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A chronic low dose of Δ(9)-tetrahydrocannabinol (THC) restores cognitive function in old mice
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.
... Thus, Cnr1 −/− mice, which have a genetic deletion of CB 1 receptors, showed enhanced agerelated deficits in learning and memory accompanied by a loss of neurons, reduced neurogenesis, and concomitantly enhanced signs of neuroinflammation. 2 Elevation of CB 1 receptor activity had the opposite effect: It alleviated several symptoms of brain aging and restored cognitive functions in older mice. 3 The long-lasting cognitive improvements in Δ 9 -THC-treated old mice were associated with hippocampal transcriptional profiles that were reminiscent of those of young animals, which lasted for several weeks after cessation of the treatment. On a cellular level, we observed enhanced synaptic protein synthesis, as well as an increased hippocampal dendritic spine density. ...
... On a cellular level, we observed enhanced synaptic protein synthesis, as well as an increased hippocampal dendritic spine density. 3 In the cortex, a similar treatment of old mice improved dendritic spine stability, also leading to a long-lasting increase in spine density. 4 It is known that dynamic changes in dendritic spines are involved in synaptic plasticity, and thus contribute to learning and memory formation. ...
... Next, we wanted to know whether Δ 9 -THC treatment increased the amount of synaptic proteins in the cortex, similarly to our previous observation in the hippocampus. 3 Interestingly, the amount of synaptophysin (+40.2%; t 12 = 2.384; p = 0.0345) and PSD-95 (+42.2%; ...
... The endocannabinoid (eCB) system is a neuromodulator system that plays important roles in learning and memory processing, distributed in areas of the brain related to cognition (Harkany et al., 2003) and implicated in cholinergic neurotransmission (Goonawardena et al., 2010;Puighermanal et al., 2012). Cannabinoid agonists induce memory impairment (Broyd et al., 2016;Urits et al., 2021), but in the last decade, evidence has been accumulating showing a beneficial effect of low cannabinoid doses upon cognitive impairment (Bilkei-Gorzo et al., 2017;Calabrese & Rubio-Casillas, 2018;Ozaita & Aso, 2017). The role of the eCB system in neurodegenerative diseases is still unknown. ...
... However, there are other reports of either a biphasic effect of cannabinoid agonism on cognition (Calabrese & Rubio-Casillas, 2018), or a beneficial effects of low, as opposed to high, doses (Nitzan et al., 2022;Sarne, 2019). These results suggest that the dual effects of cannabinoids on cognition depend on several factors, for example, the state of the baso-cortical cholinergic pathway, or, more generally, the previous cognitive status of the subjects (Bilkei-Gorzo et al., 2017). This may explain why the treatment did not yield the expected positive results in 3xTg-AD mice. ...
Background and Purpose
Recent research linking choline‐containing lipids to degeneration of basal forebrain cholinergic neurons in neuropathological states illustrates the challenge of balancing lipid integrity with optimal acetylcholine levels, essential for memory preservation. The endocannabinoid system influences learning and memory processes regulated by cholinergic neurotransmission. Therefore, we hypothesised that activation of the endocannabinoid system may confer neuroprotection against cholinergic degeneration.
Experimental Approach
We examined the neuroprotective potential of sub‐chronic treatments with the cannabinoid agonist WIN55,212‐2, using ex vivo organotypic tissue cultures including nucleus basalis magnocellularis and cortex and in vivo rat models of specific cholinergic damage induced by 192IgG‐saporin. Levels of lipids, choline and acetylcholine were measured with histochemical and immunofluorescence assays, along with [³⁵S]GTPγS autoradiography of cannabinoid and muscarinic GPCRs and MALDI‐mass spectrometry imaging analysis. Learning and memory were assessed by the Barnes maze and the novel object recognition test in rats and in the 3xTg‐AD mouse model.
Key Results
Degeneration, induced by 192IgG‐saporin, of baso‐cortical cholinergic pathways resulted in memory deficits and decreased cortical levels of lysophosphatidylcholines (LPC). WIN55,212‐2 restored cortical cholinergic transmission and LPC levels via activation of cannabinoid receptors. This activation altered cortical lipid homeostasis mainly by reducing sphingomyelins in lesioned animals. These modifications were crucial for memory recovery.
Conclusion and Implications
We hypothesise that WIN55,212‐2 facilitates an alternative choline source by breaking down sphingomyelins, leading to elevated cortical acetylcholine levels and LPCs. These results imply that altering choline‐containing lipids via activation of cannabinoid receptors presents a promising therapeutic approach for dementia linked to cholinergic dysfunction.
