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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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... The beneficial cognitive effects of chronic THC are mediated through epigenetic modifications by enhancing histone acetylation in the hippocampus. THCtreatment also induced the transcription of Bdnf and Klotho, genes that improve synaptic plasticity and extend lifespan in aged mice, and strongly downregulated Casp1 and connective tissue growth factor (Ctgf ) genes, which regulate pro-aging processes (Bilkei-Gorzo et al., 2017). These animal findings suggest the intriguing possibility that cannabinoids could also ameliorate some forms of age-or disease-associated cognitive decline in humans. ...
... Old (18 month) mice were used to assess the spatial learning and memory in the Morris water maze (MWM) according to the protocols described earlier (Albayram et al., 2016;Bilkei-Gorzo et al., 2017). A circular pool (120 cm diameter and 60 cm depth) filled with opaque water (25 • C) was separated into four equal quadrants. ...
... Potentiating CB1 receptor signaling using a chronic low dose (3 mg/kg/day) of THC, a dose where none of the psychoactive side effects were detected, alleviated the cognitive decline associated with physiological aging in mice (Bilkei-Gorzo et al., 2017). Indeed, the THC dose (3 mg/kg/day) used earlier was quite efficient and improved the cognitive performance of aged mice to a level on par with the control young mice. ...
Article
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Decline in cognitive performance, an aspect of the normal aging process, is influenced by the endocannabinoid system (ECS). Cannabinoid receptor 1 (CB1) signaling diminishes with advancing age in specific brain regions that regulate learning and memory and abolishing CB1 receptor signaling accelerates cognitive aging in mice. We recently demonstrated that prolonged exposure to low dose (3 mg/kg/day) Δ ⁹ -tetrahydrocannabinol (THC) improved the cognitive performances in old mice on par with young untreated mice. Here we investigated the potential influence of cannabidiol (CBD) on this THC effect, because preclinical and clinical studies indicate that the combination of THC and CBD often exhibits an enhanced therapeutic effect compared to THC alone. We first tested the effectiveness of a lower dose (1 mg/kg/day) THC, and then the efficacy of the combination of THC and CBD in 1:1 ratio, same as in the clinically approved medicine Sativex ® . Our findings reveal that a 1 mg/kg/day THC dose still effectively improved spatial learning in aged mice. However, a 1:1 combination of THC and CBD failed to do so. The presence of CBD induced temporal changes in THC metabolism ensuing in a transient elevation of blood THC levels. However, as CBD metabolizes, the inhibitory effect on THC metabolism was alleviated, causing a rapid clearance of THC. Thus, the beneficial effects of THC seemed to wane off more swiftly in the presence of CBD, due to these metabolic effects. The findings indicate that THC-treatment alone is more efficient to improve spatial learning in aged mice than the 1:1 combination of THC and CBD.
... To determine whether systemic exposure to YBP has beneficial effects on cognitive functions in aged mice, we performed a series of cognitive behavioural tests including novel object-location recognition test [15], novel partner recognition test [15], and spontaneous alterative Y-maze test [16]. All behavioural tests were performed between 10:00 a.m. and 3:00 p.m. ...
... To determine whether systemic exposure to YBP has beneficial effects on cognitive functions in aged mice, we performed a series of cognitive behavioural tests including novel object-location recognition test [15], novel partner recognition test [15], and spontaneous alterative Y-maze test [16]. All behavioural tests were performed between 10:00 a.m. and 3:00 p.m. ...
... The brain circuitry mediating spontaneous alteration performance in mice is different from that mediating novel object-location or partner recognition test [20,21], raising the possibility that the specific brain regions involved in the spontaneous alteration performance were somehow less sensitive to the YBP treatment. Additionally, the prefrontal cortex is critically involved in spatial working memory [22,23], while the hippocampus plays a key role in spatial reference memory and novel object/partner recognition memory [15,23,24]. This seems consistent with the result from our 18 F-FDG PET imaging, which demonstrated efficiently higher activation of the hippocampus but not the prefrontal cortex in aged mice treated with YBP. ...
Article
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PurposeTo investigate the in vivo neurofunctional changes and therapeutic effects of young blood plasma (YBP) in aged mice, as well as the molecular mechanisms underlying the therapeutic effects of YBP ex vivo and in vitro.Methods Aged C57/BL6 mice received systemic administrations of phosphate-buffered saline (PBS) or YBP twice a week, for 4 weeks. In vivo 2-[18F]-fluoro-2-deoxy-d-glucose positron emission tomography (18F-FDG PET) under conscious state and cognitive behavioural tests were performed after 4-week treatment. In addition, an in vitro senescent model was established, and the expressions of key cognition-associated proteins and/or the alterations of key neuronal pathways were analysed in both brain tissues and cultured cells.ResultsAged mice treated with YBP demonstrated higher glucose metabolism in the right hippocampus and bilateral somatosensory cortices, and lower glucose metabolism in the right bed nucleus of stria terminalis and left cerebellum. YBP treatment exerted beneficial effects on the spatial and long-term social recognition memory, and significantly increased the expressions of several cognition-related proteins and altered the key neuronal signalling pathways in the hippocampus and somatosensory cortex. Further in vitro studies suggested that YBP but not aged blood plasma significantly upregulated the expressions of several cognition-associated proteins.Conclusion Our results highlight the role of the hippocampus and somatosensory cortex in YBP-induced beneficial effects on recognition memory in aged mice. 18F-FDG PET imaging under conscious state provides a new avenue for exploring the mechanisms underlying YBP treatment against age-related cognitive decline.
... 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]. ...
Article
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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.
... Indeed, chronic inflammation in PWH on ART likely contributes to comorbidities such as HAND and depression. Several studies suggest that cannabinoids are anti-inflammatory and neuroprotective [10,[43][44][45]. Our recent studies showed that a cannabinoid receptor agonist, WIN55,212-2, may be neuroprotective by reducing neuroinflammatory gene expression in reactive astroglia, although we found that WIN55,212-2 was acting through peroxisome proliferator-activated receptors (PPAR) [13,46]. ...
... Importantly, there is evidence that the phytocannabinoids isolated from cannabis, ∆9-tetrahydrocannabinol (THC) and cannabidiol (CBD), activate PPAR  and  via signaling pathways that could be downstream of and also independent of CB1 and CB2 [47][48][49]. Other studies have shown that THC and CBD are neuroprotective in animal models for neurodegenerative diseases [45,50]. Thus, THC and CBD may mimic endocannabinoid signaling mediated down modulation of neuroinflammation, a process that may be perturbed in PWH. ...
... Astroglia and neurons are highly involved in endocannabinoid signaling [54,56,58,59]. Moreover, endocannabinoid signaling regulates neurotransmission and metabolism in and between the two brain cell types [12,45,49,[58][59][60][61][62]. These studies, for the first time, identify a shift in localization of CB1 receptors on neurons from punctate distribution to localization to the soma of neurons, which may be associated with a shift in mitochondrial fission and fusion processes in neurons as we reported in HAND brains [32]. ...
Preprint
HIV-associated neurocognitive disorders (HAND) persist despite the advent of antiretroviral therapy (ART), suggesting underlying systemic and central nervous system (CNS) inflammatory mechanisms. The endogenous cannabinoid receptors 1 and 2 (CB1 and CB2) modulate inflammatory gene expression and play an important role in maintaining neuronal homeostasis. Cannabis use is disproportionately high among people with HIV (PWH) and may provide a neuroprotective effect for those on ART due to its anti-inflammatory properties. However, expression profiles of CB1 and CB2 in the brains of PWH on ART with HAND have not been reported. In this study, biochemical and immunohistochemical analyses were performed to determine CB1 and CB2 expression in brain specimens of HAND donors. Immunoblot revealed CB1 and CB2 were differentially expressed in frontal cortices from HAND brains compared to neurocognitively unimpaired (NUI) brains from PWH. CB1 expression levels negatively correlated with memory and information processing speed. CB1 was primarily localized to neuronal soma in HAND brains versus a more punctate distribution on neuronal processes of NUI brains. CB1 expression was increased in cells with glial morphology and showed increased colocalization with an astroglial marker. These results suggest that targeting the endocannabinoid system may be a potential therapeutic strategy for HAND.
... These hypotheses need to be tested in a larger cohort with more closely age-matched controls. Several studies have suggested that cannabinoids are anti-inflammatory and neuroprotective [10,[44][45][46]. Our recent studies showed that a cannabinoid receptor agonist, WIN55,212-2, may be neuroprotective by reducing neuroinflammatory gene expression in reactive astroglia, although we found that WIN55,212-2 was acting through peroxisome proliferator-activated receptors (PPAR) [13,47]. ...
... Other studies have shown that THC and CBD are neuroprotective in animal models for neurodegenerative diseases [46,51]. Thus, THC and CBD may mimic endocannabinoid signaling mediated down modulation of neuroinflammation, a process that may be perturbed in PWH. ...
