory and learning impairment of 24-month-old mice (Sarne et al., 2018). The mechanism of action in the above-mentioned benefits in synaptogenesis is dependent on the agonistic effect of endocannabinoid upon BDNF signaling (Berghuis et al., 2005;Mulder et al., 2008). ...
... Both acute (7 days) and chronic (21 days) applications of low-dose (1.5 mg/kg) THC was also reported to facilitate steps in neurogenesis (Suliman, Taib, Moklas, & Basir, 2018). The similar treatment using THC (3 mg/kg) for a longer time (28 days) reversed age-related deficits in learning and memory as well as enhancing synaptogenesis in the hippocampus (Bilkei-Gorzo et al., 2017). Even using a single injection of ultra-low-dose THC (0.002 mg/kg) in mice was capable of increasing tissue volume of the posterior hippocampus, which is involved in spatial memory and learning functions (Sarne et al., 2018). ...
Article
Given the aging Baby Boomer generation, changes in cannabis legislation, and the growing acknowledgment of cannabis for its therapeutic potential, it is predicted that cannabis use in the older population will escalate. It is, therefore, important to determine the interaction between the effects of cannabis and aging. The aim of this report is to describe the link between cannabis use and the aging brain. Our review of the literature found few and inconsistent empirical studies that directly address the impact of cannabis use on the aging brain. However, research focused on long-term cannabis use points toward cumulative effects on multimodal systems in the brain that are similarly affected during aging. Specifically, the effects of cannabis and aging converge on overlapping networks in the endocannabinoid, opioid, and dopamine systems that may affect functional decline particularly in the hippocampus and prefrontal cortex, which are critical areas for memory and executive functioning. To conclude, despite the limited current knowledge on the potential interactive effects between cannabis and aging, evidence from the literature suggests that cannabis and aging effects are concurrently present across several neurotransmitter systems. There is a great need for future research to directly test the interactions between cannabis and aging.
... In the hippocampus, cannabis causes dysregulation of the excitatory/inhibitory neurotransmission [38,39] and this misbalance modifies cognitive process. Besides, there are studies showing that the effect of cannabinoids change according to animal development stage, presenting more deleterious effects in the pubertal phase in relation to the adult phase [40,41], with improved cognitive performance by Δ 9 -THC exposure being described in older animals [42]. Along with this, Suliman et al (2018) observed that the use of Δ 9 -THC induces neurogenesis in rats [43], and positive effects on cognition were observed in animal models of chronic cerebral hypoperfusion [44] and Alzheimer's disease [45,46]. ...
... The association between cannabinoids administration and impairments in spatial memory are controversial. While some authors observed impairment [59][60][61], others have only shown deficits at doses higher than the one used in the present study [62], no impairment [40], or even an improvement in older animals [42]. In our drug schedule, subtle cognitive impairment was observed only in acquisition for WIN-2 treated group during the training protocol (2 mg/kg, 8 h before the test and start 7 days before task), as evidenced by a longer cumulative path Fig. 8. Effects of WIN-55,212-2 (2 mg/kg) on mRNA expression of genes endocannabinoid system of the acquisition group in prefrontal cortex. ...
... Several studies on the chronic use of cannabinoids have pointed to the stage of development of the animals as an important factor. Cognitive impairments were commonly observed in young animals [42,80], whereas in adult animals the effects may be variable, with impairments being observed by some studies [81,82] but not others [41,83]. Although there is an apparent contradiction, the effects of cannabinoid drugs are not completely understood, and factors such as the cannabinoid biphasic effect [84,85], the developmental stage or the physiological state of the individual [86,87] may, indeed, result in differential effects. ...
Article
The endocannabinoid system is capable of modulating multiple physiological brain functions including learning and memory. Moreover, there is evidence that the processes of acquisition and consolidation have distinct biological basis. We used the cannabinoid agonist WIN 55,212-2 (WIN-2) to investigate whether chronic CB1 activation affects acquisition and consolidation differently by evaluating gene expression in the hippocampus (HIP) and prefrontal cortex (PFC). Swiss mice were treated with WIN-2 (2mg/kg) and submitted to the Morris water maze to evaluate different aspects of memory. We observed short-term memory impairment in acquisition of the spatial task while consolidation remained unchanged. In the PFC, animals that received WIN-2 prior to the task exhibited increased expression of the 2-AG synthesis enzyme diacylglycerol lipase and decreased levels of the degradation enzyme monoacylglycerol lipase, while mice that were treated after the task for the evaluation of consolidation exhibited the opposite profile. With respect to genes related to AEA metabolism, no correlation between the molecular and behavioral data could be established. In this sense, the cognitive impairment in the acquisition promoted by WIN-2 treatment may be related to a possible increase in the concentration of 2-AG in the PFC. Overall, this study confirms the relevance of the endocannabinoid system in the modulation of cognitive processes. A better understanding of the mechanisms underlying endocannabinoids roles in cognition could provide guidance for the development of treatments to reduce the cognitive deficits caused by drug abuse.
... In contrast, a recent study found that high CBD products may be linked with poorer cognitive function in adults using opioid medicine for chronic pain [15]. Emerging evidence also suggests that delta-9-tetrahydrocannabinol (THC), despite its known psychoactive properties, may reverse cognitive impairment in mice models when administered in low doses [16]. These beneficial effects may be unique to exposure in old ages [16]. ...
... Emerging evidence also suggests that delta-9-tetrahydrocannabinol (THC), despite its known psychoactive properties, may reverse cognitive impairment in mice models when administered in low doses [16]. These beneficial effects may be unique to exposure in old ages [16]. ...
... In particular, consistent findings from animal and human studies show that THC, the main psychoactive component of cannabis [34], causes neurotoxic changes in brain regions rich with cannabinoid receptors hence promotes persistent changes in brain structure and cognitive deficits [35]. Nevertheless, emerging evidence from mice models point to a possible differential effects of cannabis by age of use, such that low doses of THC impairs brain function in young animals but improves cognitive function and brain structure in old mice [16,36]. ...
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Introduction and aims: Cannabis exposure is becoming more common in older age but little is known about how it is associated with brain health in this population. This study assesses the relationship between long-term medical cannabis (MC) use and cognitive function in a sample of middle-aged and old chronic pain patients. Design and methods: A cross-sectional study was conducted among chronic pain patients aged 50+ years who had MC licenses (n = 63) and a comparison group who did not have MC licenses (n = 62). CogState computerised brief battery was used to assess cognitive performance of psychomotor reaction, attention, working memory and new learning. Regression models and Bayesian t-tests examined differences in cognitive performance in the two groups. Furthermore, the associations between MC use patterns (dosage, cannabinoid concentrations, length and frequency of use and hours since last use) with cognition were assessed among MC licensed patients. Results: Mean age was 63 ± 6 and 60 ± 5 years in the non-exposed and MC patients, respectively. Groups did not significantly differ in terms of cognitive performance measures. Furthermore, none of the MC use patterns were associated with cognitive performance. Discussion and conclusions: These results suggest that use of whole plant MC does not have a widespread impact on cognition in older chronic pain patients. Considering the increasing use of MC in older populations, this study could be a first step towards a better risk-benefit assessment of MC treatment in this population. Future studies are urgently needed to further clarify the implications of late-life cannabis use for brain health.
... For example, a decrease in both endocannabinoids and CB1 was found in the brain tissues of older animals (Wang et al., 2003;Piyanova et al., 2015). Restoration of CB1 signaling has been shown to reverse the agerelated decline in cognitive performance of old mice (Murphy et al., 2012;Bilkei-Gorzo et al., 2017). ...
... For example, mice lacking CB1 showed an accelerated age-dependent memory impairment, accompanied by a loss of principal neurons in the hippocampus and enhanced neuroinflammation (Bilkei-Gorzo et al., 2005;Albayram et al., 2011). Further evidence demonstrated that activation of CB1 by a chronic treatment of low dose of 9-tetrahydrocannabinol restored cognitive function in old mice, by upregulating genes with anti-aging and memory-promoting effects (Bilkei-Gorzo et al., 2017). Allied to this, in the present study, we have observed AEA (1 µM) applied locally restored the inhibited hippocampal LTP in a CB1 dependent manner in D-gal induced aging rats (Figure 3). ...
... Moreover, we have observed a dual act of CB1 activation on LTP induction:CB1 agonist facilitates LTP in D-gal-induced aging brain but impairs LTP in young brain (Figure 3). It is consistent with the study which showed cannabinoid treatment worsened memory performance in young mice but restored cognitive deficits in old animals (Bilkei-Gorzo et al., 2017). It has been demonstrated that endocannabinoid can impair hippocampal LTP through presynaptic inhibition of neurotransmitters essential for memory and learning processes (Katona and Freund, 2012;Basavarajappa et al., 2014). ...
Article
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Imbalance in redox homeostasis is a major cause of age-related cognitive impairment. The endocannabinoid system (ECS) is a key player in regulating synaptic transmission, plasticity and memory. Increasing evidence indicates an important interplay between the two systems. However, how excessive oxidative stress could alter ECS and that, in turn, impairs its modulatory role in synaptic plasticity and cognitive function remains elusive. In the present study, we examined this causal link in D-galactose-induced oxidative rats. First, the reactive oxygen species generating enzymes, especially nitric oxide synthase (NOS), indeed show an elevated expression in D-galactose-treated rats, and this was correlated to an impaired hippocampal long-term potentiation (LTP) and spatial memory loss in animal behavioral tests. Second, the cannabinoid receptor type I (CB1)-mediated signaling is known to regulate synaptic plasticity. We show that a decrease in CB1 and increase in degradation enzymes for CB1 ligand endocannabinoid anandamide all occurred to D-galactose-treated rats. Surprisingly, application of low-dose anandamide, known to reduce LTP under physiological condition, now acted to enhance LTP in D-galactose-treated rats, most likely resulted from the inhibition of GABAergic synapses. Furthermore, this reversal behavior of CB1-signaling could be fully simulated by a NOS inhibitor, diphenyleneiodonium. These observations suggest that interaction between redox dysfunction and ECS should contribute significantly to the impaired synaptic plasticity and memory loss in D-galactose-treated rats. Therefore, therapies focusing on the balance of these two systems may shed lights on the treatment of age-related cognitive impairment in the future.
... The three studies administered different doses of THC, intraperitoneally (either by injection or osmotic minipump). Bilkei-Gorzo et al. (2017) administered 3 mg/kg THC per day for 28 days, whereas Aso, Andrés-Benito, and Ferrer (2016) administered a daily injection of THC and CBD in a 1:1 ratio (0.75 mg/kg) for 5 weeks. Conversely, Sarne, Toledano, Rachmany, Sasson, and Doron (2018) exmained the effects of a single, 0.002 mg/kg injection of THC on cognition. ...
... In contrast to the human studies, a chronic low dose of THC (3 mg/kg/day for 28 days) improved memory, spatial learning, and flexibility in mature and old mice (12 and 18 months; Bilkei-Gorzo et al., 2017), whereas a single, extremely low dose (0.002 mg/kg) improved memory performance and spatial learning and was associated with a volumetric increase in entorhinal cortex, prefrontal cortex, and posterior hippocampus, in very old mice (24 months; Sarne et al., 2018). The increase in the volume of the posterior hippocampus seen in Sarne et al. (2018) is at odds with the hippocampal thinning observed in Burggren et al. (2018) and null effects seen in Thayer et al. (2019). ...
Article
Background Older adults (≥50 years) represent the fastest-growing population of people who use cannabis, potentially due to the increasing promotion of cannabis as medicine by dispensaries and cannabis websites. Given healthy aging and cannabis use are both associated with cognitive decline, it is important to establish the effects of cannabis on cognition in healthy aging. Objective This systematic scoping review used preferred reporting items for systematic reviews and meta-analyses guidelines to critically examine the extent of literature on this topic and highlight areas for future research. Method A search of six databases (PubMed, EMBASE, PsycINFO, Web of Science, Family and Society Studies Worldwide, and CINAHL) for articles published by September 2019, yielded 1,014 unique results. Results Six articles reported findings for older populations (three human and three rodent studies), highlighting the paucity of research in this area. Human studies revealed largely null results, likely due to several methodological limitations. Better-controlled rodent studies indicate that the relationship between ∆9-tetrahydrocannabinol (THC) and cognitive function in healthy aging depends on age and level of THC exposure. Extremely low doses of THC improved cognition in very old rodents. Somewhat higher chronic doses improved cognition in moderately aged rodents. No studies examined the effects of cannabidiol (CBD) or high-CBD cannabis on cognition. Conclusions This systematic scoping review provides crucial, timely direction for future research on this emerging issue. Future research that combines neuroimaging and cognitive assessment would serve to advance understanding of the effects of age and quantity of THC and CBD on cognition in healthy aging.