... Enhancing the eCB tone by using CB receptor ligands from exogenous sources showed encouraging outcomes in reversing the effects of aging [23,24]. Chronic low-dose THC treatment stabilizes dendritic spines and cognitive decline in 18-month-old mice but not in younger mice [23,25]. This impact relied on the CB1R receptors located in the glutamatergic cells of the forebrain [25]. ...
... Chronic low-dose THC treatment stabilizes dendritic spines and cognitive decline in 18-month-old mice but not in younger mice [23,25]. This impact relied on the CB1R receptors located in the glutamatergic cells of the forebrain [25]. Therefore, it can be inferred that THC has varying implications for younger individuals compared to older individuals, particularly in terms of cognitive performance. ...
... The endocannabinoid system (ECS) is a ubiquitously expressed system of receptors in the central nervous system (CNS) that has been reported to become dysfunctional in models of AD. [170][171][172][173][174][175] Moreover, the action of CBD is a highly speculative topic and has not been entirely elucidated, although it appears to act as an inverse agonist of the cannabinoid receptor type-1 (CB1) and inhibit of fatty-acid amide hydrolase (FAAH) and monoacylglycerol lipase (MAGL). Interestingly, no statistically significant changes in mRNA expression of CB1, CB2, FAAH, or MAGL were found in treated samples relative to vehicle controls (Figure 3.13). ...
... ,171 In addition to the modulatory effects of cannabinoids on the epigenome that have been reported, epigenetic regulation seems to play an important role in the expression and activity of ECS components. For example, dysregulated DNA methylation and histone modifications have been shown to alter the expression of CNR1and FAAH, genes that encode for the CB1 receptor and FAAH, respectively.172 ...
Current Alzheimer’s disease (AD) treatments display low efficacy, and most do not target the associated pathophysiology. Oxidative stress and epigenetic regulators, such as DNA methylation and histone-acetylation, can influence AD through modifying genes such as APP and BACE1. Interestingly, the endocannabinoid system, which is dysregulated in AD, is implicated in these phenomena, imploring investigation into the potential therapeutic use of cannabinoids in AD. It was hypothesized that phytocannabinoids, such as cannabidiol (CBD) and D-9-tetrahydrocannabinol (THC), are cytoprotective and reduce Aβ pathology via epigenetic modulation of amyloidogenic pathway genes. THC and CBD protected SH-SY5Y cells against oxidative stress and Aβ-induced cytotoxicity. THC but not CBD reduced APP and a histone acetyltransferase gene expression. Cell viability was assessed in 3xTg primary neuron cultures, and significant differences in mRNA levels of epigenetic markers were detected in male and female wild-type and AD mice. These findings support cannabinoids' therapeutic potential and the role of epigenetics in AD.
... Penman et al. Pharmacology, Biochemistry and Behavior 231 (2023) 173633 psychotropic doses of THC, both acute and chronic, can have restorative effects on impaired memory due to age or chemically-induced cognitive deficits (Bilkei-Gorzo et al., 2017;Fishbein-Kaminietsky et al., 2014;Nidadavolu et al., 2021;Sarne et al., 2018). This is thought to be a CB1mediated mechanism, as chronic daily treatment in aged CB1 KO mice did not show the same improvement as seen in FABP5 +/+ (Bilkei-Gorzo et al., 2017). ...
... Pharmacology, Biochemistry and Behavior 231 (2023) 173633 psychotropic doses of THC, both acute and chronic, can have restorative effects on impaired memory due to age or chemically-induced cognitive deficits (Bilkei-Gorzo et al., 2017;Fishbein-Kaminietsky et al., 2014;Nidadavolu et al., 2021;Sarne et al., 2018). This is thought to be a CB1mediated mechanism, as chronic daily treatment in aged CB1 KO mice did not show the same improvement as seen in FABP5 +/+ (Bilkei-Gorzo et al., 2017). Further investigation from the same group showed that chronic low dose treatment of THC in aged mice stabilized dendritic spines, while having a destabilizing effect in young mice; the authors hypothesized that this could possibly be a CB1-mediated mechanism through modulation of the WAVE1 complex (Komorowska-Müller et al., 2023). ...
Fatty acid binding protein 5 (FABP5) interacts with the endocannabinoid system in the brain via intracellular transport of anandamide, as well as Δ9-tetrahydrocannabinol (THC), the main psychoactive component of cannabis. Previous work has established the behavioral effects of genetic deletion of FABP5, but not in the presence of THC. The present study sought to further elucidate the role of FABP5 on the pharmacokinetic and behavioral response to THC through global deletion. Adult FABP5+/+ and FABP5−/− mice were tested for behavioral response to THC using Open Field (OF), Novel Object Recognition (NOR), T-Maze, Morris Water Maze (MWM), and Elevated Plus Maze (EPM). An additional cohort of mice was used to harvest blood, brains, and liver samples to measure THC and metabolites after acute administration of THC. Behavioral tests showed that some cognitive deficits from FABP5 deletion, particularly in MWM, were blocked by THC administration, while this was not observed in other measures of memory and anxiety (such as T-Maze and EPM). Measurement of THC and metabolites in blood serum and brain tissue through UPLC-MS/MS analysis showed that the pharmacokinetics of THC was altered by FABP5. The present study shows further evidence of the importance of FABP5 in cognitive function. Additionally, results showed that FABP5 is an important regulator of the physiological effects and pharmacokinetics of THC.