... Astroglia and neurons are highly involved in endocannabinoid signaling [55,57,59,60]. Moreover, endocannabinoid signaling regulates neurotransmission and metabolism in and between the two brain cell types [12,46,50,[59][60][61][62][63]. These studies, for the first time, identified a shift in the localization of CB1 receptors on neurons from punctate distribution to localization to the soma of neurons, which may be associated with a shift in mitochondrial fission and fusion processes in neurons, as we reported in HAND brains [33]. ...
Article
Full-text available
HIV-associated neurocognitive disorders (HAND) persist despite the advent of antiretroviral therapy (ART), suggesting underlying systemic and central nervous system (CNS) inflammatory mechanisms. The endogenous cannabinoid receptors 1 and 2 (CB1 and CB2) modulate inflammatory gene expression and play an important role in maintaining neuronal homeostasis. Cannabis use is disproportionately high among people with HIV (PWH) and may provide a neuroprotective effect for those on ART due to its anti-inflammatory properties. However, expression profiles of CB1 and CB2 in the brains of PWH on ART with HAND have not been reported. In this study, biochemical and immunohistochemical analyses were performed to determine CB1 and CB2 expression in the brain specimens of HAND donors. Immunoblot revealed that CB1 and CB2 were differentially expressed in the frontal cortices of HAND brains compared to neurocognitively unimpaired (NUI) brains of PWH. CB1 expression levels negatively correlated with memory and information processing speed. CB1 was primarily localized to neuronal soma in HAND brains versus a more punctate distribution of neuronal processes in NUI brains. CB1 expression was increased in cells with glial morphology and showed increased colocalization with an astroglial marker. These results suggest that targeting the endocannabinoid system may be a potential therapeutic strategy for HAND.
... Male and female rats were also found to have their working memories enhanced by acute THC [93]. Along with this, and the fact that BDNF and other hippocampus proteins exhibited a higher expression within the THC-treated rats in both [92,94], it was concluded that low-dose acute and chronic THC administration resulted in increased memory and learning processes. Other aspects, including decision making mediated by the amygdala and orbitofrontal cortex, have also been tested as a factors affected by THC, but at a much lower level than in the studies that explored cognitive and executive functions. ...
... Much of the literature published on THC use and its effects on cognitive function seems to vary greatly. In particular, there were human studies suggesting that midlife cannabis use, even when used chronically, had no effects on verbal recall and other cognitive functions [87]; while in other cases, rodent models that went as far as to propose that THC at low doses had the ability to restore the cognitive performance of advanced-age mice back to the hippocampal gene expression levels of 2-month-old mice (considered young) [94]. Chronic THC use in rodent and human studies, and given shortly before cognitive tests (verbal learning tests and recognition recall), resulted in decreased cognitive performance and decreased activity in brain regions involved in memory and attention, as well as synaptic changes and reduced volume within the hippocampus, prefrontal cortex, and cerebellum [86,[101][102][103][104]. ...
... Both human and rodent studies have concluded that chronic administration of THC resulted in longlasting effects, including on brain structure and behavior, especially within the adolescent brain [91,101,[107][108][109]. Others have found the opposite: that chronic exposure to THC had no long-lasting effects on the neuroplasticity and connectivity within the nervous system [94,105,106]. Of course, these differences across studies and models could be due to differences in amount or potency of THC, developmental period (even within adulthood), measurement and route of administration. ...
Article
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The Cannabis sativa plant has historically been used for both recreational and medical purposes. With the recent surge in recreational use of cannabis among adolescents and adults in particular, there is an increased obligation to determine the short- and long-term effects that consuming this plant may have on several aspects of the human psyche and body. The goal of this article was to examine the negative effects of obesity, and how the use of Δ9-tetrahydrocannibinol (THC) or cannabidiol (CBD) can impact rates of this global pandemic at different timepoints of life. Conflicting studies have been reported between adult and adolescents, as there are reports of THC use leading to increased weight due to elevated appetite and consumption of food, while others observed a decrease in overall body weight due to the regulation of omega-6/omega-3 endocannabinoid precursors and a decrease in energy expenditure. Studies supported a positive correlation between prenatal cannabis use and obesity rates in the children as they matured. The data did not indicate a direct connection between prenatal THC levels in cannabis and obesity rates, but that this development may occur due to prenatal THC consumption leading to low birthweight, and subsequent obesity. Due to the fact that there are not many studies that directly measured the effects that prenatal THC administration has on obesity risks within offspring, this could potentially be a topic of interest to investigate closer in the future.
... This result indicates that THC and CBD had no cytotoxic effect on human PBMCs and mouse N2a/APPswe cells within the concentration range tested. at the ages of 12 and 18 months [25,26] whereas a 1:1 combination of THC and CBD (1 mg/kg/d for each) failed to achieve the same effect as THC monotherapy [26]. Another study showed that single-dose intraperitoneal (IP) administration of THC at 0.002 mg/kg restored the cognitive function in 24-month-old female wild-type mice [27]. ...
... In this regard, the THC doses used in this study were much lower than the dose that could induce the anxiety-like behavior in mice. Contrary to common belief, a handful of preclinical studies have revealed the beneficial effect of in vivo THC treatment at doses ranging of 0.002 and 3 mg/kg against the age-related decline in cognitive performance of aged mice [25][26][27]. Unlike the documented in vivo studies [25][26][27], the present study was carried out on aged APP/PS1 mice, and the animals were treated with 0.02 and 0.2 mg/kg of THC once every other day, which were lower than the doses of 1 and 3 mg/kg/d reported by Zimmer's group [25,26]. Results of our study confirmed that aged APP/PS1 mice exhibited significantly elevated Aβ production and impaired spatial memory that recapitulated the early-stage AD in humans (Figures 3-5 and Figure 6C-G), suggesting that aged APP/PS1 mice are a better model than aged wild-type mice for evaluating the potential of THC in the treatment of AD. ...
... Contrary to common belief, a handful of preclinical studies have revealed the beneficial effect of in vivo THC treatment at doses ranging of 0.002 and 3 mg/kg against the age-related decline in cognitive performance of aged mice [25][26][27]. Unlike the documented in vivo studies [25][26][27], the present study was carried out on aged APP/PS1 mice, and the animals were treated with 0.02 and 0.2 mg/kg of THC once every other day, which were lower than the doses of 1 and 3 mg/kg/d reported by Zimmer's group [25,26]. Results of our study confirmed that aged APP/PS1 mice exhibited significantly elevated Aβ production and impaired spatial memory that recapitulated the early-stage AD in humans (Figures 3-5 and Figure 6C-G), suggesting that aged APP/PS1 mice are a better model than aged wild-type mice for evaluating the potential of THC in the treatment of AD. ...
Article
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Studies on the effective and safe therapeutic dosage of delta-9-tetrahydrocannabinol (THC) for the treatment of Alzheimer’s disease (AD) have been sparse due to the concern about THC’s psychotropic activity. The present study focused on demonstrating the beneficial effect of low-dose THC treatment in preclinical AD models. The effect of THC on amyloid-β (Aβ) production was examined in N2a/AβPPswe cells. An in vivo study was conducted in aged APP/PS1 transgenic mice that received an intraperitoneal injection of THC at 0.02 and 0.2 mg/kg every other day for three months. The in vitro study showed that THC inhibited Aβ aggregation within a safe dose range. Results of the radial arm water maze (RAWM) test demonstrated that treatment with 0.02 and 0.2 mg/kg of THC for three months significantly improved the spatial learning performance of aged APP/PS1 mice in a dose-dependent manner. Results of protein analyses revealed that low-dose THC treatment significantly decreased the expression of Aβ oligomers, phospho-tau and total tau, and increased the expression of Aβ monomers and phospho-GSK-3β (Ser9) in the THC-treated brain tissues. In conclusion, treatment with THC at 0.2 and 0.02 mg/kg improved the spatial learning of aged APP/PS1 mice, suggesting low-dose THC is a safe and effective treatment for AD.
... In pre-clinical models, low doses of THC appear to be neuroprotective and even reverse age-related cognitive decline in older animals, while at the same time, these same THC doses appear to have deleterious effects in younger animals (Bilkei-Gorzo et al., 2017). Specifically, THC administration to aged mice increased hippocampal spine density and synaptic connectivity and enhanced cognitive performance, while THC administration in younger animals worsened cognitive performance and had no effect on spine density. ...
... Second, we investigate networks involving the posterior cingulate, given its central role in the default mode network (Greicius et al., 2003) and fMRI evidence that it is modulated by cannabis use (Bossong et al., 2013;Pujol et al., 2014). Finally, based on animal and human evidence implicating hippocampal changes with cannabis use (Yücel et al., 2008;Ashtari et al., 2011;Demirakca et al., 2011;Bilkei-Gorzo et al., 2017) and aging (Miller and O'Callaghan, 2005;Barrientos et al., 2015;Leal and Yassa, 2015), we test whether networks involving this region differs between older cannabis users and non-users. To facilitate the interpretation of our findings in older adults, we additionally investigate rsFC differences found in older vs. younger adult non-users. ...