... A chronic low dose of THC showed differential effects in mice, boosting performance in older animals while dropping performance in younger mice. 51 This low dose regulated CB 1 gene transcription in a protective and cognitive performanceenhancing manner, and this effect was absent in CB 1 knockout animals. In addition, THC may have a biphasic effect on cognition, or even procognitive effects associated with acetylcholinesterase inhibition. ...
... 62 Finally, results from this study echo other recent research reporting that medical cannabis use may be associated with improved executive functioning, potentially as a result of reduced symptom burden and improved well-being. 51 This calls into question whether ''impairment'' or ''intoxication'' associated with recreational use is a valid descriptor for medical use. Prospective studies using standardized ...
Article
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Objectives: There is a rapidly evolving legal and medical culture around cannabis, with corresponding changes in the demographics of users. For instance, the percentage of the aging population accessing cannabis is growing substantially, outpacing other age groups. The goals of this study were to describe the acute effects of cannabis, subjective experiences of withdrawal, and beliefs around the addictiveness of cannabis, as well as to determine whether these effects differ as a function of age or reason for use (medical vs. recreational use). It was hypothesized that medical users and younger users would report fewer adverse effects. Subjects: Survey responses from 2905 cannabis users were analyzed. Results: Hierarchical logistic regression analyses were used to compare group percentages after statistically controlling for confounding differences in their demographic and cannabis use characteristics. The most commonly endorsed acute effects were improved sleep, more calm/peaceful, desire to eat, more creative, and dry mouth; while the most commonly endorsed withdrawal symptoms were irritability, insomnia, and anxiety. Relative to recreational users, medical users were less likely to report undesirable acute effects but were more likely to report undesirable withdrawal symptoms. Older (50+) individuals reported fewer undesirable acute effects and withdrawal symptoms compared with younger users (18-29). Only 17% of the total sample reported believing that cannabis is addictive, and this did not vary as a function of reason for use. Conclusions: Older people and medical users appear to experience acute and withdrawal effects of cannabis differently than recreational and younger users, perhaps because these groups benefit more from the medicinal properties of cannabis. These data can provide descriptive information to help inform health care providers and potential consumers about effects of cannabis use.
... CB1-KO mice show age-dependent acceleration of cognitive decline with a significant neuronal loss in hippocampal CA1 and CA3 region (Albayram et al., 2011;Bilkei-Gorzo et al., 2005). A chronic low dose Δ 9 -tetrahydrocannabinol (THC) treatment restores learning ability, synapse density and gene expression profile in old animals to those typical to young individuals (Bilkei-Gorzo et al., 2017). These observations raise the possibility that CB1 activity might be critical for neuronal integrity and memory performance through lifespan, however the causative link between CB1 activity and neuronal homeostasis is still missing. ...
... Consistently, memory and learning in CB1-KO rapidly decreases with advancing age, while in young ages, they perform cognitive tasks as well or in some models even better than age-matched WT controls (Bilkei-Gorzo et al., 2005). CB1 agonist THC reverses age-dependent memory deficits, but these THC effects are abolished in CB1-KO (Bilkei-Gorzo et al., 2017). Altogether, these findings suggest that CB1 receptor may have differential effects on cellular, physiological and behavioral events in the CNS depending on the age of animals. ...
Article
Endocannabinoid system activity contributes to the homeostatic defense against aging and thus may counteract the progression of brain aging. The cannabinoid type 1 (CB1) receptor activity declines with aging in the brain, which impairs neuronal network integrity and cognitive functions. However, the underlying mechanisms that link CB1 activity and memory decline remain unknown. Mitochondrial activity profoundly influences neuronal function, therefore age-dependent mitochondrial activity change is one of the known hallmarks of brain aging. As CB1 receptor is expressed on mitochondria and may regulate neuronal energy metabolism in hippocampus, we hypothesized that CB1 receptors might influence mitochondria in hippocampal neurons. We found that CB1 receptor significantly affected mitochondrial autophagy (mitophagy) and morphology in an age-dependent manner. We also found that Serine 65-phosphorylated ubiquitin, a key marker for mitophagy, was reduced in adult CB1-deficient mice (CB1-KO) compared to those in wild type controls, particularly in CA1 pyramidal cell layer. Transmission electron microscopy (TEM) analysis showed reduced mitophagy-like events in hippocampus of adult CB1-KO. TEM analysis also showed an increase in thin and elongated mitochondria in hippocampal neurons of adult CB1-KO. 3D reconstruction revealed that mitochondrial morphology in adult CB1-KO was altered as represented by an enhanced density of elongated and interconnected mitochondria. Altogether, these findings suggest that reduced CB1 signaling in CB1-KO mice leads to reduced mitophagy and abnormal mitochondrial morphology in hippocampal neurons during aging. These mitochondrial changes might be due to the impairments in mitochondrial quality control system, which links age-related decline in CB1 activity and impaired memory.
... There is emerging evidence that cannabis use may buffer the deleterious neuroimmune effects of high inflammation (O'Sullivan and Kendall 2010;Bilkei-Gorzo et al. 2017;Rizzo et al. 2019;Ellis et al. 2020;Henriquez et al. 2020;Watson et al. 2020). This may occur through cannabinoid (CB) 1 receptor-mediated dampening of glutamatergic excitotoxicity and CB 2 receptor-mediated initiation of anti-inflammatory cascades (Rom and Persidsky 2013). ...
... Δ9-tetrahydroconnabinol (THC) effects on neurogenesis and memory are not linear, with low to moderate concentrations stimulating neurogenesis and high doses inhibiting neurogenesis and memory in multiple model systems. For example, THC provides protection from neurodegenerative processes by reducing inflammation in aged mouse models for neurodegenerative diseases but induces memory impairment in healthy mice, young or aged mice (Fishbein-Kaminietsky et al. 2014;Bilkei-Gorzo et al. 2017). Similarly, endocannabinoids exert neuroprotective effects through CB 1 in models for HIV Tat-induced neurotoxicity (Xu et al. 2017). ...
Article
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HIV infection and drug use intersect epidemiologically, and their combination can result in complex effects on brain and behavior. The extent to which drugs affect the health of persons with HIV (PWH) depends on many factors including drug characteristics, use patterns, stage of HIV disease and its treatment, comorbid factors, and age. To consider the range of drug effects, we have selected two that are in common use by PWH: methamphetamine and cannabis. We compare the effects of methamphetamine with those of cannabis, to illustrate how substances may potentiate, worsen, or even buffer the effects of HIV on the CNS. Data from human, animal, and ex vivo studies provide insights into how these drugs have differing effects on the persistent inflammatory state that characterizes HIV infection, including effects on viral replication, immune activation, mitochondrial function, gut permeability, blood brain barrier integrity, glia and neuronal signaling. Moving forward, we consider how these mechanistic insights may inform interventions to improve brain outcomes in PWH. This review summarizes literature from clinical and preclinical studies demonstrating the adverse effects of METH, as well as the potentially beneficial effects of cannabis, on the interacting systemic (e.g., gut barrier leakage/microbial translocation, immune activation, inflammation) and CNS-specific (e.g., glial activation/neuroinflammation, neural injury, mitochondrial toxicity/oxidative stress) mechanisms underlying HIV-associated neurocognitive disorders
... In opposition to concerns of cannabis exacerbating agerelated cognitive decline, preclinical evidence suggests that the main constituents of cannabis (i.e., delta-9tetrahydrocannabinol [THC] and cannabidiol [CBD]) may have neuroprotective properties in normal and pathological aging, particularly in Alzheimer's disease (AD). Recent in vivo and in vitro studies have shown that chronic low doses of THC paradoxically reverse age-related cognitive dysfunction in aged mice, promote hippocampal neurogenesis, and prevent neurodegenerative and neuroinflammatory processes in animal models of AD [13][14][15][16][17]. Clinical evidence of the neuroprotective benefits of cannabinoids in older adults and in dementia, however, is lacking. ...
Article
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Purpose of Review Older adults currently represent the fastest growing demographic of cannabis users, yet few studies have investigated the effects of cannabis use on cognitive functioning in aging. We conducted a systematic review of the recent literature examining cognitive outcomes associated with cannabis use in older adults, with and without neurocognitive disorders, to clarify the potential neuroprotective benefits or risks of cognitive decline in this population. Recent Findings We identified 26 studies examining cognitive outcomes associated with medical and recreational use of cannabis in healthy aging, dementia, Parkinson’s disease, multiple sclerosis, HIV, and pain populations. Although variability in the cannabis products used, outcomes assessed, and study quality limits the conclusions that can be made, modest reductions in cognitive performance were generally detected with higher doses and heavier lifetime use. Summary This review highlights the need for additional high-quality research using standardized, validated assessments of cannabis exposure and cognitive outcomes. Reliable measures and longitudinal data are necessary to better characterize the effects of cannabis use on cognitive aging, as well as differential effects of recreational and medical cannabis.
... Since Mgll inhibitors provide many of the beneficial effects observed with direct cannabinoid receptor agonists or cyclooxygenase inhibitors without exerting their respective unwanted side-effects, several animal studies have reported Mgll as a promising therapeutic target for AD to ameliorate AD-associated neuropathology and memory decline [10,11]. Interestingly, a recent report shows that 2-AG/eCBR signaling exhibits an age-dependent decline in activity that is associated with cognitive impairment [12,13]. Despite the promising therapeutic potential of Mgll against AD, there are no FDA-approved drugs targeting Mgll other than a couple of Mgll inhibitors currently in Phase II clinical trials [14]. ...
Article
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Rationale: Monoacylglycerol lipase (Mgll), a hydrolase that breaks down the endocannabinoid 2-arachidonoyl glycerol (2-AG) to produce arachidonic acid (ARA), is a potential target for neurodegenerative diseases, such as Alzheimer's disease (AD). Increasing evidence shows that impairment of adult neurogenesis by perturbed lipid metabolism predisposes patients to AD. However, it remains unknown what causes aberrant expression of Mgll in AD and how Mgll-regulated lipid metabolism impacts adult neurogenesis, thus predisposing to AD during aging. Here, we identify Mgll as an aging-induced factor that impairs adult neurogenesis and spatial memory in AD, and show that metformin, an FDA-approved anti-diabetic drug, can reduce the expression of Mgll to reverse impaired adult neurogenesis, prevent spatial memory decline and reduce β-amyloid accumulation. Methods: Mgll expression was assessed in both human AD patient post-mortem hippocampal tissues and 3xTg-AD mouse model. In addition, we used both the 3xTg-AD animal model and the CbpS436A genetic knock-in mouse model to identify that elevated Mgll expression is caused by the attenuation of the aPKC-CBP pathway, involving atypical protein kinase C (aPKC)-stimulated Ser436 phosphorylation of histone acetyltransferase CBP through biochemical methods. Furthermore, we performed in vivo adult neurogenesis assay with BrdU/EdU labelling and Morris water maze task in both animal models following pharmacological treatments to show the key role of Mgll in metformin-corrected neurogenesis and spatial memory deficits of AD through reactivating the aPKC-CBP pathway. Finally, we performed in vitro adult neurosphere assays using both animal models to study the role of the aPKC-CBP mediated Mgll repression in determining adult neural stem/progenitor cell (NPC) fate. Results: Here, we demonstrate that aging-dependent induction of Mgll is observed in the 3xTg-AD model and human AD patient post-mortem hippocampal tissues. Importantly, we discover that elevated Mgll expression is caused by the attenuation of the aPKC-CBP pathway. The accumulation of Mgll in the 3xTg-AD mice reduces the genesis of newborn neurons and perturbs spatial memory. However, we find that metformin-stimulated aPKC-CBP pathway decreases Mgll expression to recover these deficits in 3xTg-AD. In addition, we reveal that elevated Mgll levels in cultured adult NPCs from both 3xTg-AD and CbpS436A animal models are responsible for their NPC neuronal differentiation deficits. Conclusion: Our findings set the stage for development of a clinical protocol where Mgll would serve as a biomarker in early stages of AD to identify potential metformin-responsive AD patients to restore their neurogenesis and spatial memory.