... Further, age-dependent cognitive declines in CB1 mutants are accompanied by increased agerelated hippocampal neuroinflammation and accelerated loss of hippocampal neurons (Bilkei-Gorzo et al., 2005;Albayram et al., 2011;Bilkei-Gorzo, 2012). A recent animal study by Bilkei-Gorzo found that low doses of THC administered to older mice increased hippocampal spine density as well as molecular markers associated with synaptogenesis (Bilkei-Gorzo et al., 2017). These anatomical changes in the hippocampus were accompanied by changes in cognition, such that cognitive performances attained in treated old mice were indistinguishable from those in untreated younger mice. ...
Article
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Several lines of evidence suggest that older adults (aged 65+) sharply increased their cannabis use over the last decade, highlighting a need to understand the effects of cannabis in this age group. Pre-clinical models suggest that cannabinoids affect the brain and cognition in an age-dependent fashion, having generally beneficial effects on older animals and deleterious effects on younger ones. However, there is little research on how cannabis affects the brains of older adults or how older adults differ from younger adults who use cannabis. Resting state functional connectivity (rsFC) measures provide sensitive metrics of age-related cognitive decline. Here we compared rsFC in older adults who are either regular users of cannabis or non-users. We found stronger connectivity between sources in the hippocampus and parahippocampal cortex, and targets in the anterior lobes of the cerebellum in older adult cannabis users relative to non-users. A similar pattern of strengthened connectivity between hippocampal and cerebellar structures was also present in 25–35 year old non-users in comparison to 60–88 year old non-users. These findings suggest that future studies should examine both the potential risks of cannabinoids, as well as a potential benefits, on cognition and brain health for older adults.
... 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.
... These data are consistent with studies in animal models that show that cannabinoids can slow progression of neurodegenerative disease and behavioral deficits through reductions in inflammatory responses. [78][79][80] Follow-up experiments are needed to determine if the immunosuppressive effect is a property of other cannabinoids. In future studies, it will be important to assess toxicity using in vitro and in vivo models to optimize the therapeutic use of WIN and other cannabinoids. ...
... The global anti-inflammatory activity of WIN may explain recent studies that suggest cannabis is neuroprotective in AD and HAND. 78,86 Future studies examining the effects of different stimuli and combinations of varying proportions on astrocytes and other brain cells may lead to better modeling of and therapeutic testing for neurodegenerative diseases. ...
Article
Background: Alterations of astrocyte function play a crucial role in neuroinflammatory diseases due to either the loss of their neuroprotective role or the gain of their toxic inflammatory properties. Accumulating evidence highlights that cannabinoids and cannabinoid receptor agonists, such as WIN55,212-2 (WIN), reduce inflammation in cellular and animal models. Thus, the endocannabinoid system has become an attractive target to attenuate chronic inflammation in neurodegenerative diseases. However, the mechanism of action of WIN in astrocytes remains poorly understood. Objective: We studied the immunosuppressive property of WIN by examining gene expression patterns that were modulated by WIN in reactive astrocytes. Materials and Methods: Transcriptomic analysis by RNA-seq was carried out using primary human astrocyte cultures stimulated by the proinflammatory cytokine interleukin 1 beta (IL1β) in the presence or absence of WIN. Real-time quantitative polymerase chain reaction analysis was conducted on selected transcripts to characterize the dose-response effects of WIN, and to test the effect of selective antagonists of cannabinoid receptor 1 (CB1) and peroxisome proliferator-activated receptors (PPAR). Results: Transcriptomic analysis showed that the IL1β-induced inflammatory response is robustly inhibited by WIN pretreatment. WIN treatment alone also induced substantial gene expression changes. Pathway analysis revealed that the anti-inflammatory properties of WIN were linked to the regulation of kinase pathways and gene targets of neuroprotective transcription factors, including PPAR and SMAD (mothers against decapentaplegic homolog). The inhibitory effect of WIN was dose-dependent, but it was not affected by selective antagonists of CB1 or PPAR. Conclusions: This study suggests that targeting the endocannabinoid system may be a promising strategy to disrupt inflammatory pathways in reactive astrocytes. The anti-inflammatory activity of WIN is independent of CB1, suggesting that alternative receptors mediate the effects of WIN. These results provide mechanistic insights into the anti-inflammatory activity of WIN and highlight that astrocytes are a potential therapeutic target to ameliorate neuroinflammation in the brain.
... Notably, however, eCS signaling declines with age (Di Marzo et al., 2015), and there is limited research on the neural and health impacts of cannabis use among older adults. It is also relevant to note that chronically-administered THC may reverse age-related cognitive impairment in animal models (Bilkei-Gorzo et al., 2017). Thus, it is important to consider the role that cannabis use might play in the relationships between aging, inflammation, and cognitive function in humans. ...
... Finally, we included cannabis as a covariate in all models, given the potential neuroprotective role of the eCS (Paloczi et al., 2018), the potential for cannabis to reverse age-related cognitive decline in animal models (Bilkei-Gorzo et al., 2017), and the fact that older individuals (including 15 individuals in the present study) are increasingly reporting regular cannabis use (Han and Palamar, 2020). Because cannabis use was associated with hippocampal volume in the path model, we conducted exploratory comparisons of GM volume between cannabis users and non-users across several subcortical structures. ...
Article
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Background : Exploring biological variables that may serve as indicators of the development and progression of cognitive decline is currently a high-priority research area. Recent studies have demonstrated that during normal aging, individuals experience increased inflammation throughout the brain and body, which may be linked to cognitive impairment and reduced gray matter volume in the brain. Neurofilament light polypeptide (NfL), which is released into the circulation following neuronal damage, has been proposed as a biomarker for neurodegenerative diseases, and may also have utility in the context of normal aging. The present study tested associations between age, peripheral levels of the pro-inflammatory cytokine IL-6, peripheral NfL, brain volume, and cognitive performance in a sample of healthy adults over 60 years old. Methods : Of the 273 individuals who participated in this study, 173 had useable neuroimaging data, a subset of whom had useable blood data (used for quantifying IL-6 and NfL) and completed a cognitive task. Gray matter (GM) thickness values were extracted from brain areas of interest using Freesurfer. Regression models were used to test relationships between IL-6, NfL, GM, and cognitive performance. To test putative functional relationships between these variables, exploratory path analytic models were estimated, in which the relationship between age, IL-6, and working memory performance were linked via four different operationalizations of brain health: (1) a latent GM variable composed of several regions linked to cognitive impairment, (2) NfL alone, (3) NfL combined with the GM latent variable, and (4) the hippocampus alone. Results : Regression models showed that IL-6 and NfL were significantly negatively associated with GM volume and that GM was positively associated with cognitive performance. The path analytic models indicated that age and cognitive performance are linked by GM in the hippocampus as well as several other regions previously associated with cognitive impairment, but not by NfL alone. Peripheral IL-6 was not associated with age in any of the path models. Conclusions : Results suggest that among healthy older adults, there are several GM regions that link age and cognitive performance. Notably, NfL alone is not a sufficient marker of brain changes associated with aging, inflammation, and cognitive performance.
... Although cannabinoid use is generally associated with cognitive impairment [23], a recent study showed that, while in young mice a chronic low dose THC treatment acts through CB1 to impair memory, it has the opposite effect in aged mice [24]. This result, along with findings of reduced CB1 expression and function in aged mice [25] and of early onset cognitive dysfunction in mice with CB1 deletion [26], suggests that CB1 agonists may have a beneficial effect in the treatment of age-related cognitive impairment. ...
... Importantly, GAT211 could be useful as an opioid-sparing treatment, which is especially relevant in the face of the current opioid epidemic. GAT211, as a CB1 ago-PAM, may also have therapeutic potential in disorders associated with an impaired endocannabinoid system, such as during aging and neurodegeneration, as it would be able to counteract reduced CB1 expression and boost endogenous cannabinoid signaling [24][25][26]148]. ...
Article
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The CB1 cannabinoid receptor is a G-protein coupled receptor highly expressed throughout the central nervous system that is a promising target for the treatment of various disorders, including anxiety, pain, and neurodegeneration. Despite the wide therapeutic potential of CB1, the development of drug candidates is hindered by adverse effects, rapid tolerance development, and abuse potential. Ligands that produce biased signaling—the preferential activation of a signaling transducer in detriment of another—have been proposed as a strategy to dissociate therapeutic and adverse effects for a variety of G-protein coupled receptors. However, biased signaling at the CB1 receptor is poorly understood due to a lack of strongly biased agonists. Here, we review studies that have investigated the biased signaling profile of classical cannabinoid agonists and allosteric ligands, searching for a potential therapeutic advantage of CB1 biased signaling in different pathological states. Agonist and antagonist bound structures of CB1 and proposed mechanisms of action of biased allosteric modulators are used to discuss a putative molecular mechanism for CB1 receptor activation and biased signaling. Current studies suggest that allosteric binding sites on CB1 can be explored to yield biased ligands that favor or hinder conformational changes important for biased signaling.
... the transcriptional effects of THC were critically dependent on CB1R on glutamatergic neurons, as inhibition of these receptors blocked the positive effects of THC. The authors formulated the optimistic conclusion that recovery of CB1 signaling in elderly humans may be an effective strategy for treating age-related cognitive impairments [Bilkei-Gorzo et al., 2017]. Analysis of published data provides evidence that cannabinoids can mediate differential modulation of the formation of aversive memory depending on different brain structures or may not affect it. ...
... It is interesting to note that aging animals displayed improvements in cognitive characteristics on exposure to THC [Bilkei-Gorzo et al., 2017]. The authors showed that a low dose of THC (3 mg/kg/day for 28 days) reversed the age-related decline in cognitive functions in mice at ages 12 and 18 months on performance of a spatial memory task in the Morris water maze. ...
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Cannabinoids are natural compounds found in the hemp (Cannabis sativa). Scientific interest in cannabinoids arose after the discovery of the major psychoactive component in hemp, Δ9-tetrahydrocannabinol. Subsequent studies detected receptors in the brain subject to the actions of this compound, along with ligands for these receptors, i.e., endogenous cannabinoids (EC), which make up, along with the enzymes synthesizing, transporting, and degrading them, the endocannabinoid system (ECS). Interest in EC has consistently increased in recent years, especially after their important role in cognitive functions was discovered. They are regulators of synaptic transmission in the brain, mediate numerous forms of plasticity, and control neuron energy metabolism. EC exert influences using a series of mechanisms and interactions with neuromediators, neurotrophic factors, and neuropeptides. The main functions of EC in the brain are retrograde synaptic signaling and neuromodulation, which maintain cellular homeostasis. Information on the influences of cannabinoid drugs on cognitive functions is very contradictory. The cause of this may be that there are still inadequate strictly scientific data from clinical and sociological studies, while in animal experiments different authors use different methods and approaches for actions on the ECS. Thus, effects can differ depending on the substances used, their doses, and routes of administration, and the tasks and experimental conditions selected for testing. There is an extensive literature on the protective effect of ECS activation in neurodegenerative diseases in humans and models of cognitive deficit in animals. This review addresses data providing evidence of the influences of cannabinoid drugs and activation of the EC system on cognitive functions in the normal brain and in neurodegenerative diseases, Alzheimer’s disease, and temporal epilepsy. The possible causes of contradictions in existing data are also discussed.
... In one study, chronic administration of low doses of THC was shown to reverse age-related cognitive decline. These effects were associated with molecular and neuronal changes in the hippocampus [66]. Similarly, in another study, a single low dose of THC improved neurocognitive functioning [67]. ...
... Similarly, in another study, a single low dose of THC improved neurocognitive functioning [67]. These results contrast with the deleterious effect of THC in brain development and neurocognitive functioning in young animals [66]. These intriguing initial findings highlight the need for further animal studies to better model and understand the impact of cannabis on aging in humans. ...
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Purpose of Review This review examines the neurocognitive effects of cannabis and relevant developmental factors across adolescence (age 13–21), adulthood (21–65), and older adulthood (65 +). Recent Findings Cannabis use is robustly associated with poorer neurocognitive functioning; however, studies that carefully control for confounds have often not found any evidence for impairment. Notably, the endocannabinoid system may underly how cannabis use affects neurocognitive functions, including heightened vulnerability during adolescence. In contrast, the endocannabinoid system may underlie protective neurocognitive effects of cannabis in older adults. Notably, older adults have reported sharp increases in recent cannabis use. Summary As legalization increases the accessibility, variety, and potency of cannabis, strong empirical evidence is needed to understand its neurocognitive effects across the lifespan. In particular, rigorous study designs are needed to investigate the neurocognitive effects of cannabis, including among vulnerable populations (adolescents, older adults) and mediating (e.g., endocannabinoid system) and moderating factors (e.g., alcohol use).
... 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). ...
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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
... According to this hypothesis, the paucity of papers investigating the effect of modulation of the endocannabinoid system in aged rodents seems to suggest that replenishing the lost endocannabinoid signaling would be beneficial to slowing down the physiological aging process (Table 4) [62][63][64]. Low doses of THC have been employed to reach this goal, i.e., to improve the cognitive performance of aged mice. ...
... Low doses of THC have been employed to reach this goal, i.e., to improve the cognitive performance of aged mice. Interestingly, while Bilkei-Gorzo [62] and Nidadavolu [63] obtained this result after chronic treatment, Sarne [64] demonstrated the positive effect of a single ultralow dose of THC (0.002 mg/kg) in aged female mice that lasted at least 7 weeks. They suggested that a single dose of THC was able to induce long-lasting structural alterations, likely through the involvement of Sirtuin-1, a protein deacetylase that was shown to be involved in synaptic plasticity, memory formation, learning capability, neuronal development, and neuroprotection, and that was found decreased in old mice [64]. ...
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Cannabis is still the most widely used illicit drug around the world. While its use has always been prevalent among adolescents, recent evidence suggests that its consumption is also increasing among other population groups, such as pregnant women and aged people. Given the known impact of cannabis on brain development and behavior, it is important to dissect the possible long-term impact of its use across different age groups, especially on measures of cognitive performance. Animal models of cannabinoid exposure have represented a fundamental tool to characterize the long-lasting consequences of cannabinoids on cognitive performance and helped to identify possible factors that could modulate cannabinoids effects in the long term, such as the age of exposure and doses administered. This scoping review was systematically conducted using PubMed and includes papers published from 2015 to December 2021 that examined the effects of cannabinoids, either natural or synthetic, on cognitive performance in animal models where exposure occurred in the prenatal period, during adolescence, or in older animals. Overall, available data clearly point to a crucial role of age in determining the long-term effect of cannabinoid on cognition, highlighting possible detrimental consequences during brain development (prenatal and adolescent exposure) and beneficial outcomes in old age. In contrast, despite the recent advances in the field, it appears difficult to clearly establish a possible role of dosage in the effects of cannabinoids on cognition, especially when the adolescent period is taken into account.
... Exposure of aged mice to ΔTHC reverses age-related cognitive performance decline, elevates synaptic marker proteins expression, and improves hippocampal spine density via glutamatergic CB1 receptor-dependent stimulation (Bilkei-Gorzo et al. 2017). Δ-9-tetrahydrocannabinol (ΔTHC) has also been observed to help treat glaucoma and increase acquired immunodeficiency syndrome (AIDS) victims' appetite to maintain their body size (Datta et al. 2021). ...
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Cannabis sativa, Datura stramonium, Nicotiana tabacum, and Carica papaya are plants that naturally grow in Nigeria. They are reportedly rich in neuroactive compounds that are capable of reacting with the nervous system to elicit psychoactive and/or toxic effects that deter predators. However, despite the toxicological potential of these plants, their recreational use is on the rise due to the psychoactivity they proffer and prevalence in Nigeria. The aim of the present study is to evaluate the plants’ recreational use, mechanism of actions and toxicities. Relevant published documents on psychoactive plants in Nigeria were obtained from Web of Science between 2002 and 2020. Non-English documents, documents not in Science Citation Index Expanded and Google Scholar were removed while 1186 documents were reviewed. Results showed that the plants are recreationally used in Nigeria with a higher prevalence than the global frequency. They are very addictive and lead to dependence. The plants were also observed to elicit different mechanism of action, though the activation of monoaminergic neurotransmission system was common to all. Regrettably, the plants could be toxic when ingested under non-medical conditions. Conclusively, these plants are addictive with potential toxic effects. Therefore, control of the recreational use of these plants should be revamped and overhauled.
... Chronic cannabis use was found, in preclinical models, to decrease degenerative and inflammatory processes in the central nervous system, by modulating cannabinoid (CB1) and CB2 receptors. When activated, these receptors reduce excitotoxicity, phosphorylation and plaque formation, all neuropathological hallmarks of Alzheimer's disease (Martín-Moreno et al., 2012;Bilkei-Gorzo et al., 2017;Sarne et al., 2018;Suliman et al., 2018). Clinically, cannabis use in older adults has many physical and mental health adverse effects ). ...
Article
Purpose This study aims to review the presentation of substance use disorders in older adults, how addiction intertwines with neurocognitive disorders and how to approach this vulnerable population. Design/methodology/approach Electronic data searches of PubMed, Medline and the Cochrane Library (years 2000–2021) were performed using the keywords “neurocognitive,” “dementia,” “substance use,” “addiction,” “older adults” and “elderly.” The authors, in consensus, selected pivotal studies and conducted a narrative synthesis of the findings. Findings Research about substance use disorders in older adults is limited, especially in those with superimposed neurocognitive disorders. Having dual diagnoses can make the identification and treatment of either condition challenging. Management should use a holistic multidisciplinary approach that involves medical professionals and caregivers. Originality/value This review highlights some of the intertwining aspects between substance use disorders and neurocognitive disorders in older adults. It provides a comprehensive summary of the available evidence on treatment in this population.
... 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.
... Aging describes physiological progressive functional decline at the molecular and systemic levels. Age has a significant effect on internal immunoinflammatory responses to acute injury and might induce chronic brain dysfunction (Sinha et al., 2014;Bilkei-Gorzo et al., 2017). The previous studies reported that age results in impaired immunity, including the loss of naive T cells and the accumulation of NK cells (Smithey et al., 2018;Jin et al., 2021). ...