... Preclinical studies have also suggested that the impact of repeated cannabis dosing on impairment levels may differ with age. Several studies in rats and mice have shown that prolonged cannabis use during adolescence can impair brain maturation and predispose to neurodevelopmental disorders ( Saravia et al., 2019 ;Zamberletti et al., 2015 ), whereas chronic exposure to low doses of cannabis restored cognitive function in old mice ( Bilkei-Gorzo et al., 2017 ). Also, the development of tolerance to THC induced motility was evident in young adult but not in aged mice ( Feliszek et al., 2016 ). ...
Article
Acute exposure to cannabis comes with neurocognitive impairment, leading to increased risk of human error and injury. Evidence however indicates that such acute effects are less prominent in chronic users, suggesting cannabis tolerance. Models of cannabis tolerance stress the importance of neurobiological or behavioral adaptations following repeated cannabis exposure. The pharmacodynamic model relates neuroadaptive changes in the brain to a blunted response to cannabis. Downregulation of CB1 receptors in chronic cannabis users has been associated with a normalization of dopaminergic output from the ventral tegmental area to the mesolimbic circuit, and a reduction of impairment during acute cannabis exposure. Such neuroadaptions are absent in occasional users, who show strong increments of dopamine and glutamate levels in the striatum, a loss of functional connectivity within the mesolimbic circuit and neurocognitive impairments when exposed to cannabis. Evidence for a behavioral model of cannabis tolerance that poses that users can have volitional control to overcome functional impairment during cannabis intoxication is relatively weak, and at best shows limited control over a limited number of behavioral functions. Cannabis tolerance is most likely to occur in users that consume high doses of cannabis continuously, at a high pace, for a prolonged period of time. Knowledge on frequency, dose and duration of cannabis use that is needed to achieve, maintain or lessen tolerance however is very limited, but will be of importance in the context of cannabis therapeutics and in legal settings when evaluating the impact of cannabis exposure on human function.
... The anti-inflammatory effects of THC may contribute to some of its protection against neurodegenerative diseases (Ramírez et al., 2005). While high doses of THC can cause memory deficits (Varvel et al., 2001), low dose exposure to THC can slow or halt Alzheimer's disease progression by reducing amyloid beta (Cao et al., 2014), as well as restoring cognitive function in old mice (Bilkei-Gorzo et al., 2017). Together, with previous findings that high dose exposure to THC in utero causes disrupted brain development and other teratogenic effects (Carty et al., 2018;Fish et al., 2019), it is easy to hypothesize that the dose and the age of exposure determine the beneficial versus detrimental effects of THC on neuronal health. ...
Article
Increased availability of cannabis and cannabinoid-containing products necessitates the need for an understanding of how these substances influence aging. In this study, zebrafish (Danio rerio) were exposed to different concentrations of THC (0.08, 0.4, 2 μM) during embryonic-larval development and the effects on aging were measured 30 months later and in the offspring of the exposed fish (F1 generation). Exposure to 0.08 μM THC resulted in increased male survival at 30 months of age. As the concentration of THC increased, this protective effect was lost. Treatment with the lowest concentration of THC also significantly increased egg production, while higher concentrations resulted in impaired fecundity. Treatment with the lowest dose of THC significantly reduced wet weight, the incidence of kyphosis, and the expression of several senescence and inflammatory markers (p16ink4ab, tnfα, il-1β, il-6, pparα and pparγ) in the liver, but not at higher doses indicating a biphasic or hormetic effect. Exposure to THC did not affect the age-related reductions in locomotor behavior. Within the F1 generation, many of these changes were not observed. However, the reduction in fecundity due to THC exposure was worse in the F1 generation because offspring whose parents received high dose of THC were completely unable to reproduce. Together, our results demonstrate that a developmental exposure to THC can cause significant effects on longevity and healthspan of zebrafish in a biphasic manner.
... THC, a psychoactive component of cannabis, reversibly disrupts short-term memory and dose-dependently impairs attention and cognition [333][334][335][336][337][338]; however, when chronically administered at low doses, THC improves neurological function in aged animals and promotes hippocampal neurogenesis while reducing neurodegeneration in animal models of AD [99, EPMA Journal [339][340][341][342][343]. A recent open-label pilot study showed THC oil (7.5 mg twice daily) was well tolerated and reduced ADassociated delusions, agitation/aggression, irritability, apathy, and sleep disturbances in 11 AD patients [344]. ...
Article
Cannabis-inspired medical products are garnering increasing attention from the scientific community, general public, and health policy makers. A plethora of scientific literature demonstrates intricate engagement of the endocannabinoid system with human immunology, psychology, developmental processes, neuronal plasticity, signal transduction, and metabolic regulation. Despite the therapeutic potential, the adverse psychoactive effects and historical stigma, cannabinoids have limited widespread clinical application. Therefore, it is plausible to weigh carefully the beneficial effects of cannabinoids against the potential adverse impacts for every individual. This is where the concept of “personalized medicine” as a promising approach for disease prediction and prevention may take into the account. The goal of this review is to provide an outline of the endocannabinoid system, including endocannabinoid metabolizing pathways, and will progress to a more in-depth discussion of the therapeutic interventions by endocannabinoids in various neurological disorders.
... It shows that activation of this receptor is an example of hormesis, with high doses of agonists exhibiting deleterious and low doses-a beneficial effect on cognitive functions. Moreover, in the case of the modulation of CB1 transmission, the age is also a very important factor [150]. Additionally, patients using medicinal Cannabis improved their cognitive performance after chronic administration of this plant. ...
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The endocannabinoid system (ECS) is one of the most crucial systems in the human organism, exhibiting multi-purpose regulatory character. It is engaged in a vast array of physiological processes, including nociception, mood regulation, cognitive functions, neurogenesis and neuroprotection, appetite, lipid metabolism, as well as cell growth and proliferation. Thus, ECS proteins, including cannabinoid receptors and their endogenous ligands’ synthesizing and degrading enzymes, are promising therapeutic targets. Their modulation has been employed in or extensively studied as a treatment of multiple diseases. However, due to a complex nature of ECS and its crosstalk with other biological systems, the development of novel drugs turned out to be a challenging task. In this review, we summarize potential therapeutic applications for ECS-targeting drugs, especially focusing on promising synthetic compounds and preclinical studies. We put emphasis on modulation of specific proteins of ECS in different pathophysiological areas. In addition, we stress possible difficulties and risks and highlight proposed solutions. By presenting this review, we point out information pivotal in the spotlight of ECS-targeting drug design, as well as provide an overview of the current state of knowledge on ECS-related pharmacodynamics and show possible directions for needed research.
... It is therefore not unreasonable to speculate that 9-THC and CBD effects may vary depending on patients' aging and disease progression . Limited preclinical evidence suggests that low 9-THC doses may reverse the age-related decline in cognitive performance, while still impairing performance in youth (Bilkei-Gorzo et al., 2017). On the other hand, CBD does not seem to produce additional benefit as add-on treatment for psychosis patients in their middle age (≥45 years) (Boggs et al., 2018), while ameliorating psychosis and tending to improve cognition (McGuire et al., 2018), as well as normalizing underlying neurophysiological processes in earlier phases of the disorder (Figure 1). ...
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Research evidence suggests a dose–response relationship for the association between cannabis use and risk of psychosis. Such relationship seems to reflect an increased risk of psychosis not only as a function of frequent cannabis use, but also of high-potency cannabis use in terms of concentration of Δ-9-tetrahydrocannabinol (Δ9-THC), its main psychoactive component. This finding would be in line with the evidence that Δ9-THC administration induces transient psychosis-like symptoms in otherwise healthy individuals. Conversely, low-potency varieties would be less harmful because of their lower amount of Δ9-THC and potential compresence of another cannabinoid, cannabidiol (CBD), which seems to mitigate Δ9-THC detrimental effects. A growing body of studies begins to suggest that CBD may have not only protective effects against the psychotomimetic effects of Δ9-THC but even therapeutic properties on its own, opening new prospects for the treatment of psychosis. Despite being more limited, evidence of the effects of cannabis on cognition seems to come to similar conclusions, with increasing Δ9-THC exposure being responsible for the cognitive impairments attributed to recreational cannabis use while CBD preventing such effects and, when administered alone, enhancing cognition. Molecular evidence indicates that Δ9-THC and CBD may interact with cannabinoid receptors with almost opposite mechanisms, with Δ9-THC being a partial agonist and CBD an inverse agonist/antagonist. With the help of imaging techniques, pharmacological studies in vivo have been able to show opposite effects of Δ9-THC and CBD also on brain function. Altogether, they may account for the intoxicating and therapeutic effects of cannabis on psychosis and cognition.
... The mRNA and protein levels and protein activity of FAAH are increased in late-onset (age > 65) Alzheimer's disease (LOAD) patients 86 . Low doses of THC can reverse the age-related decline in cognitive performance in older animals, accompanied by enhanced expression of synaptic markers and increased hippocampal spine density 87 . In summary, the activity of the ECS declines during aging with decreased receptor levels and activity and decreased levels of an endogenous cannabinoid ligand because of increased levels of its catabolizing enzyme. ...
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Beyond being one the most widely used psychoactive drugs in the world, cannabis has been identified as an environmental risk factor for psychosis. Though the relationship between cannabis use and psychiatric disorders remains controversial, consistent association between early adolescent cannabis use and the subsequent risk of psychosis suggested adolescence may be a particularly vulnerable period. Previous findings on gene by environment interactions indicated that cannabis use may only increase the risk for psychosis in the subjects who have a specific genetic vulnerability. The type 1 cannabinoid receptor (CB1), encoded by the CNR1 gene, is a key component of the endocannabinoid system. As the primary endocannabinoid receptor in the brain, CB1 is the main molecular target of the endocannabinoid ligand, as well as tetrahydrocannabinol (THC), the principal psychoactive ingredient of cannabis. In this study, we have examined mRNA expression and DNA methylation of CNR1 in human prefrontal cortex (PFC), hippocampus, and caudate samples. The expression of CNR1 is higher in fetal PFC and hippocampus, then drops down dramatically after birth. The lifespan trajectory of CNR1 expression in the DLPFC differentially correlated with age by allelic variation at rs4680, a functional polymorphism in the COMT gene. Compared with COMT methionine158 carriers, Caucasian carriers of the COMT valine158 allele have a stronger negative correlation between the expression of CNR1 in DLPFC and age. In contrast, the methylation level of cg02498983, which is negatively correlated with the expression of CNR1 in PFC, showed the strongest positive correlation with age in PFC of Caucasian carriers of COMT valine158. Additionally, we have observed decreased mRNA expression of CNR1 in the DLPFC of patients with schizophrenia. Further analysis revealed a positive eQTL SNP, rs806368, which predicted the expression of a novel transcript of CNR1 in human DLPFC, hippocampus and caudate. This SNP has been associated with addiction and other psychiatric disorders. THC or ethanol are each significantly associated with dysregulated expression of CNR1 in the PFC of patients with affective disorder, and the expression of CNR1 is significantly upregulated in the PFC of schizophrenia patients who completed suicide. Our results support previous studies that have implicated the endocannabinoid system in the pathology of schizophrenia and provided additional insight into the mechanism of increasing risk for schizophrenia in the adolescent cannabis users.
... Although previous studies examined the acute behavioral effects of cannabinoids in rodents, only a few concerned their lasting effects at different developmental ages. Prior experiments with rodents documented cognitive impairment [14,[51][52][53][54][55], lack of effects [56], or even enhanced spatial memory [57] after THC administration. Furthermore, some studies indicated that the endocannabinoid system plays a neuroprotective role [58][59][60][61]. ...