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Age is a well-known risk factor that is independently associated with poor outcomes after intracerebral hemorrhage (ICH). However, the interrelationship between age and poor outcomes after ICH is not well defined. In this study, we aimed to investigate this relationship based on collagenase-induced ICH mice models. After being assessed neurological deficit 24 h after ICH, mice were euthanized and brain perihematomal tissues were used for RNA-sequencing (RNA-seq). And then the functions of differentially expressed genes (DEGs) identified by RNA-seq were analyzed using Gene Ontology (GO) analysis, Kyoto Encyclopedia of Genes and Genomes (KEGG) analysis, Ingenuity Pathway Analysis (IPA) and protein-protein interaction (PPI) analysis. In addition, we performed real-time quantitative polymerase chain reaction (RT-qPCR) for validation of candidate DEGs. In the behavioral tests, aged mice presented significantly worse neurological function than young mice and greater weight loss than aged sham controls 24 h after ICH. In DEGs analysis, ICH affected the expression of more genes in young mice (2,337 DEGs) compared with aged mice (2,005 DEGs). We found aged mice exhibited increased brain inflammatory responses compared with young animals and ICH induced significant activation of the interferon-β (IFN-β) and IFN signaling pathways exclusively in aged mice. Moreover, further analysis demonstrated that ICH resulted in the activation of cytosolic DNA-sensing pathway with the production of downstream molecule type I IFN, and the response to type I IFN was more significant in aged mice than in young mice. In agreement with the results of RNA-seq, RT-qPCR indicated that the expression of candidate genes of cyclic GMP-AMP synthase (cGAS), Z-DNA-binding protein 1 (ZBP1), and IFN-β was significantly altered in aged mice after ICH. Taken together, our study indicated that compared to young animals, aged mice exhibit increased vulnerability to ICH and that the differences in transcriptional response patterns to ICH between young and aged mice. We believe that these findings will facilitate our understanding of ICH pathology and help to translate the results of preclinical studies into a clinical setting.
... 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.
... This is especially true when investigating emotional behavior since the pharmacological increase in AEA levels might induce opposite effects on anxiety behavior depending on the emotional status of the animals [17]. Both positive and negative effects of altered cannabinoid receptor signaling have also been described for memory formation, which can be influenced by different agonist or antagonist treatments depending on the application, dosage, and behavioral paradigm [18,43]. For exogenous cannabinoid administrations of CB1 receptor agonists, it is well known to have a biphasic dose-dependent effect on anxiety with anxiolytic effects of low and anxiogenic effects of high doses [19]. ...
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Elementary emotional states and memory can be regulated by the homeostasis of the endocannabinoid system (ECS). Links between the ECS and the autophagy receptor p62 have been found at the molecular level and in animal studies. This project aimed to validate the anxiety and memory phenotype of p62 knockout (KO) animals and whether the ECS plays a role in this. We examined the behavior of p62 KO animals and analyzed whether endocannabinoid levels are altered in the responsible brain areas. We discovered in age-dependent obese p62-KO mice decreased anandamide levels in the amygdala, a brain structure important for emotional responses. Against our expectation, p62 KO animals did not exhibit an anxiety phenotype, but showed slightly increased exploratory behavior as evidenced in novel object and further tests. In addition, KO animals exhibited decreased freezing responses in the fear conditioning. Administration of the phytocannabinoid delta9-tetrahydrocannabinol (THC) resulted in lesser effects on locomotion but in comparable hypothermic effects in p62 KO compared with WT littermates. Our results do not confirm previously published results, as our mouse line does not exhibit a drastic behavioral phenotype. Moreover, we identified further indications of a connection to the ECS and hence offer new perspectives for future investigations.
... Cannabinoid receptors have been shown to modulate adult neurogenesis by acting at specific neurogenic phases [51]. Significantly, CB1 or CB2 receptors by selective agonists have been shown to play a role in cell proliferation, neuronal differentiation, and maturation [61][62][63]. In NSCs and their neuronal progenies, CB1 and CB2 receptors' expression varies during the various stages of neuronal differentiation, with CB1 increasing with neural maturation and CB2 becoming more abundant in less dedicated cells [64]. ...
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Background Cannabis and its extracts are now being explored due to their huge health benefits. Although, the effect it elicits whether in humans or rodents may vary based on the age of the animal/subject and or the time in which the extract is administered. However, several debates exist concerning the various medical applications of these compounds. Nonetheless, their applicability as therapeutics should not be clouded based on their perceived negative biological actions. Methodology Articles from reliable databases such as Science Direct, PubMed, Google scholar, Scopus and Ovid were searched. Specific search methods were employed using multiple keywords: ‘‘Medicinal Cannabis; endocannabinoid system; cannabinoids receptors; cannabinoids and cognition; brain disorders; neurodegenerative diseases’’. For the inclusion/exclusion criteria, only relevant articles related to medicinal cannabis and its various compounds were considered. Result and conclusion The current review highlights the role, effects and involvement of cannabis; cannabinoids and endocannabinoids in preventing selected neurodegenerative diseases and possible amelioration of cognitive impairments. Also, cannabis utilization in many disease conditions such as Alzheimer’s and Parkinson’s disease among others. In conclusion, the usage of cannabis should be further explored as accumulating evidence suggests that it could be effective and somewhat safe especially when recommended dosage is adhered to. Furthermore, an in-depth studies should be conducted in order to unravel the specific mechanism underpinning the involvement of cannabinoids at the cellular level and their therapeutic applications.
... Considering that high doses of THC potentially produce undesirable effects, some authors have addressed the importance of using low to ultra-low doses of THC. In this line, low doses of THC reverse cognitive impairment in old mice (Bilkei-Gorzo et al., 2017), also, ultra-low doses of THC improved cognitive performance in a spatial memory test in old female mice (Sarne et al., 2018) and did not affect anxiety (Fishbein-Kaminietsky et al., 2014), an undesirable effect of THC. ...
Article
Δ9-tetrahydrocannabinol (THC) is the main phytocannabinoid present in the Cannabis sativa. It can produce dose-dependent anxiolytic or anxiogenic effects in males. THC effects on anxiety have scarcely been studied in females, despite their higher prevalence of anxiety disorders. Cannabidiol, another phytocannabinoid, has been reported to attenuate anxiety and some THC-induced effects. The present study aimed to investigate the behavioral and neurochemical effects of THC administered alone or combined with CBD in naturally cycling female rats tested in the elevated plus-maze. Systemically administered THC produced biphasic effects in females, anxiolytic at low doses (0.075 or 0.1 mg/kg) and anxiogenic at a higher dose (1.0 mg/kg). No anxiety changes were observed in males treated with the same THC dose range. The anxiogenic effect of THC was prevented by co-administration of CBD (1.0 or 3.0 mg/kg). CBD (3.0 mg/kg) caused an anxiolytic effect. At a lower dose (1.0 mg/kg), it facilitated the anxiolytic effect of the low THC dose. The anxiogenic effect of THC was accompanied by increased dopamine levels in the medial prefrontal cortex (mPFC) and nucleus accumbens (NAc). In contrast, its anxiolytic effect was associated with increased mPFC serotonin concentrations. The anxiolytic effect of CBD was accompanied by increased mPFC serotonin turnover. Together, these results indicate that female rats are susceptible to the biphasic effects of low THC doses on anxiety. These effects could depend on mPFC and NAc dopaminergic and serotoninergic neurotransmissions. CBD could minimize potential THC high-dose side effects whereas enhancing the anxiolytic action of its low doses in females.
... Preclinical models show activation of CB1 and CB2 receptors can induce apoptosis of activated T-cells and macrophages (Persidsky et al., 2015), downregulate pro-inflammatory cytokine and chemokine production (Nagarkatti, Pandey, Rieder, Hegde, & Nagarkatti, 2009), and inhibit HIV-associated synapse loss and neural injury (Kim, Shin, & Thayer, 2011;Ramirez et al., 2013). Both natural and synthetic cannabinoids have demonstrated neuroprotective effects after various types of CNS insults, and in particular under conditions of high inflammation (Bilkei-Gorzo et al., 2017;Chen et al., 2017). In vitro, THC treatment has been shown to suppress a number of pro-inflammatory factors including TNF-α, IL-6, and IL-8 and decrease NF-κB secretion in human osteosarcoma cells (Yang, Li, Han, Jia, & Ding, 2015) as well as monocyte-derived interleukin IL-1ß production and astrocyte secretion of MCP-1 and IL-6 from a human coculture system (Rizzo et al., 2019). ...
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Objective Recent cannabis exposure has been associated with lower rates of neurocognitive impairment in people with HIV (PWH). Cannabis’s anti-inflammatory properties may underlie this relationship by reducing chronic neuroinflammation in PWH. This study examined relations between cannabis use and inflammatory biomarkers in cerebrospinal fluid (CSF) and plasma, and cognitive correlates of these biomarkers within a community-based sample of PWH. Methods 263 individuals were categorized into four groups: HIV− non-cannabis users ( n = 65), HIV+ non-cannabis users ( n = 105), HIV+ moderate cannabis users ( n = 62), and HIV+ daily cannabis users ( n = 31). Differences in pro-inflammatory biomarkers (IL-6, MCP-1/CCL2, IP-10/CXCL10, sCD14, sTNFR-II, TNF- α ) by study group were determined by Kruskal–Wallis tests. Multivariable linear regressions examined relationships between biomarkers and seven cognitive domains, adjusting for age, sex/gender, race, education, and current CD4 count. Results HIV+ daily cannabis users showed lower MCP-1 and IP-10 levels in CSF compared to HIV+ non-cannabis users ( p = .015; p = .039) and were similar to HIV− non-cannabis users. Plasma biomarkers showed no differences by cannabis use. Among PWH, lower CSF MCP-1 and lower CSF IP-10 were associated with better learning performance (all p s < .05). Conclusions Current daily cannabis use was associated with lower levels of pro-inflammatory chemokines implicated in HIV pathogenesis and these chemokines were linked to the cognitive domain of learning which is commonly impaired in PWH. Cannabinoid-related reductions of MCP-1 and IP-10, if confirmed, suggest a role for medicinal cannabis in the mitigation of persistent inflammation and cognitive impacts of HIV.
... This becomes important in natural aging processes in which 2-AG levels decrease 10 and there is a depletion of NSPC in the hippocampus possibly leading to cognitive deficits. In fact, a chronic low dose of Δ9-tetrahydrocannabinol can restore the age-related decline on cognitive functions in old mice 30 . ...
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The endocannabinoid system modulates adult hippocampal neurogenesis by promoting the proliferation and survival of neural stem and progenitor cells (NSPCs). This is demonstrated by the disruption of adult neurogenesis under two experimental conditions: (1) NSPC-specific deletion of cannabinoid receptors and (2) constitutive deletion of the enzyme diacylglycerol lipase alpha (DAGLa) which produces the endocannabinoid 2-arachidonoylglycerol (2-AG). However, the specific cell types producing 2-AG relevant to neurogenesis remain unknown. Here we sought to identify the cellular source of endocannabinoids in the subgranular zone of the dentate gyrus (DG) in hippocampus, an important neurogenic niche. For this purpose, we used two complementary Cre-deleter mouse strains to delete Dagla either in neurons, or in astroglia and NSPCs. Surprisingly, neurogenesis was not altered in mice bearing a deletion of Dagla in neurons (Syn-Dagla KO), although neurons are the main source for the endocannabinoids in the brain. In contrast, a specific inducible deletion of Dagla in NPSCs and astrocytes (GLAST-CreERT2-Dagla KO) resulted in a strongly impaired neurogenesis with a 50% decrease in proliferation of newborn cells. These results identify Dagla in NSPCs in the DG or in astrocytes as a prominent regulator of adult hippocampal neurogenesis. We also show a reduction of Daglb expression in GLAST-CreERT2-Dagla KO mice, which may have contributed to the neurogenesis phenotype.
... The function of the brain's endogenous cannabinoid system diminishes with normal aging [49][50][51][52]. According to a recent report, the administration of low-dose cannabinoids to young mice impairs the ability to perform learning and memory tasks; however, the same dose can improve the ability to perform learning and memory tasks in aged mice [53]. Therefore, the reduction of LCPUFA levels that accompanies aging may influence the cognitive function of the part of the brain that is responsible for emotions and memory. ...
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Background There is a growing interest in the significance of adopting a variety of lifestyle habits for maintaining cognitive function among older adults. A lifestyle that is easy to modify, simple, and less burdensome for older people is ideal. We investigated the longitudinal association between global cognitive decline and cognitive leisure activities (CLAs) combined with long-chain polyunsaturated fatty acids (LCPUFAs) intake. Methods The National Institute for Longevity Sciences-Longitudinal Study of Aging (NILS-LSA) enrolled community-dwelling middle-aged and older men and women who were randomly selected from Obu-City and Higashiura Town, Aichi, Japan. Baseline data (2006–2008), including CLAs and dietary intake, were obtained from 517 participants (aged 60–84 years) with normal cognition. Global cognitive decline, defined as the Mini-Mental State Examination (MMSE) score ≤ 27, was assessed at baseline and four years later. Interaction between CLAs and LCPUFAs on cognitive decline was investigated using a multiple logistic analysis with adjustment for confounders. CLA engagement and LCPUFA intake were divided into high and low groups according to the frequency at which each participant engaged in the activity and the median intake level according to sex, respectively. Results A significant interaction was detected for the combination of CLA engagement and LCPUFA intake. Logistic regression coefficients revealed significant interactions when participants engaged in more than five CLA varieties. One of the CLAs, art appreciation, produced a significant main effect against cognitive decline and a significant interaction in combination with LCPUFA intake. The major LCPUFAs—docosahexaenoic acid and arachidonic acid—also exhibited a significant interaction. The combination of high LCPUFA intake and high art appreciation frequency yielded a lower adjusted odds ratio for cognitive decline than the combination of low LCPUFA and low art appreciation [0.25 (95 % confidence intervals, 0.11–0.56)]. Conclusions Preserving cognitive function might be associated with a combination of varied and high-frequency engagement in CLAs combined with high LCPUFA intake.
... Human studies have similarly revealed higher CB1 receptor binding in younger individuals relative to older adults (Di Marzo, Stella, & Zimmer, 2015). In addition, although few studies have examined cognition secondary to MC use in older adults, several animal studies highlight the potential for cannabis to improve cognition in this population (Weinstein & Sznitman, 2020), including one study demonstrating that administration of low-dose THC reversed age-related decline in older adult mice (Bilkei-Gorzo et al., 2017) While results from the current study are promising, findings must be considered given several limitations. Although the demographic makeup of the current sample reflects Massachusetts, this sample of patients has limited diversity; thus, findings may not be generalizable to all populations. ...
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Objective: Cannabis use has increased dramatically across the country; however, few studies have assessed the long-term impact of medical cannabis (MC) use on cognition. Studies examining recreational cannabis users generally report cognitive decrements, particularly in those with adolescent onset. As MC patients differ from recreational consumers in motives for use, product selection, and age of onset, we assessed cognitive and clinical measures in well-characterized MC patients over 1 year. Based on previous findings, we hypothesized MC patients would not show decrements and might instead demonstrate improvements in executive function over time. Method: As part of an ongoing study, MC patients completed a baseline visit prior to initiating MC and evaluations following 3, 6, and 12 months of treatment. At each visit, patients completed a neurocognitive battery assessing executive function, verbal learning/memory, and clinical scales assessing mood, anxiety, and sleep. Exposure to delta-9-tetrahydrocannabinol (THC) and cannabidiol (CBD) was also quantified. Results: Relative to baseline, MC patients demonstrated significant improvements on measures of executive function and clinical state over the course of 12 months; verbal learning/memory performance generally remained stable. Improved cognitive performance was not correlated with MC use; however, clinical improvement was associated with higher CBD use. Analyses suggest cognitive improvements were associated with clinical improvement. Conclusions: Study results extend previous pilot findings, indicating that MC patients may exhibit enhanced rather than impaired executive function over time. Future studies should examine distinctions between recreational and MC use to identify potential mechanisms related to cognitive changes and the role of clinical improvement.
... A chronic low dose of THC restored cognitive function in old mice and reversed the age-related decline. This effect was accompanied by increased hippocampal spine density [38]. ...
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The development of a high-end cannabinoid-based therapy is the result of intense translational research, aiming to convert recent discoveries in the laboratory into better treatments for patients. Novel compounds and new regimes for drug treatment are emerging. Given that previously unreported signaling mechanisms for cannabinoids have been uncovered, clinical studies detailing their high therapeutic potential are mandatory. The advent of novel genomic, optogenetic, and viral tracing and imaging techniques will help to further detail therapeutically relevant functional and structural features. An evolutionarily highly conserved group of neuromodulatory lipids, their receptors, and anabolic and catabolic enzymes are involved in a remarkable variety of physiological and pathological processes and has been termed the endocannabinoid system (ECS). A large body of data has emerged in recent years, pointing to a crucial role of this system in the regulation of the behavioral domains of acquired fear, anxiety, and stress-coping. Besides neurons, also glia cells and components of the immune system can differentially fine-tune patterns of neuronal activity. Dysregulation of ECS signaling can lead to a lowering of stress resilience and increased incidence of psychiatric disorders. Chronic pain may be understood as a disease process evoked by fear-conditioned nociceptive input and appears as the dark side of neuronal plasticity. By taking a toll on every part of your life, this abnormal persistent memory of an aversive state can be more damaging than its initial experience. All strategies for the treatment of chronic pain conditions must consider stress-related comorbid conditions since cognitive factors such as beliefs, expectations, and prior experience (memory of pain) are key modulators of the perception of pain. The anxiolytic and anti-stress effects of medical cannabinoids can substantially modulate the efficacy and tolerability of therapeutic interventions and will help to pave the way to a successful multimodal therapy. Why some individuals are more susceptible to the effects of stress remains to be uncovered. The development of personalized prevention or treatment strategies for anxiety and depression related to chronic pain must also consider gender differences. An emotional basis of chronic pain opens a new horizon of opportunities for developing treatment strategies beyond the repeated sole use of acutely acting analgesics. A phase I trial to determine the pharmacokinetics, psychotropic effects, and safety profile of a novel nanoparticle-based cannabinoid spray for oromucosal delivery highlights a remarkable innovation in galenic technology and urges clinical studies further detailing the huge therapeutic potential of medical cannabis (Lorenzl et al.; this issue).