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Research demonstrates that adolescents differ from adults in their response to drugs of abuse. The aim of the present study was to examine the influence of ethanol, Δ9-tetrahydrocannabinol hydrochloride (THC), and a combination of these drugs given during adolescence on spatial memory in adolescent and adult rats. Thus, adolescent rats (postnatal day (PND) 30) were subjected to the following groups: 0.9% NaCl; 1.5 g/kg ethanol; 1.0 mg/kg THC; 1.5 g/kg ethanol + 1.0 mg/kg THC. Rats received drug injection four times at three-day intervals. One day after the last injection, half of the treated animals were tested in the Barnes maze task, whereas the remaining animals were tested on PND 70. Results show that there was a significant age effect on spatial memory in the Barnes maze task after these drug administrations. Adolescent animals demonstrated more potent deficits in the spatial learning and memory (probe trial) and in cognitive flexibility (reversal learning) than did adults. However, in adult rats that received these drugs in adolescence, memory decline was observed only after ethanol and ethanol + THC administration. Thus, our results are important in understanding the deleterious impact of THC and/or ethanol abuse during adolescence on memory function across the lifespan (adolescent versus adult).
... However, pharmacological manipulation of endocannabinoid signaling does not appear to produce consistent effects across the lifespan. This is evidenced in studies where chronic infusion of the phytocannabinoid Δ-9-tetrahydrocannabinol (THC) was shown to enhance cognition in aged mice at doses which impair younger animals' performance 5 . ...
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Use of cannabis and cannabinoid-containing substances is increasing among geriatric patients, despite relatively sparse preclinical evidence in aged models. To better understand the effects of exogenous cannabinoids on aging male and female rodents, we compared the age- and dose-dependent physiological and behavioral effects of the synthetic cannabinoid CP55940 in young–adult and aged C57BL/6 mice. Locomotion, body temperature, thermal nociception, and fecal output were measured following CP55940 administration. Our findings indicate that CP55940 is more potent and efficacious in older mice, evidenced by exaggerated antinociception and locomotor inhibition when compared to younger adult mice. In addition, we report that low doses of CP55940 paradoxically stimulate locomotion in young–adult (4 m) mice; however, this hormesis-like response is not as evident in aged animals (21–24 m). These bidirectional effects appear to be mediated via the endocannabinoid CB1 and CB2 receptors.
... However, in WT mice, we noticed a delay in their learning abilities, although at the end of the training period all animals learned the task. Previously, a deleterious effect of cannabinoids had been observed in young mice following continuous administration of a low dose of Δ 9tetra-hydro-cannabinol, while mature or aged animals showed beneficial effects [45]. Interestingly, hippocampal gene expression changes paralleled those effects. ...
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Alzheimer’s disease (AD), the leading cause of dementia in the elderly, is a neurodegenerative disorder marked by progressive impairment of cognitive ability. Patients with AD display neuropathological lesions including senile plaques, neurofibrillary tangles, and neuronal loss. There are no disease-modifying drugs currently available. With the number of affected individuals increasing dramatically throughout the world, there is obvious urgent need for effective treatment strategy for AD. The multifactorial nature of AD encouraged the development of multifunctional compounds, able to interact with several putative targets. Here, we have evaluated the effects of two in-house designed cannabinoid receptors (CB) agonists showing inhibitory actions on β-secretase-1 (BACE-1) (NP137) and BACE-1/butyrylcholinesterase (BuChE) (NP148), on cellular models of AD, including immortalized lymphocytes from late-onset AD patients. Furthermore, the performance of TgAPP mice in a spatial navigation task was investigated following chronic administration of NP137 and NP148. We report here that NP137 and NP148 showed neuroprotective effects in amyloid-β-treated primary cortical neurons, and NP137 in particular rescued the cognitive deficit of TgAPP mice. The latter compound was able to blunt the abnormal cell response to serum addition or withdrawal of lymphoblasts derived from AD patients. It is suggested that NP137 could be a good drug candidate for future treatment of AD.
... 14,15 However, recent studies have shown that THC promotes hippocampal neurogenesis and restores memory and cognitive function in aged animals. 16,17 Despite the beneficial effects of THC, its psychoactive effects have limited the medical use of cannabis. On the contrary, CBD is known as the main nonpsychoactive component of cannabis and has shown anti-inflammatory, immunosuppressive, analgesic, and anxiolytic effects. ...
... The use of cannabimimetics as CEs seems counter-intuitive as both pre-clinical and human studies have found a link between consumption of cannabinoids and long-term deficits of cognitive functions, especially high-order cognitive functions (83)(84)(85)(86)(87)(88). However, recent pre-clinical studies have found that delta-9-THC can improve cognitive performances in rats (89) and mice (90). THC, in fact, appears to promote hippocampal neurogenesis to prevent neurodegenerative processes occurring in animal models of Alzheimer's disease, to protect from inflammation-induced cognitive damage, and to restore memory and cognitive function in old mice (91). ...
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Background: There is growing availability of novel psychoactive substances (NPS), including cognitive enhancers (CEs) which can be used in the treatment of certain mental health disorders. Whilst treating cognitive deficit symptoms in neuropsychiatric or neurodegenerative disorders using CEs might have significant benefits for patients, the increasing recreational use of these substances by healthy individuals raises many clinical, medico-legal and ethical issues. Moreover, it has become very challenging for clinicians to keep up-to-date with CEs currently available as comprehen-sive official lists do not exist. Methods: Using a web crawler (NPSfinder®), the present study aimed at assessing psychonaut fora/ platforms to better understand the online situation regarding CEs. We compared NPSfinder® entries with those from the European Monitoring Centre for Drugs and Drug Addiction (EMCDDA), and from the United Nations Office on Drugs and Crime (UNODC) NPS databases, up to spring 2019. Any substance that was iden-tified by NPSfinder® was considered a CE if it was either described as having nootropic abilities by psychonauts or if it was listed among the known CEs by Froestl and colleagues. Results: A total of 142 unique CEs were identified by NPSfinder®. They were divided into 10 categories, including plants/ herbs/products (29%), prescribed drugs (17%), image and performance enhancing drugs (IPEDs) (15%), psychostimulants (15%), miscellaneous (8%), Phenethylamines (6%), GABAergic drugs (5%), cannabimimetic (4%), tryptamines derivatives (0.5%) and piperazine derivatives (0.5%). A total of 105 chemically different substances were uniquely identified by NPSfinder®. Only one CE was uniquely identified by the EMCDDA; no CE was uniquely identified by the UNODC. Conclusions: These results show that NPSfinder® is helpful as part of an Early Warning System, which could update clinicians with the growing numbers and types of nootropics in the increasingly difficult-to-follow internet world. Improving clinicians’ knowledge of NPS could promote more effective prevention and harm reduction measures in clinical settings.
... For example, murine models lacking the CB 1 cannabinoid receptors display an early onset of learning disturbances linked with aging. These findings have contributed to the design of drugs aimed to manage age-related human pathologies via the endocannabinoid system elements, such as the CB 1 cannabinoid receptors, anandamide, FAAH, AMT, amongst others [124][125][126][127][128][129][130][131][132]. We would like to describe a hypothetical framework regarding the likely modulatory role of the endocannabinoid system on sleep disorders in the elderly (Fig. 1). ...
Article
Aging is an inevitable process that involves changes along life in multiple neurochemical, neuroanatomical, hormonal systems, and many others. In addition, these biological modifications lead to an increase in age-related sickness such as cardiovascular diseases, osteoporosis, neurodegenerative disorders, and sleep disturbances, among others that affect activities of daily life. Demographic projections have demonstrated that aging will increase its worldwide rate in the coming years. The research on chronic diseases of the elderly is important to gain insights into this growing global burden. Novel therapeutic approaches aimed for treatment of age-related pathologies have included the endocannabinoid system as an effective tools since this biological system shows beneficial effects in preclinical models. However, and despite these advances, little has been addressed in the arena of the endocannabinoid system as option for treating sleep disorders in aging since experimental evidence suggests that some elements of the endocannabinoid system modulate the sleep-wake cycle. This article addresses this less-studied field, focusing on the likely perspective of the implication of the endocannabinoid system in the regulation of sleep problems reported in aged. We conclude that beneficial effects regarding the putative efficacy of the endocannabinoid system as therapeutic tools in aging is either inconclusive or still missing.
... In case endocannabinoid signaling is affected by the pathomechanisms, THC use might be beneficial (e.g., endocannabinoid signaling is reorganized in Alzheimer's disease, and low-dose THC treatment rescues dementia-like behavioral deficits in mouse models; refs. 131,132). Ultimately, and considering the recent introduction of plant-derived and synthetic preparations with extraordinarily high THC contents (130), we caution against their use in either pediatric care or upon incidental exposure of healthy children. ...
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Ongoing societal changes in views on medical and recreational roles of cannabis increased the use of concentrated plant extracts with a Δ9-tetrahydrocannabinol (THC) content of >90%. Even though prenatal THC exposure is widely considered adverse for neuronal development, equivalent experimental data for young age cohorts are largely lacking. Here, we administered plant-derived THC (1 or 5 mg/kg) to mice daily during postnatal days (P)5-16 and P5-35 and monitored its effects on hippocampal neuronal survival and specification by high resolution imaging and the hippocampal proteome by iTRAQ proteomics, respectively. We find that THC indiscriminately affects pyramidal cells and both cannabinoid receptor 1 (CB1R)+ and CB1R- interneurons by P16. THC particularly disrupted the expression of mitochondrial proteins (complexes I-IV), a change that had persisted even 4 months after the end of drug exposure. This was reflected by a THC-induced loss of membrane integrity occluding mitochondrial respiration and could be partially or completely rescued by pH stabilization, antioxidants, bypassed glycolysis, and targeting either mitochondrial soluble adenylyl cyclase or the mitochondrial voltage-dependent anion channel. Overall, THC exposure during infancy induces significant and long-lasting reorganization of neuronal circuits through mechanisms that, in a large part, render cellular bioenergetics insufficient to sustain key developmental processes in otherwise healthy neurons.
... Mice were anesthetized by intraperitoneal injection of 3% pentobarbital sodium (40 mg/kg), and serum samples were collected from the abdominal aorta and centrifuged at 3000 rpm for 10 min and stored at − 80 • C. Half of the kidney and colon tissues were removed on ice and fixed with neutral paraformaldehyde at room temperature for 48 h, cut into 4-μm sections, and embedded in paraffin, and the other half was directly stored at − 80 • C. The blood, urine, faeces, and kidney tissue samples of the four groups were tested together at the end of the 12th week. Although the mice in FMT-AS group were sacrificed 6 weeks later, they were still in a stable state before aging (Bilkei-Gorzo et al., 2017), and the four groups were raised in the same environment, so they were comparable. ...
Article
Ethnopharmacological relevance The combination of Astragalus membranaceus and Salvia miltiorrhiza (AS) is an effective prescription that is widely used to treat chronic kidney disease (CKD) clinically in traditional Chinese medicine. Our previous studies have shown that AS can alleviate early CKD through the "gut-kidney axis", but the regulatory role of AS in the "gut-kidney axis" in the middle and late stages of CKD caused by cyclosporin A-induced chronic nephrotoxicity (CICN) has remained unclear. Aim of the study To explore the protective effect of AS by regulating the intestinal flora to further control the miRNA-mRNA interaction profiles in CICN. Materials and methods Thirty-two mice were divided into four groups: Normal (N) (olive oil), Model (M) (CsA, 30 mg kg⁻¹ d⁻¹), AS (CsA + AS, 30 + 8.4 g kg⁻¹ d⁻¹) and FMT-AS (CsA + Faeces of AS group, 30 mg + 10 mL kg⁻¹ d⁻¹). The mice were treated for 6 weeks. Changes in renal function related metabolites were detected, pathological changes in the colon and kidney were observed, and 16S rDNA sequencing was performed on mouse faeces. In addition, miRNA and mRNA sequencing were performed on the kidney to construct differential expression (DE) profiles of the other 3 groups compared with group M. The target mRNAs among the DE miRNAs were then predicted, and an integrated analysis was performed with the DE mRNAs to annotate gene function by KEGG. DE miRNAs and DE mRNAs related to CICN in the overlapping top 20 KEGG pathways were screened and verified. Results Eight metabolites that could worsen renal function were increased in group M, accompanied by thickening of the glomerular basement membrane, vacuolar degeneration of renal tubules, and proliferation of collagen fibres, while AS and FMT-AS intervention amended these changes to varying degrees. Simultaneously, intestinal permeability increased, the abundance and diversity of the flora decreased, and the ratio of Firmicum to Bacteroides (F/B) increased in group M. The AS and FMT-AS treatments reversed the flora disorder and increased probiotics producing butyric acid and lactic acid, especially Akkermansia and Lactobacillus, which might regulate the 12 overlapping top 20 KEGG pathways, such as Butanoate metabolism, Tryptophan metabolism and several RF-related pathways, leading to the remission of renal metabolism. Finally, 15 DE miRNAs and 46 DE mRNAs were screened as the therapeutic targets, and the results coincided with the sequencing results. Conclusion AS could alleviate renal fibrosis and metabolism caused by CICN through the "gut-kidney axis". Probiotics such as Akkermansia and Lactobacillus were the primary driving factors, and the miRNA-mRNA interaction profiles, especially Butanoate metabolism and Tryptophan metabolism, may be an important subsequent response and regulatory mechanism.
... Test session takes advantage of the innate tendency of mice to explore novel unexplored areas (e.g., the previously blocked arm). The time spent in novel unexplored areas of each animal was measured [79][80][81] . Mice first tested 2-months after the last injury, and then were retested 6-months later in the same maze but in a different environment. ...
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Brain degeneration, including that caused by traumatic brain injury (TBI) often leads to severe bladder dysfunction, including incontinence and lower urinary tract symptoms; with the causes remaining unknown. Male C57BL/6J mice underwent repetitive moderate brain injury (rmdTBI) or sham injury, then mice received either cis P-tau monoclonal antibody (cis mAb), which prevents brain degeneration in TBI mice, or control (IgG). Void spot assays revealed age-dependent incontinence in IgG controls 8 months after injury, while cis mAb treated or sham mice showed no dysfunction. No obvious bladder pathology occurred in any group. Urodynamic cystometry in conscious mice revealed overactive bladder, reduced maximal voiding pressures and incontinence in IgG control, but not sham or cis mAb treated mice. Hyperphosphorylated tau deposition and neural tangle-like pathology occurred in cortical and hippocampal regions only of IgG control mice accompanied with post-traumatic neuroinflammation and was not seen in midbrain and hindbrain regions associated with bladder filling and voiding reflex arcs. In this model of brain degeneration bladder dysfunction results from rostral, and not hindbrain damage, indicating that rostral brain inputs are required for normal bladder functioning. Detailed analysis of the functioning of neural circuits controlling bladder function in TBI should lead to insights into how brain degeneration leads to bladder dysfunction, as well as novel strategies to treat these disorders.
... However, placebo-controlled experimental trials comparing the effects of THC relative to placebo on memory have reported discrepant findings, reporting no effects on memory (Ganon-Elazar and Akirav 2009;Geresu et al. 2016), memory enhancing (Amal et al. 2010;Bilkei-Gorzo et al. 2017), and memory-impairing effects (Yousefi et al. 2013;Santana et al. 2016;Goodman and Packard 2014). Similarly, while cannabidiol has been postulated to have cognitive enhancing effects (Englund et al. 2013b), the evidence regarding the therapeutic potential of these compounds is largely mixed (McGuire et al. 2017;Boggs et al. 2018;Rosenberg et al. 2017). ...
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Rationale: While cannabis-based medicinal products have been shown to be effective for numerous neurological and psychiatric disorders, the evidence base regarding their adverse cognitive effects is poorly understood. The cannabinoid 1 receptor modulates memory performance via intracellular and extracellular mechanisms that alter synaptic transmission and plasticity. While previous literature has consistently shown that chronic cannabis users exhibit marked cognitive impairments, mixed findings have been reported in the context of placebo-controlled experimental trials. It is therefore unclear whether these compounds inherently alter cognitive processes or whether individuals who are genetically predisposed to use cannabis may have underlying cognitive deficits. Objective: We conducted a meta-analysis to investigate the effects of full and partial cannabinoid 1 receptor (CB1R) agonists, antagonists, and negative allosteric modulators on non-spatial and spatial memory. Methods: In accordance with the PRISMA guidelines, the EMBASE, MEDLINE, and PsycINFO databases were systematically searched for studies examining the effects of CB1R agonists, antagonists, and negative allosteric modulators on memory performance. Results: We systematically reviewed 195 studies investigating the effects of cannabinoid compounds on memory. In humans (N = 35 studies, comprising N = 782 subjects), delta-9-tetrahydrocannabinol (THC) (1.5-5 mg/kg) relative to placebo impaired performance on non-spatial memory tests, whereas only high THC doses (67 mg/kg) impaired spatial memory. Similarly, THC (0.2-4 mg/kg) significantly impaired visuospatial memory in monkeys and non-human primates (N = 8 studies, comprising N = 71 subjects). However, acute THC (0.002-10 mg/kg) had no effect on non-spatial (N = 6 studies, comprising 117 subjects; g = 1.72, 95% confidence interval (CI) - 0.18 to 3.63, p = 0.08) or spatial memory (9 studies, comprising 206 subjects; g = 0.75, 95% confidence interval (CI) - 1.09 to 2.58, p = 0.43). However, acute, full CB1R agonists significantly impaired non-spatial memory (N = 23 studies, 519 subjects; g = - 1.39, 95% CI - 2.72 to - 0.06, p = 0.03). By contrast, the chronic administration of CB1R agonists had no effect on non-spatial memory (N = 5 studies, comprising 146 subjects; g = - 0.05, 95% confidence interval (CI) - 1.32 to 1.22, p = 0.94). Moreover, the acute administration of CB1R antagonists had no effect on non-spatial memory in rodents (N = 9 studies, N = 149 subjects; g = 0.40, 95% CI - 0.11 to 0.92, p = 0.12). Conclusions: The acute administration of THC, partial CB1R agonist, significantly impaired non-spatial memory in humans, monkeys, and non-human primates but not rodents. However, full CB1R agonists significantly impaired non-spatial memory in a dose-dependent manner but CB1R antagonists had no effect on non-spatial memory in rodents. Moreover, chronic THC administration did not significantly impair spatial or non-spatial memory in rodents, and there is inconclusive evidence on this in humans. Our findings highlight species differences in the effects of cannabinoid compounds on memory.
Article
Prenatal neurodevelopment is dependent on precise functioning of multiple signaling pathways in the brain, including those mobilized by glucocorticoids (GC) and endocannabinoids (eCBs). Prenatal exposure to drugs of abuse, including opioids, alcohol, cocaine, and cannabis have been shown to not only impact GC signaling, but also alter functioning of the hypothalamic‐pituitary‐adrenal (HPA) axis. Such exposures can have long‐lasting neurobehavioral consequences, including alterations in stress response in the offspring. Furthermore, cannabis contains cannabinoids that signal via the eCB pathway, which is linked to some components of GC signaling in the adult brain. Given that GCs are frequently used in pregnancy to prevent complications of prematurity, and rates of cannabis use in pregnancy are increasing, the likelihood of fetal co‐exposure to these compounds is high, and may have additional implications for long‐term neurodevelopment. Here, we present a discussion of GC signaling and the HPA axis, effects of prenatal drug exposures on these pathways and the stress response, and explore the interactions between GC and EC signaling in the developing brain and potential for neurodevelopmental consequences. This article is protected by copyright. All rights reserved.
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Cannabis has the potential to modulate some of the most common and debilitating symptoms of cancer and its treatments, including nausea and vomiting, loss of appetite, and pain. However, the dearth of scientific evidence for the effectiveness of cannabis in treating these symptoms in patients with cancer poses a challenge to clinicians in discussing this option with their patients. A review was performed using keywords related to cannabis and important symptoms of cancer and its treatments. Literature was qualitatively reviewed from preclinical models to clinical trials in the fields of cancer, human immunodeficiency virus (HIV), multiple sclerosis, inflammatory bowel disease, post-traumatic stress disorder (PTSD), and others, to prudently inform the use of cannabis in supportive and palliative care in cancer. There is a reasonable amount of evidence to consider cannabis for nausea and vomiting, loss of appetite, and pain as a supplement to first-line treatments. There is promising evidence to treat chemotherapy-induced peripheral neuropathy, gastrointestinal distress, and sleep disorders, but the literature is thus far too limited to recommend cannabis for these symptoms. Scant, yet more controversial, evidence exists in regard to cannabis for cancer- and treatment-related cognitive impairment, anxiety, depression, and fatigue. Adverse effects of cannabis are documented but tend to be mild. Cannabis has multifaceted potential bioactive benefits that appear to outweigh its risks in many situations. Further research is required to elucidate its mechanisms of action and efficacy and to optimize cannabis preparations and doses for specific populations affected by cancer.
Article
Background: Cannabis is the most widely used illicit substance worldwide, and legalization for recreational and medical purposes has substantially increased its availability and use in the United States.Objectives: Decades of research have suggested that recreational cannabis use confers risk for cognitive impairment across various domains, and structural and functional differences in the brain have been linked to early and heavy cannabis use.Methods: With substantial evidence for the role of the endocannabinoid system in neural development and understanding that brain development continues into early adulthood, the rising use of cannabis in adolescents and young adults raises major concerns. Yet some formulations of cannabinoid compounds are FDA-approved for medical uses, including applications in children.Results: Potential effects on the trajectory of brain morphology and cognition, therefore, should be considered. The goal of this review is to update and consolidate relevant findings in order to inform attitudes and public policy regarding the recreational and medical use of cannabis and cannabinoid compounds.Conclusions: The findings point to considerations for age limits and guidelines for use.
Article
Background Geriatric patients often suffer from a long history of pain and have a limited life expectancy. Cannabinoid receptor agonists like dronabinol may be an effective, low-risk treatment option for geriatric patients with chronic pain. Objectives The effectiveness and side effects of dronabinol therapy in geriatric patients are analyzed. The effects of the approval requirement are presented. Methods In our retrospective monocentric cohort study, the study population comprised all geriatric patients over the age of 80 years who were treated in our office since the cannabis law came into effect on 10 March 2017 until 17 July 2018 (evaluation date). Geriatric, nonpalliative pain patients (group A) and geriatric palliative patients (group B) were investigated. The basis of the evaluation was a questionnaire sheet that we use in our office with details of dosages, pain intensity, treatment effects and side effects from dronabinol therapy. Results By using dronabinol, 21 of the 40 geriatric patients (52.5%) achieved pain relief of more than 30%, 10% of the patients of more than 50%. On average, about four symptoms or side effects related to previous treatment were positively influenced. 26% of patients reported side effects. The rejection rates on the part of the health insurances were 38.7% (group A) and 10.3% (group B). Conclusions This study is one of the few analyses of the use of Dronabinol in geriatric patients. We show that cannabis-based drugs (in this case dronabinol) are an effective, low-risk treatment option that should be considered early in therapy. Regarding the indication spectrum, further clinical studies and an approval-free test phase are necessary.
Chapter
Traditionell hat die Chemie ein inniges Verhältnis zu Fermentationsprozessen sowie zur Destillation des dabei von den Hefen erzeugten Alkohols. Diese uralten Kulturtraditionen sind uns heilig, aber hin und wieder kommt doch jemand spätabends in der Kneipe auf eine glorreiche Idee, wie man sie verbessern könnte. Wein in Pulverform, Bier in Tausenden von Geschmacksvarianten, Champagner mit noch stärker prickelnden Blasen und der Schwips ohne Kater – diese Innovationen gehören alle zu der schönen neuen Welt, die uns versprochen wird.
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Zubereitungen aus der Hanfpflanze Cannabis sativa werden seit Jahrtausenden als Genussdrogen und Arzneimittel eingesetzt. Die wichtigsten Inhaltsstoffe sind das psychoaktive (−)‑trans-∆⁹-Tetrahydrocannabinol (THC), das als Partialagonist an den Cannabinoid (CB)-Rezeptoren CB1 und CB2 fungiert, und das nicht psychoaktive, pleiotrop wirkende Cannabidiol (CBD). Beide Verbindungen sind hoch lipophil wie die endogenen CB-Rezeptor-Agonisten, die Arachidonsäure-Derivate Anandamid und Arachidonoylglycerol. Die CB-Rezeptoren gehören zur Familie der G‑Protein-gekoppelten Rezeptoren und in den letzten Jahren konnten die ersten Röntgenstrukturen beider Rezeptor-Subtypen erhalten werden, die das rationale Design neuer synthetischer Liganden erleichtern werden. Neben den bereits weitgehend etablierten Indikationen wie chronischer Schmerz, Chemotherapie-induziertem Erbrechen, Spasmen bei multipler Sklerose und Kachexie gibt es Hinweise auf eine Reihe weiterer Cannabinoid-Wirkungen, die noch durch klinische Studien bestätigt werden müssen.