... Altogether, our results may help to explain the antidepressant and anxiolytic effects of serotonergic psychedelics Davis et al., 2020;Osório et al., 2015;Palhano-Fontes et al., 2018;Sanches et al., 2016;Winne et al., 2020), which seem to stem at least in part from a boost in synaptogenesis, improving both local and long-range connectivity. The synaptogenesis-stimulating mechanisms triggered by LSD make it one of the most significant promises as a cognitive enhancer (Aday et al., 2020), side by side with delta-9-tetrahydrocannabinol, which also induces synaptic plasticity in the elderly (Bilkei-Gorzo et al., 2017). An alternative interpretation is that LSD-induced cognitive gains may derive from an increase in salience (Lebedev et al., 2015;Pasquini et al., 2020), via a process more connected to motivation than learning. ...
Article
The therapeutic use of classical psychedelic substances such as d-lysergic acid diethylamide (LSD) surged in recent years. Studies in rodents suggest that these effects are produced by increased neural plasticity, including stimulation of the mTOR pathway, a key regulator of metabolism, plasticity, and aging. Could psychedelic-induced neural plasticity be harnessed to enhance cognition? Here we show that LSD treatment enhanced performance in a novel object recognition task in rats, and in a visuo-spatial memory task in humans. A proteomic analysis of human brain organoids showed that LSD affected metabolic pathways associated with neural plasticity, including mTOR. To gain insight into the relation of neural plasticity, aging and LSD-induced cognitive gains, we emulated the experiments in rats and humans with a neural network model of a cortico-hippocampal circuit. Using the baseline strength of plasticity as a proxy for age and assuming an increase in plasticity strength related to LSD dose, the simulations provided a good fit for the experimental data. Altogether, the results suggest that LSD has nootropic effects.
... Several studies have shown that administration of THC to old animals was able to reverse many of the adverse consequences of aging on brain physiology and cognitive functions [30,34,35]. Whereas it has been established that CB1 receptors are the main target for these pro-cognitive effects of THC, the involvement of CB2 is less clear. ...
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Physiological brain aging is characterized by gradual, substantial changes in cognitive ability, accompanied by chronic activation of the neural immune system. This form of inflammation, termed inflammaging, in the central nervous system is primarily enacted through microglia, the resident immune cells. The endocannabinoid system, and particularly the cannabinoid receptor 2 (CB2R), is a major regulator of the activity of microglia and is upregulated under inflammatory conditions. Here, we elucidated the role of the CB2R in physiological brain aging. We used CB2R-/- mice of progressive ages in a behavioral test battery to assess social and spatial learning and memory. This was followed by detailed immunohistochemical analysis of microglial activity and morphology, and of the expression of pro-inflammatory cytokines in the hippocampus. CB2R deletion decreased social memory in young mice, but did not affect spatial memory. In fact, old CB2R-/- mice had a slightly improved social memory, whereas in WT mice we detected an age-related cognitive decline. On a cellular level, CB2R deletion increased lipofuscin accumulation in microglia, but not in neurons. CB2R-/- microglia showed an increase of activity markers Iba1 and CD68, and minor upregulation in tnfa and il6 expression and downregulation of ccl2 with age. This was accompanied by a change in morphology as CB2R-/- microglia had smaller somas and lower polarity, with increased branching, cell volume, and tree length. We present that CB2Rs are involved in cognition and age-induced microglial activity, but may also be important for microglial activation itself.
... Better understanding of age-related changes in CB1 receptor expression and function and the subsequent changes in behavioral effects of cannabinoid agonists may impact the therapeutic and recreational use of cannabinoids in aging populations. There is increasing interest in the therapeutic use of cannabinoids among the aged for a variety of indications including memory and cognitive function as well as pain and inflammation (Bilkei-Gorzo et al., 2017;Minerbi et al., 2019). ...
Article
Cannabinoid use has increased among aging individuals. However, little information on age-related differences in the behavioral effects of these agents is available. To explore potential differences in the behavioral effects of cannabinoids, we determined effects of Δ9-tetrahydrocannabinol (THC, 1-10 mg/kg) or rimonabant (0.3-3.2 mg/kg) on operant fixed-ratio responding (FR10) for food in young adult (6 months) and aged (29 months) rats. THC dose-dependently decreased responding for food. Rimonabant alone had little or no effect on responding up to 1.0 mg/kg, but disrupted responding following a 3.2 mg/kg dose. Rimonabant (1.0 mg/kg) partially antagonized response disruption by THC. These effects were similar in young adult and aged rats. However, aging has been reported to change the neurobiology of cannabinoid CB1 receptors. To confirm our rats exhibited such differences, we assessed CB1 receptor binding sites and function in six subcortical (caudate, nucleus accumbens CA1, and CA2/CA3), and three cortical regions (medial prefrontal, temporal, entorhinal) in young adult (6 months) or aged (26 months) male Lewis rats using quantitative autoradiography. CB1 receptor binding sites were reduced in cortical, but not subcortical brain regions of aged rats. CB1 receptor function, at the level of receptor-G protein interaction, was not different in any region studied. Results indicate that down-regulation of CB1 receptor binding sites observed in cortical regions of aged rats was not accompanied by a commensurate decrease in CB1 receptor-stimulated [35S]GTPγS binding, suggesting a compensatory increase in receptor function in cortical areas. Together, our results provide additional evidence of age-related changes in central CB1 receptor populations. However, the functional compensation for decreased CB1 receptor binding may mitigate changes in behavioral effects of cannabinoids. With the rising use of cannabinoid-based therapeutics among aging populations, further evaluation of age-related changes in the cannabinoid system and the impact of these changes on effects of this class of drugs is warranted.
... CB2r agonists may also have disease-modifying effects since JWH133 repeated treatment normalized proinflammatory markers and favored subchondral bone protection in young rats [72]. In spite of the high prevalence of osteoarthritis in females and aged individuals, none of the studies reported the use of females or old age groups, which could have an impact when translating the results into the clinics since the effects of other cannabinoid drugs already have been reported to be different in these populations [74,75] and the contribution of CB2r to the effects of mixed CB1r/CB2r agonists was different in males and females [76]. A phase II clinical study assessing the efficacy of GW842166 [22] in aged patients with osteoarthritis pain was concluded. ...
Article
Introduction Targeting CB2 cannabinoid receptor (CB2r) represents a promising approach for the treatment of central nervous system disorders. These receptors were identified in peripheral tissues, but also in neurons in the central nervous system. New findings have highlighted the interest to target these central receptors to obtain therapeutic effects devoid of the classical cannabinoid side-effects. Areas covered In this review, we searched the PubMed (January1991-May2021), ClinicalTrials.gov and Cochrane Library databases for articles, reviews and clinical trials. We first introduce the relevance of CB2r as a key component of the endocannabinoid system. We discuss CB2r interest as a possible novel target in the treatment of pain. This receptor has also raised interest as a potential target for neurodegenerative disorders treatment, as we then discussed. Finaly, we underline studies revealing a novel potential CB2r interest in mental disorders treatment. Expert opinion In spite of the interest of targeting CB2r for pain, clinical trials evaluating CB2r agonist analgesic efficacy have currently failed. The preferential involvement of CB2r in preventing the development of chronic pain could influence the failure of clinical trials designed for the treatment of already established pain syndromes. Specific trials should be designed to target the prevention of chronic pain development.
... In addition, based on our results, medical cannabis compounds such as Avidekel and Erez have a greater impact on InsG3680 Shank3 mutant mice's autistic-like phenotypes than purified CBD and THC, probably due to an "entourage effect" caused by other components found aplenty in medical cannabis extracts [88][89][90]. Notably, other studies showed that treatment with THC in extremely low doses did have a long lasting significant effect on mice's behavior, however it was mainly relevant to cognitive functions rather than autistic-like behaviors [91][92][93]. ...
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Autism spectrum disorder (ASD) is a neurodevelopmental disease with a wide spectrum of manifestation. The core symptoms of ASD are persistent deficits in social communication, and restricted and repetitive patterns of behavior, interests, or activities. These are often accompanied by intellectual disabilities. At present, there is no designated effective treatment for the core symptoms and co-morbidities of ASD. Recently, interest is rising in medical cannabis as a treatment for ASD, with promising clinical data. However, there is a notable absence of basic pre-clinical research in this field. In this study, we investigate the behavioral and biochemical effects of long-term oral treatment with CBD-enriched medical cannabis oil in a human mutation-based Shank3 mouse model of ASD. Our findings show that this treatment alleviates anxiety and decreases repetitive grooming behavior by over 70% in treated mutant mice compared to non-treated mutant mice. Furthermore, we were able to uncover the involvement of CB1 receptor (CB1R) signaling in the Avidekel oil mechanism, alongside a mitigation of cerebrospinal fluid (CSF) glutamate concentrations. Subsequently, RNA sequencing (RNA seq) of cerebellar brain samples revealed changes in mRNA expression of several neurotransmission-related genes post-treatment. Finally, our results question the relevancy of CBD enrichment of medical cannabis for treating the core symptoms of ASD, and emphasize the importance of the THC component for alleviating deficits in repetitive and social behaviors in ASD.
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NG2 glia represent a distinct type of macroglial cells in the CNS and are unique among glia because they receive synaptic input from neurons. They are abundantly present in white and grey matter. While the majority of white matter NG2 glia differentiates into oligodendrocytes, the physiological impact of grey matter NG2 glia and their synaptic input are ill defined yet. Here we asked whether dysfunctional NG2 glia affect neuronal signaling and behavior. We generated mice with inducible deletion of the K ⁺ channel Kir4.1 in NG2 glia and performed comparative electrophysiological, immunohistochemical, molecular and behavioral analyses. Focussing on the hippocampus, we found that loss of the Kir4.1 potentiated synaptic depolarizations of NG2 glia and enhanced the expression of myelin basic protein. Notably, while mice with targeted deletion of the K ⁺ channel in NG2 glia showed impaired long term potentiation at CA3-CA1 synapses, they demonstrated improved spatial memory as revealed by testing new object location recognition. Our data demonstrate that proper NG2 glia function is critical for normal brain function and behavior.
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Introduction: Adolescence is an important phase in brain maturation, specifically it is a time during which weak synapses are pruned and neural pathways are strengthened. Adolescence is also a time of experimentation with drugs, including cannabis, which may have detrimental effects on the developing nervous system. The cannabinoid type 1 receptor (CB1) is an important modulator of neurotransmitter release and plays a central role in neural development. Neurotrophic factors such as brain-derived neurotrophic factor (BDNF) and its receptor, tropomyosin receptor kinase B (TrkB), are also critical during development for axon guidance and synapse specification. Objective: The objective of this study was to examine the effects of the phytocannabinoids, Δ9-tetrahydrocannabinol (THC) and cannabidiol (CBD), on the expression of BDNF, its receptor TrkB, and other synaptic markers in the adolescent mouse hippocampus. Materials and Methods: Mice of both sexes were injected daily from P28 to P49 with 3 mg/kg THC, CBD, or a combination of THC/CBD. Brains were harvested on P50, and the dorsal and ventral hippocampi were analyzed for levels of BDNF, TrkB, and several synaptic markers using quantitative polymerase chain reaction, western blotting, and image analyses. Results: THC treatment statistically significantly reduced transcript levels of BDNF in adolescent female (BDNF I) and male (BDNF I, II, IV, VI, and IX) hippocampi. These changes were prevented when CBD was co-administered with THC. CBD by itself statistically significantly increased expression of some transcripts (BDNF II, VI, and IX for females, BDNF VI for males). No statistically significant changes were observed in protein expression for BDNF, TrkB, phospho-TrkB, phospho-CREB (cAMP response element-binding protein), and the synaptic markers, vesicular GABA transporter, vesicular glutamate transporter, synaptobrevin, and postsynaptic density protein 95. However, CB1 receptors were statistically significantly reduced in the ventral hippocampus with THC treatment. Conclusions: This study found changes in BDNF mRNA expression within the hippocampus of adolescent mice exposed to THC and CBD. THC represses transcript expression for some BDNF variants, and this effect is rescued when CBD is co-administered. These effects were seen in both males and females, but sex differences were observed in specific BDNF isoforms. While a statistically significant reduction in CB1 receptor protein in the ventral dentate gyrus was seen, no other changes in protein levels were observed.
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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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Cannabis sativa L. produces over 200 known secondary metabolites that contribute to its distinctive aroma. Studies on compounds traditionally associated with the scent of this plant have focused on those within the terpenoid class. These isoprene-derived compounds are ubiquitous in nature and are the major source of many plant odors. Nonetheless, there is little evidence that they provide the characteristic “skunk-like” aroma of cannabis. To uncover the chemical origins of this scent, we measured the aromatic properties of cannabis flowers and concentrated extracts using comprehensive two-dimensional gas chromatography equipped with time-of-flight mass spectrometry, flame ionization detection, and sulfur chemiluminescence. We discovered a new family of volatile sulfur compounds (VSCs) containing the prenyl (3-methylbut-2-en-1-yl) functional group that is responsible for this scent. In particular, the compound 3-methyl-2-butene-1-thiol was identified as the primary odorant. We then conducted an indoor greenhouse experiment to monitor the evolution of these compounds during the plant’s lifecycle and throughout the curing process. We found that the concentrations of these compounds increase substantially during the last weeks of the flowering stage, reach a maximum during curing, and then drop after just one week of storage. These results shed light on the chemical origins of the characteristic aroma of cannabis and how volatile sulfur compound production evolves during plant growth. Furthermore, the chemical similarity between this new family of VSCs and those found in garlic (allium sativum) suggests an opportunity to also investigate their potential health benefits.
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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.
Chapter
Dementia is a group of diseases characterized by gradual impairment of brain function. Alzheimer’s disease is the most common form of dementia and is characterized by many neuropsychiatric symptoms, of which loss of memory is only one and possibly not the most problematic. The pathophysiology of Alzheimer’s disease involves a triad of neuroinflammation, formation of amyloid plaques, and hyperphosphorylation of tau protein. The endocannabinoid system is involved in the pathophysiology of Alzheimer’s disease and, because of this, may be an important therapeutic target in the future. Preclinical and clinical research indicates that cannabidiol, tetrahydrocannabinol, and some of terpenes found in cannabis may be useful in the treatment of the neurobehavioural aspects of the condition. Medicinal cannabis may be a valuable part of a holistic approach to the treatment of AD that considers a range of factors including diet, exercise, stress reduction, and others. This chapter explores the evidence that key phytocannabinoids such as cannabidiol and tetrahydrocannabinol and some of the other phytonutrients of Cannabis sativa may have a role to play in the treatment of this disease that, as yet, has no cure.
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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.
Chapter
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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.
Chapter
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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The cis-stereoisomers of Δ⁹-THC [(−)-3 and (+)-3] were identified and quantified in a series of low-THC-containing varieties of Cannabis sativa registered in Europe as fiber hemp and in research accessions of cannabis. While Δ⁹-cis-THC (3) occurs in cannabis fiber hemp in the concentration range of (−)-Δ⁹-trans-THC [(−)-1], it was undetectable in a sample of high-THC-containing medicinal cannabis. Natural Δ⁹-cis-THC (3) is scalemic (ca. 80–90% enantiomeric purity), and the absolute configuration of the major enantiomer was established as 6aS,10aR [(−)-3] by chiral chromatographic comparison with a sample available by asymmetric synthesis. The major enantiomer, (−)-Δ⁹-cis-THC [(−)-3], was characterized as a partial cannabinoid agonist in vitro and elicited a full tetrad response in mice at 50 mg/kg doses. The current legal discrimination between narcotic and non-narcotic cannabis varieties centers on the contents of “Δ⁹-THC and isomers” and needs therefore revision, or at least a more specific wording, to account for the presence of Δ⁹-cis-THCs [(+)-3 and (−)-3] in cannabis fiber hemp varieties.
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Mechanistic insights into cannabinoid signaling could improve therapeutic applications.
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Abstract Gene expression changes in the brain affect cognition during normal and pathological aging. Progress in understanding the cellular processes regulating gene expression networks in cognition is relevant to develop therapeutic interventions for age-related cognitive disorders. Synaptic efficacy mediating memory storage requires the activation of specific gene expression programs regulated, among others, by the transcription factor cAMP-response element binding protein (CREB). CREB signaling is essential for long-lasting changes in synaptic plasticity that mediates the conversion of short-term memory to long-term memory. CREB signaling has been recently involved in several brain pathological conditions including cognitive and neurodegenerative disorders. The β-amyloid (Aβ) peptide, which plays a crucial role in the pathogenesis of Alzheimer's disease, alters hippocampal-dependent synaptic plasticity and memory and mediates synapse loss through the CREB signaling pathway. The fact that altered CREB signaling has been implicated in other cognitive disorders including Huntington's disease and Rubinstein-Taybi and Coffin-Lowry syndromes suggests a crucial role of CREB signaling in cognitive dysfunction. In this review paper, we summarize recent findings indicating a role of CREB and its coactivators CREB binding protein and CREB-regulated transcription coactivator in cognition during normal and pathological aging. We also discuss the development of novel therapeutic strategies based on CREB targeting to ameliorate cognitive decline in aging and cognitive disorders.
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Molecular Psychiatry publishes work aimed at elucidating biological mechanisms underlying psychiatric disorders and their treatment
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