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The global march towards legalization of marijuana consumption is pursued in reason of the supposed harmless properties of this plant. Actually, a wide range of cannabinoids is endogenously produced and interacts with different classes of receptors ubiquitously distributed in the human body. Such endocannabinoid system (ECS) modulates several functions in health and disease. However, studies on synthetic ligands with selective agonist/antagonist activity on specific cannabinoid receptors, have clarified how complex the cannabinoid system is. The whole biological activity of cannabis sativa remains difficult to establish, due to the fact that it is a complex mixture of phytocannabinoids with different or even opposing effects. Δ9-tetrahydrocannabinol is the most represented phytocannabinoid in the marijuana plant and then the most studied compound. It has been widely associated with adverse CV effects in marijuana smokers. Conversely, less is known about the role of other phytocannabinoids. Here, we summarized the current knowledge about the effects of phytocannabinoids in CV disease, mainly focusing on atherosclerosis and myocardial infarction. We critically discussed clinical and experimental evidence linking phytocannabinoids to CV disease, attempting at explaining some controversies and suggesting the direction for future studies.
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Marijuana use among older adults is on an unprecedented rise, yet little is known about its effects on cognition in this population where, due to advanced age, risk for cognitive decline is high. Thus, we investigated whether marijuana use and use characteristics were associated with self-reported cognition among older adults ages ≥ 50 years using the National Epidemiologic Survey on Alcohol and Related Conditions-III. Respondents either had never used marijuana (“never”: n=10,976), used but not in the past 12 months (“former”: n=2,990), or used in the past 12 months (“current”: n=712). Self-reported cognition was measured using the Executive Function Index. Marijuana and substance use characteristics were obtained using the Alcohol Use Disorder and Associated Disabilities Interview Schedule-5. Covariates included demographics, mental health and disability, and comorbid mental and substance use disorder. Using general linear models of cross-sectional data, we found that current users, particularly those with cannabis use disorder, reported worse cognition than never or former users, but these effects were small in magnitude. Among both former and current users, greater duration of past use was associated with worse cognition. Frequent use within the past 12 months was associated worse cognition among current users, but daily users reported better cognition compared to monthly or weekly users. Thus, marijuana use may impact self-reported cognition in older adulthood, although these effects may be subtle, specific to particular use characteristics, and possibly affected by self-awareness of deficits. Future work using objective measures such as neuropsychological testing or neuroimaging may better elucidate these effects.
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Psychedelic agonists of serotonin receptors induce neural plasticity and synaptogenesis, but their potential to enhance learning remains uncharted. Here we show that a single dose of d-LSD, a potent serotonergic agonist, increased novel object preference in young and adult rats several days after treatment. d-LSD alone did not increase preference in old animals, but could rescue it to young levels when followed by a 6-day exposure to enriched environment (EE). Mass spectrometry-based proteomics in human brain organoids treated with d-LSD showed upregulation of proteins from the presynaptic active zone. A computational model of synaptic connectivity in the hippocampus and prefrontal cortex suggests that d-LSD enhances novelty preference by combining local synaptic changes in mnemonic and executive regions, with alterations of long-range synapses. Better pattern separation within EE explained its synergy with d-LSD in rescuing novelty preference in old animals. These results advance the use of d-LSD in cognitive enhancement.
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Endometriosis is a chronic painful disease highly prevalent in women that is defined by growth of endometrial tissue outside the uterine cavity and lacks adequate treatment. Medical use of cannabis derivatives is a current hot topic and it is unknown whether phytocannabinoids may modify endometriosis symptoms and development. Here we evaluate the effects of repeated exposure to Δ9-tetrahydrocannabinol (THC) in a mouse model of surgically-induced endometriosis. In this model, female mice develop mechanical hypersensitivity in the caudal abdomen, mild anxiety-like behavior and substantial memory deficits associated with the presence of extrauterine endometrial cysts. Interestingly, daily treatments with THC (2 mg/kg) alleviate mechanical hypersensitivity and pain unpleasantness, modify uterine innervation and restore cognitive function without altering the anxiogenic phenotype. Strikingly, THC also inhibits the development of endometrial cysts. These data highlight the interest of scheduled clinical trials designed to investigate possible benefits of THC for women with endometriosis.
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Most of the drugs of abuse affect the brain by interacting with naturally expressed molecular receptors. Marihuana affects a series of receptors including cannabinoid receptor 1 (CB1R) and CB2R, among others. Endogenous molecules with cannabinoid activity interact with these receptors naturally. Receptors, ligands, synthesizing and degrading enzymes, as well as transporters, have been described. This endocannabinoid system modulates behaviors and physiological processes, i.e. food intake, the sleep-waking cycle, learning and memory, motivation, and pain perception, among others. The rather broad distribution of endocannabinoids in the brain explains the different effects marihuana induces in its users. However, this very same anatomical and physiological distribution makes this system a useful target for therapeutic endeavors. In this review, we briefly discuss the potential of small molecules that target the endocannabinoids as therapeutic tools to improve behaviors and treat illnesses. We believe that under medical supervision, endocannabinoid targets offer new advantages for patients for controlling multiple medical disorders.
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While medical and recreational cannabis use is becoming more frequent among older adults, the neurocognitive consequences of cannabis use in this age group are unclear. The aim of this literature review was to synthesize and evaluate the current knowledge on the association of cannabis use during older-adulthood with cognitive function and brain aging. We reviewed the literature from old animal models and human studies while focusing on the link of middle- and old-age use of cannabis with cognition. The report highlights the gap in knowledge on cannabis use in late-life and cognitive health, and discusses the limited findings in the context of substantial changes in attitudes and policies. Furthermore, we outline possible theoretical mechanisms and propose recommendations for future research. The limited evidence on this important topic suggests that use in older ages may not be linked with poorer cognitive performance, thus detrimental effects of early-life cannabis use may not translate to use in older ages. Rather, use in old ages may be associated with improved brain health, in accordance with the known neuroprotective properties of several cannabinoids. Yet, firm conclusions cannot be drawn from the current evidence-base due to lack of research with strong methodological designs.
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A growing body of literature suggests that cannabis intake can induce memory loss in humans and animals. Besides the recreational use, daily cannabis users may also belong to the ever-increasing population of patients who are administered cannabis as a medicine. As such, they also can experience impairments in memory as a negative side effect of their therapy. Comprehension of the neurobiological mechanisms responsible for such detrimental effects would be therefore of paramount relevance to public health. The investigation of neurobiological mechanisms in humans, despite the progress in the development of imaging technologies that allow the study of brain structure and function, still suffers substantial limitations. Animal models, instead, enable us to establish a causal relationship and thus to better elucidate the neurobiological mechanisms underlying the process under study. In this review, we will attempt to collect the insight coming from animal models about cannabis effects on memory, trying to depict a picture of the neurobiological mechanisms contributing to the development of cognitive deficits following cannabis use.
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Cannabis has been shown to be beneficial in the treatment of pain and inflammatory diseases. The biological effect of cannabis is mainly attributed to two major cannabinoids, tetrahydrocannabinol and cannabidiol. In the majority of studies to-date, a purified tetrahydrocannabinol and cannabidiol alone or in combination have been extensively examined in many studies for the treatment of numerous disorders including pain and inflammation. However, few studies have investigated the biological benefits of full-spectrum cannabis plant extract. Given that cannabis is known to generate a large number of cannabinoids along with numerous other biologically relevant products including terpenes, studies involving purified tetrahydrocannabinol and/or cannabidiol may not precisely consider the potential biological benefits of the full-spectrum cannabis extracts. This may be especially true in the role of cannabis as a treatment of pain and inflammation. Herein, we review the pre-clinical physiological and molecular mechanisms in biological systems that are affected by cannabis.
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Electroconvulsive therapy (ECT) is one of the most effective treatments for depression, but it can cause cognitive deficit. Unfortunately, effective preventive measures are still lacking. The endocannabinoid system is thought to play a key role in regulation of cognitive process. Whether the endocannabinoid system is involved in the learning and memory impairment caused by ECS remain unclear. In this work, we first found that cannabinoid receptor type 1 (CB1R) and 2-arachidonoylglycerol (2-AG) were strongly expressed in hippocampus by electroconvulsive shock (ECS) in a rat depression model established by chronic mild stress (CMS). Pharmacological inhibition of CB1R using AM251 in vivo resulted in a pronounced relief in ECS-induced spatial learning and memory impairment as well as in a marked reversal of impaired hippocampal long-term potentiation (LTP), and reduced synapse-related proteins expression. Furthermore, results of sucrose preference test (SPT) and open-field test (OFT) showed that AM251 had no significant impact on the therapeutic effects of ECS on pleasure and psychomotor activity. Taken together, we identified that CB1R is involved in the ECS-induced spatial learning and memory impairment and Inhibition of CB1R facilitates the recovery of memory impairment and hippocampal synaptic plasticity, without interfering with the therapeutic effects of ECS in depressed rats.
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Objective Moderate to severe spasticity is commonly reported in Multiple Sclerosis (MS) and its management is still a challenge. Cannabinoids were recently suggested as add-on therapy for the treatment of spasticity and chronic pain in MS but there is no conclusive scientific evidence on their safety, especially on cognition and over long periods. The aim of this prospective pilot study was to assess the long-term effects of a tetrahydrocannabinol-cannabidiol (THC/CBD) oromucosal spray (Sativex®) on cognition, mood and anxiety. Patients and Methods An extensive and specific battery of neuropsychological tests (Symbol Digit Modalities Test-SDMT, California Verbal Learning Test-CVLT, Brief Visuospatial Memory Test-BVMT; PASAT-3 and 2; Free and Cued Selective Remind Test-FCSRT, Index of Sensitivity of Cueing-ISC) was applied to longitudinally investigate different domains of cognition in 20 consecutive MS patients receiving Sativex for spasticity. The primary endpoint was to assess any variation in cognitive performance. Secondary outcomes regarding mood and anxiety were investigated by means of Beck Depression Inventory (BDI) and Hamilton Anxiety Rating Scale (HAM-A). Any change in patients’ spasticity was evaluated using the 0-10 numerical rating scale (NRS). Results Twenty per protocol patients were followed up and evaluated at baseline, 6 and 12 months. Domains involving processing speed and auditory verbal memory significantly improved within the first 6 months of therapy (SDMT: p < 0.001; CVLT: p = 0.0001). Mood and anxiety did not show any significant variation. Additionally, the NRS score significantly improved since the beginning (p < 0.0001). Conclusions These results are encouraging in supporting possible long-term benefits of Sativex on cognition and a wider role than symptom alleviator. Further studies on larger groups of patients would be necessary in order to test this intriguing possibility.
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Cannabinoid receptor type 1 (CB1R) modulates synaptic activity and is widely distributed in brain areas such as the hippocampus, cerebellum, cerebral cortex, and striatum, among others. CB1R is involved in processes such as memory, learning, motor coordination, and mood. Genetic deletion of CB1R causes behavioral alterations. In this work, we evaluated neuronal morphology and synaptic structure in the hippocampus of adult male CB1R knockout mice (CB1R−/−). Morphological changes in the CB1R−/− hippocampus evidenced a decrease in the expression of cytoskeletal proteins neurofilaments 160 KDa, neurofilaments 200 KDa, and microtubule‐associated protein 2. CA1 neurons showed decreased arborization and changes in synaptic structure such as lower thickness of postsynaptic density and a reduction in synaptophysin levels. Results obtained in the present work provide evidence of the participation of CB1R in the establishment of neuronal structure and networks that could have an important role in neuronal plasticity. In addition, these changes observed in CB1R−/− could be correlated with behavioral alterations reported. CB1R knockout mice showed decreased neuronal dendritic arborization and changes in synaptic structure, as such as lower thickness of postsynaptic density and a reduction in synaptophysin levels in hippocampus.
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With the advent of medical cannabis usage globally, there has been a renewed interest in exploring the chemical diversity of this unique plant. Cannabis produces hundreds of unique phytocannabinoids, which not only have diverse chemical structures but also a range of cellular and molecular actions, interesting pharmacological properties, and biological actions. In addition, it produces other flavonoids, stilbenoids, and terpenes that have been variably described as conferring additional or so-called entourage effects to whole-plant extracts when used in therapeutic settings. This review explores this phytochemical diversity in relation to specific bioactivity ascribed to phytocannabinoids as neuroprotective agents. It outlines emergent evidence for the potential for selected phytocannabinoids and other cannabis phytochemicals to mitigate factors such as inflammation and oxidative stress as drivers of neurotoxicity, in addition to focusing on specific interactions with pathological misfolding proteins, such as amyloid β, associated with major forms of neurodegenerative diseases such as Alzheimer’s disease.
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Age-related level changes of hormones, endocannabinoids and their ratios are of pathophysiological significance for understanding functions, activities and interactions of the endocrine systems, including the hypothalamic–pituitaryadrenal (HPA), hypothalamic-pituitary–gonadal (HPG) axes and endogenous cannabinoid system (ECS). The present study aimed to investigate the age-dependent fluctuations of glucocorticoids, gonadal steroids, endocannabinoids and their ratios from 21 days to 10 months in both plasma and hair from the male C57BL/6 mice. A novel framework based on the liquid chromatography-tandem mass spectrometry was developed to simultaneously determine ten hormones and two endocannabinoids in plasma and hair. Results showed that glucocorticoids, corticosterone (CORT), aldosterone (ALD), 11-dehydrocorticosterone (11-DHC), gonadal steroids, progesterone (P), dehydroepiandrosterone (DHEA), testosterone (T) and dihydrotestosterone (DHT) in plasma were unimodally fluctuated (ps < 0.001) along age with the maximum value at 2.7-month-old. In contrast, the other two gonadal steroids, estrone (E1) and estradiol (E2) were declined with age (ps < 0.001). Differently, endocannabinoids, N-arachidonoyl-ethanolamine (AEA) and 1-arachydonoyl glycerol (1-AG) showed nadir and zenith values at 2.7-month-old and 3.4-month-old, respectively (ps < 0.001). Additionally, the ratios of CORT to 11-DHC and ALD in plasma were dropped similarly with age (ps < 0.001). The ratios of 1-AG to AEA, and of T to A4 and DHT, and of DHEA to A4 were unimodally changed (ps < 0.001) along age with maximum value at 2.7- or 3.4-month-old. In contrast, the ratios of E2 to T and E1 to A4 were decreased with age (ps < 0.05). The rest six ratios that reflected the interactions among the three endocrine systems, were similar age-dependent and showed nadir and zenith values at 2.7-month-old and 3.4-month-old, respectively (ps < 0.05). Most importantly, these findings in light of age-related changing patterns in plasma were repeated in hair, suggesting that the fi41-ndings in the two matrices were mutually validated. However, it was worth noting that their magnitude of levels in the two bio-matrices were markedly different. The current findings could provide reliable hormone and endocannabinoid signatures with age on neuroendocrine profiles as well as their ratios for the male C57BL/6 mice.
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As the frequency of cannabis use by 14–16-year-olds increases, it becomes increasingly important to understand the effect of cannabis on the developing central nervous system. Using mice as a model system, we treated adolescent (28 day old) C57BL6/J mice of both sexes for 3 weeks with 3 mg/kg tetrahydrocannabinol (THC). Starting a week after the last treatment, several cognitive behaviors were analyzed. Mice treated with THC as adolescents acquired proficiency in a working memory task more slowly than vehicle-treated mice. Working memory recall in both sexes of THC-treated mice was also deficient during increasing cognitive load compared to vehicle-treated mice. Our adolescent THC treatment did not strongly affect social preference, anxiety behaviors, or decision-making behaviors on the elevated T maze task. In summary, under the conditions of this study, adolescent THC treatment of mice markedly affected the establishment, and persistence of working memory, while having little effect on decision-making, social preference or anxiety behaviors. This study provides further support that adolescent THC affects specific behavioral domains.
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The endocannabinoid system modulates adult hippocampal neurogenesis by promoting the proliferation and survival of neural stem and progenitor cells (NSPCs). Specifically, deleting cannabinoid receptors on NSPCs or the constitutive deletion of the endocannabinoid 2-arachidonoylglycerol (2-AG) producing enzyme diacylglycerol lipase alpha (DAGLa) disrupts adult neurogenesis. However, it is not known which cells are the producers of 2-AG relevant to neurogenesis. In this paper, we investigated the cellular source of endocannabinoids in the subgranular zone (SGZ) of the hippocampus, an important neurogenic niche. For this purpose, we used two complementary Cre-deleter mouse strains to delete DAGLa either in neurons or astroglia and NSPCs. Surprisingly, neurogenesis was not altered in mice with a deletion of Dagla in neurons (Syn-Dagla KO), although they are the main source for the endocannabinoids in the brain. In contrast, mice with a specific inducible deletion of Dagla in NPSCs and astrocytes (GLAST-CreERT2-Dagla KO) showed a strongly impaired neurogenesis with significantly reduced proliferation and survival of newborn cells. These results identify Dagla in NSPCs in the SGZ of dentate gyrus or in astrocytes, as the cellular source for 2-AG in adult hippocampal neurogenesis. In summary, 2-AG produced by progenitor cells or astrocytes in the SGZ regulates adult hippocampal neurogenesis. Summary DAGLa in neuronal progenitor cells in the SGZ of dentate gyrus is identified as the cellular source for 2-AG in adult hippocampal neurogenesis.
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Alzheimer’s disease is a leading cause of dementia in the elderly population for which there is no cure at present. Deposits of neurotoxic plaques are found in the brains of patients which are composed of fibrils of the amyloid-β peptide. Molecules which can disrupt these fibrils have gained attention as potential therapeutic agents. Δ-tetrahydrocannabidiol (THC) is a cannabinoid, which can bind to the receptors in the brain, and has shown promise in reducing the fibril content in many experimental studies. In our present study, by employing all atom molecular dynamics simulations, we have investigated the mechanism of the interaction of the THC molecules with the amyloid-β protofibrils. Our results show that the THC molecules disrupts the protofibril structure by binding strongly to them. The driving force for the binding was the hydrophobic interactions with the hydrophobic residues in the fibrils. As a result of these interactions, the tight packing of the hydrophobic core of the protofibrils was made loose, and salt bridges, which were important for stability were disrupted. Hydrogen bonds between the chains of the protofibrils which are important for stability were disrupted, as a result of which the β-sheet content was reduced. The destabilization of the protofibrils by the THC molecules leads to the conclusion that THC molecules may be considered for the therapy in treating Alzheimer’s disease.
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Sehen ist einer der wichtigsten Wege, um Signale aus der Umwelt aufzunehmen und sich in der Umwelt orientieren zu können. Wir diskutieren hier einige Aspekte der Sehbahn und der genetischen Elemente, wie die Neurone des Sehnerven ihren Weg finden, um sich im Chiasma opticum zu kreuzen – oder auch nicht. Wir werden sehen, dass die Wahrnehmung von Licht für viele zyklisch ablaufende Prozesse von entscheidender Bedeutung ist. Verhaltensgenetische Experimente, die in den letzten Jahren systematisch an verschiedenen Modellorganismen durchgeführt wurden, zeigen, dass wesentliche Teile tierischen und menschlichen Verhaltens genetisch bestimmt werden. Das gilt für verschiedene rhythmische Verhaltensweisen bei Pflanzen, Pilzen, Insekten und Säugern genauso wie für so schwer verständliche und komplexe Verhaltensweisen wie z. B. das Zugverhalten von Vögeln. Verhalten ist vielfach genetisch in polygenen Regulationssystemen festgelegt; die individuelle Ausprägung von Verhaltensweisen wird jedoch in unterschiedlichem Ausmaß durch Umwelteinflüsse mitbestimmt. Das macht es zunächst schwierig, festzustellen, wie hoch die erblichen Komponenten solcher Verhaltensweisen sind.
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Diacylglycerol lipase-α (DAGL-α), the principal biosynthetic enzyme of the endogenous cannabinoid 2-arachidonylglycerol (2-AG) on neurons, plays a key role in CB1 receptor-mediated synaptic plasticity and hippocampal neurogenesis, but its contribution to global hippocampal-mediated processes remains unknown. Thus, the present study examines the role that DAGL-α plays on LTP in hippocampus, as well as in hippocampal-dependent spatial learning and memory tasks, and on the production of endocannabinoid and related lipids through the use of complementary pharmacologic and genetic approaches to disrupt this enzyme in male mice. Here we show that DAGL-α gene deletion or pharmacological inhibition disrupts LTP in CA1 of the hippocampus but elicits varying magnitudes of behavioral learning and memory deficits in mice. In particular, DAGL-α-/- mice display profound impairments in the Object Location assay and Morris Water Maze (MWM) acquisition engaging in nonspatial search strategies. In contrast, WT mice administered the DAGL-α inhibitor DO34 show delays in MWM acquisition and reversal learning, but no deficits in expression, extinction, forgetting, or perseveration processes in this task, as well as no impairment in Object Location. The deficits in synaptic plasticity and MWM performance occur in concert with decreased 2-AG and its major lipid metabolite (arachidonic acid), but increases of a 2-AG diacylglycerol precursor in hippocampus, PFC, striatum, and cerebellum. These novel behavioral and electrophysiological results implicate a direct and perhaps selective role of DAGL-α in the integration of new spatial information.SIGNIFICANCE STATEMENT Here we show that genetic deletion or pharmacologic inhibition of diacylglycerol lipase-α (DAGL-α) impairs hippocampal CA1 LTP, differentially disrupts spatial learning and memory performance in Morris water maze (MWM) and Object Location tasks, and alters brain levels of endocannabinoids and related lipids. Whereas DAGL-α-/- mice exhibit profound phenotypic spatial memory deficits, a DAGL inhibitor selectively impairs the integration of new information in MWM acquisition and reversal tasks, but not memory processes of expression, extinction, forgetting, or perseveration, and does not affect performance in the Objection Location task. The findings that constitutive or short-term DAGL-α disruption impairs learning and memory at electrophysiological and selective in vivo levels implicate this enzyme as playing a key role in the integration of new spatial information.
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The Klotho protein is a β-glucuronidase, and its overexpression is associated with life extension. Its mechanism of action is not fully understood, although it has been recently reported that αKlotho improves synaptic and cognitive functions, and it may also influence a variety of structures and functions during CNS maturation and aging. The αKlotho gene has two transcripts, one encoding a transmembrane isoform (m-KL), and the other a putative secreted isoform (s-KL). Unfortunately, little is known about the secreted αKlotho isoform, since available antibodies cannot discriminate s-KL from the KL1 domain cleaved from the transmembrane isoform. This study shows, for the first time, that the klotho transcript produced by alternative splicing generates a stable protein (70 kDa), and that in contrast to the transmembrane Klotho isoform, it is ten times more abundant in the brain than in the kidney suggesting that the two isoforms may have different functions. We also studied whether klotho expression in the CNS was influenced by aging, Alzheimer's disease (AD), or a healthy lifestyle, such as voluntary moderate continuous exercise. We observed a strong correlation between high expression levels of the two klotho transcripts and the healthy status of the animals. Expression of Klotho in brain areas decayed more rapidly in the 3xTg-AD model of AD than in healthy animals, whilst moderate continuous exercise in adulthood prevents the decline in expression of both klotho transcripts.
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Aging is the primary risk factor for cognitive decline, an emerging health threat to aging societies worldwide. Whether anti-aging factors such as klotho can counteract cognitive decline is unknown. We show that a lifespan-extending variant of the human KLOTHO gene, KL-VS, is associated with enhanced cognition in heterozygous carriers. Because this allele increased klotho levels in serum, we analyzed transgenic mice with systemic overexpression of klotho. They performed better than controls in multiple tests of learning and memory. Elevating klotho in mice also enhanced long-term potentiation, a form of synaptic plasticity, and enriched synaptic GluN2B, an N-methyl-D-aspartate receptor (NMDAR) subunit with key functions in learning and memory. Blockade of GluN2B abolished klotho-mediated effects. Surprisingly, klotho effects were evident also in young mice and did not correlate with age in humans, suggesting independence from the aging process. Augmenting klotho or its effects may enhance cognition and counteract cognitive deficits at different life stages.
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As human lifespan increases, a greater fraction of the population is suffering from age-related cognitive impairments, making it important to elucidate a means to combat the effects of aging. Here we report that exposure of an aged animal to young blood can counteract and reverse pre-existing effects of brain aging at the molecular, structural, functional and cognitive level. Genome-wide microarray analysis of heterochronic parabionts-in which circulatory systems of young and aged animals are connected-identified synaptic plasticity-related transcriptional changes in the hippocampus of aged mice. Dendritic spine density of mature neurons increased and synaptic plasticity improved in the hippocampus of aged heterochronic parabionts. At the cognitive level, systemic administration of young blood plasma into aged mice improved age-related cognitive impairments in both contextual fear conditioning and spatial learning and memory. Structural and cognitive enhancements elicited by exposure to young blood are mediated, in part, by activation of the cyclic AMP response element binding protein (Creb) in the aged hippocampus. Our data indicate that exposure of aged mice to young blood late in life is capable of rejuvenating synaptic plasticity and improving cognitive function.
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The multifunctional Creb-binding protein (CBP) protein plays a pivotal role in many critical cellular processes. Here we demonstrate that the bromodomain of CBP binds to histone H3 acetylated on lysine 56 (K56Ac) with higher affinity than to its other monoacetylated binding partners. We show that autoacetylation of CBP is critical for the bromodomain-H3 K56Ac interaction, and we propose that this interaction occurs via autoacetylation-induced conformation changes in CBP. Unexpectedly, the bromodomain promotes acetylation of H3 K56 on free histones. The CBP bromodomain also interacts with the histone chaperone anti-silencing function 1 (ASF1) via a nearby but distinct interface. This interaction is necessary for ASF1 to promote acetylation of H3 K56 by CBP, indicating that the ASF1-bromodomain interaction physically delivers the histones to the histone acetyl transferase domain of CBP. A CBP bromodomain mutation manifested in Rubinstein-Taybi syndrome has compromised binding to both H3 K56Ac and ASF1, suggesting that these interactions are important for the normal function of CBP.
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The role of endocannabinoids as inhibitory retrograde transmitters is now widely known and intensively studied. However, endocannabinoids also influence neuronal activity by exerting neuroprotective effects and regulating glial responses. This review centres around this less-studied area, focusing on the cellular and molecular mechanisms underlying the protective effect of the cannabinoid system in brain ageing. The progression of ageing is largely determined by the balance between detrimental, pro-ageing, largely stochastic processes, and the activity of the homeostatic defence system. Experimental evidence suggests that the cannabinoid system is part of the latter system. Cannabinoids as regulators of mitochondrial activity, as anti-oxidants and as modulators of clearance processes protect neurons on the molecular level. On the cellular level, the cannabinoid system regulates the expression of brain-derived neurotrophic factor and neurogenesis. Neuroinflammatory processes contributing to the progression of normal brain ageing and to the pathogenesis of neurodegenerative diseases are suppressed by cannabinoids, suggesting that they may also influence the ageing process on the system level. In good agreement with the hypothesized beneficial role of cannabinoid system activity against brain ageing, it was shown that animals lacking CB1 receptors show early onset of learning deficits associated with age-related histological and molecular changes. In preclinical models of neurodegenerative disorders, cannabinoids show beneficial effects, but the clinical evidence regarding their efficacy as therapeutic tools is either inconclusive or still missing.
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Exogenous cannabinoids, such as delta9-tetrahydrocannabinol (THC), as well as the modulation of endogenous cannabinoids, affect cognitive function through the activation of cannabinoid receptors. Indeed, these compounds modulate a number of signalling pathways critically implicated in the deleterious effect of cannabinoids on learning and memory. Thus, the involvement of the mammalian target of rapamycin pathway and extracellular signal-regulated kinases, together with their consequent regulation of cellular processes such as protein translation, play a critical role in the amnesic-like effects of cannabinoids. In this study, we summarize the cellular and molecular mechanisms reported in the modulation of cognitive function by the endocannabinoid system.
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The analysis of the contributions to synaptic plasticity and memory of cAMP, PKA, CRE, CREB-1, CREB-2, and CPEB has recruited the efforts of many laboratories all over the world. These are six key steps in the molecular biological delineation of short-term memory and its conversion to long-term memory for both implicit (procedural) and explicit (declarative) memory. I here first trace the background for the clinical and behavioral studies of implicit memory that made a molecular biology of memory storage possible, and then detail the discovery and early history of these six molecular steps and their roles in explicit memory.
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Impairment of working memory is one of the most important deleterious effects of marijuana intoxication in humans, but its underlying mechanisms are presently unknown. Here, we demonstrate that the impairment of spatial working memory (SWM) and in vivo long-term depression (LTD) of synaptic strength at hippocampal CA3-CA1 synapses, induced by an acute exposure of exogenous cannabinoids, is fully abolished in conditional mutant mice lacking type-1 cannabinoid receptors (CB(1)R) in brain astroglial cells but is conserved in mice lacking CB(1)R in glutamatergic or GABAergic neurons. Blockade of neuronal glutamate N-methyl-D-aspartate receptors (NMDAR) and of synaptic trafficking of glutamate α-amino-3-hydroxy-5-methyl-isoxazole propionic acid receptors (AMPAR) also abolishes cannabinoid effects on SWM and LTD induction and expression. We conclude that the impairment of working memory by marijuana and cannabinoids is due to the activation of astroglial CB(1)R and is associated with astroglia-dependent hippocampal LTD in vivo.
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Normal ageing is associated with impairments in cognitive function, including memory. These impairments are linked, not to a loss of neurons in the forebrain, but to specific and relatively subtle synaptic alterations in the hippocampus and prefrontal cortex. Here, we review studies that have shed light on the cellular and synaptic changes observed in these brain structures during ageing that can be directly related to cognitive decline in young and aged animals. We also discuss the influence of the hormonal status on these age-related alterations and recent progress in the development of therapeutic strategies to limit the impact of ageing on memory and cognition in humans.
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Previous studies have demonstrated that the endocannabinoid system significantly influences the progression of brain ageing, and the hippocampus is one of the brain regions most vulnerable to ageing and neurodegeneration. We have further examined age-related changes in the hippocampal endocannabinoid system by measuring the levels of anandamide (AEA) and 2-arachidonoylglycerol (2-AG) in young and old mice from two different mouse strains. We found a decrease in 2-AG but not AEA levels in aged mice. In order to identify the cause for 2-AG level changes, we investigated the levels of several enzymes that contribute to synthesis and degradation of 2-AG in the hippocampus. We found a selective decrease in DAGLα mRNA and protein levels as well as an elevated MAGL activity during ageing. We hypothesize that the observed decrease of 2-AG levels is probably caused by changes in DAGLα expression and MAGL activity. This finding can contribute to the existing knowledge about the processes underlying selective vulnerability of the hippocampus to ageing and age-related neurodegeneration. Copyright © 2015. Published by Elsevier Ireland Ltd.
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The robust translocation of MAPK during synaptic plasticity (11xMartin, K.C, Michael, D, Rose, J.C, Barad, M, Casadio, A, Zhu, H, and Kandel, E.R. Neuron. 1997; 18: 899–912Abstract | Full Text | Full Text PDF | PubMed | Scopus (411)See all References, 9xImpey, S, Obrietan, K, Wong, S.T, Poser, S, Yano, S, Wayman, G, Deloulme, J.C, Chan, G, and Storm, D.R. Neuron. 1998; 21: 869–883Abstract | Full Text | Full Text PDF | PubMed | Scopus (644)See all References, 15xSgambato, V, Pages, C, Rogard, M, Besson, M.J, and Caboche, J. J. Neurosci. 1998; 18: 8814–8825PubMedSee all References) indicates that there are likely additional nuclear targets of MAPK signaling other than CREB. For example, several recent reports suggest that the transcription factor Elk1 is a major nuclear target of MAPK during synaptic plasticity and memory consolidation (2xBerman, D.E, Hazvi, S, Rosenblum, K, Seger, R, and Dudai, Y. J. Neurosci. 1998; 18: 10037–10044PubMedSee all References, 15xSgambato, V, Pages, C, Rogard, M, Besson, M.J, and Caboche, J. J. Neurosci. 1998; 18: 8814–8825PubMedSee all References).The prominent dendritic localization of activated MAPK following synaptic activity (Impey et al. 1998xImpey, S, Obrietan, K, Wong, S.T, Poser, S, Yano, S, Wayman, G, Deloulme, J.C, Chan, G, and Storm, D.R. Neuron. 1998; 21: 869–883Abstract | Full Text | Full Text PDF | PubMed | Scopus (644)See all ReferencesImpey et al. 1998) suggests that it may also have important cytosolic targets. The best example of such a target is the Aplysia cell adhesion molecule ApCAM. MAPK activity is required for the downregulation and internalization of ApCAM, a key step in the induction of LTF. This is an important observation because the Drosophila (Fas II) and murine (NCAM) homologs of ApCAM have also been implicated in neuronal plasticity.Collectively, these studies indicate that the MAPK pathway is a fundamental component of LTM formation in invertebrates and vertebrates. Thus, the MAPK cascade joins the cAMP/PKA pathway and the CREB transcriptional pathway as an evolutionarily conserved regulator of LTM consolidation (Figure 1Figure 1). Work showing that MAPK is a major activator of plasticity-associated CREB-dependent gene expression also strongly suggests that MAPK signaling facilitates memory consolidation and L-LTP by promoting de novo CREB-regulated gene expression. There are a number of unanswered questions regarding the role of MAPK in neuronal plasticity and memory formation. Is CREB a target of Ras/MAPK signaling during memory consolidation? How is MAPK activated during adaptive neuronal plasticity and memory consolidation? What are the cytosolic and nuclear targets of MAPK that facilitate memory formation and modulate synaptic efficacy? Additional research using temporally and spatially restricted transgenic technologies should help clarify and confirm the role of Ras/MAPK signaling in LTM.*To whom correspondence should be addressed (e-mail: dstorm@u.washington.edu).
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Ageing is characterized by the progressive impairment of physiological functions and increased risk of developing debilitating disorders, including chronic inflammation and neurodegenerative diseases. These disorders have common molecular mechanisms that can be targeted therapeutically. In the wake of the approval of the first cannabinoid-based drug for the symptomatic treatment of multiple sclerosis, we examine how endocannabinoid (eCB) signalling controls - and is affected by - normal ageing and neuroinflammatory and neurodegenerative disorders. We propose a conceptual framework linking eCB signalling to the control of the cellular and molecular hallmarks of these processes, and categorize the key components of endocannabinoid signalling that may serve as targets for novel therapeutics.
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Neurogenesis underlies plastic changes in defined neuronal circuits in the postnatal and adult brain. Here we identify connective tissue growth factor (CTGF) as a critical factor in the mouse olfactory bulb (OB) in determining the efficiency of incorporation of postnatally born inhibitory neurons, thus gating the output of glomeruli, the first relay station of olfactory processing in the brain. In the OB, CTGF expression was restricted to prenatally born external tufted cells. CTGF enhanced the proapoptotic activity of glial-derived TGF-β2, decreasing the survival of periglomerular inhibitory neurons. Changes in CTGF expression levels in the OB led to modifications in local neuronal circuitry and olfactory behaviors. We show that the odorant-specific recruitment of distinct glomeruli resulted in enhanced local CTGF expression levels in the activated glomeruli. Collectively our data reveal a molecular mechanism controlling the survival of defined postnatally born neurons, thus adapting neuronal integration to the sensory experiences.
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Long-lasting memories require specific gene expression programmes that are, in part, orchestrated by epigenetic mechanisms. Of the epigenetic modifications identified in cognitive processes, histone acetylation has spurred considerable interest. Whereas increments in histone acetylation have consistently been shown to favour learning and memory, a lack thereof has been causally implicated in cognitive impairments in neurodevelopmental disorders, neurodegeneration and ageing. As histone acetylation and cognitive functions can be pharmacologically restored by histone deacetylase inhibitors, this epigenetic modification might constitute a molecular memory aid on the chromatin and, by extension, a new template for therapeutic interventions against cognitive frailty.