... forgetting the prior time we used the pen in the office so we can correctly anticipate finding it in the bedroom, where we actually used it most recently). Regarding the underlying neurobiology of the aged EdM phenotype, we also present results in parallel from bioRxiv Stevens et al. 4 a preliminary investigation inspired by recent studies into the role of age-related alteration of the endocannabinoid system in mnemonic decline (Bilkei-Gorzo, 2012;Bilkei-Gorzo et al., 2017). Notably, using the Dlx-CB1-KO transgenic mouse line (Monory et al., 2006), we provide the first evidence of a critical role for cannabinoid type-I receptors expressed on GABAergic neurons of the forebrain (whose signaling is known to alter with age, diminishing or augmenting depending on the area considered: Burjanadze et al., 2022;Ethiraj et al., 2021;Pandya et al., 2019) in successful active forgetting-dependent EdM performance. ...
... Convergent evidence from other recent studies also points in the direction of a major eCS contribution to EM function. Notably, chronic exposure to a CB1 agonist (THC) restored memory reversal performance (being a type of cognitive flexibility putatively requiring a basic level of active forgetting) in aged mice in a Morris water maze task (Bilkei-Gorzo et al., 2017). Replication of such a THC protocol in aged mice performing the EdM protocol could directly test whether improved memory function in aged mice following chronic THC stimulation of the eCS is specifically the result of a rejuvenation of active forgetting capacities. ...
Recalling a specific past episode that will enable us to decide which action is suited to a given present situation is a core element of everyday life. A wealth of research has demonstrated that such selective remembering is dependent upon a capacity to inhibit or provisionally 'forget' related yet inappropriate memory episodes which could orient behavior in unwilled directions. Everyday-like memory (EdM) refers to this type of common organizational mnemonic capacity, known to deteriorate significantly with age, putatively as a result of decline in the cognitive capacity for selective inhibition or 'active forgetting'. Moreover, this memory retrieval-concomitant active forgetting comes at the cost of genuine amnesic weakening of the inhibited episodes, a phenomenon referred to as retrieval-induced forgetting (RIF). In the present study, we introduce a novel characterization of our previously validated mouse model of EdM in terms of the existing active forgetting and RIF literature. We also introduce novel behavioral analyses of the deliberation processes elicited by EdM challenge and use detailed multi-factorial explorations to reveal how these processes are impacted by age, temporal retention demand, difficulty of EdM challenge, and anticipation of trial outcome. Our observations indicate that deliberation requires remembering while accurate anticipation - in which a critical age-related deficit is also observed - requires active forgetting. Our results represent a significant advance towards unifying our understanding of the neurocognitive processes underpinning everyday-like memory, RIF, mnemonic deliberation, anticipatory function, and how they all are impacted by the physiological ageing process. In parallel, we present preliminary results using a transgenic mouse model which point to a fundamental role for the endocannabinoid system (eCS) in active forgetting and EdM, thereby demonstrating that deeper investigation of previously characterized age-related decline of the eCS should be a pre-clinical priority with a view to developing treatments for age-related decline of EdM function.
... Hence, it is reasonable to assume that additional unmeasured factors might influence the association, potentially confounding the result. Nevertheless, our findings of less cognitive decline among cannabis users compared to nonusers align with previous in vivo studies indicating that cannabinoids have a positive impact on cognitive function and memory in rats (Marchalant et al. 2008) and mice (Bilkei-Gorzo et al. 2017;Sarne et al. 2018). ...
Introduction
Cannabis is by far the most widely used and abused drug listed on the Drug Enforcement Administration's Schedule I, which includes drugs with a high potential for abuse. There is evidence of short‐term negative effects of cannabis use on cognition, but only a limited number of studies have explored the association between cannabis use and age‐related cognitive decline. The aim of the present study was to investigate the relationship between cannabis use and age‐related cognitive decline from early adulthood to late midlife.
Methods
The study population consisted of 5162 men who had participated in Danish follow‐up studies on cognitive aging. These studies included scores on the military intelligence test Børge Prien's Prøve from both the conscription assessment (mean age = 20 years; p1 and p99: 18 and 26 years) and from the follow‐up (mean age = 64 years; p1 and p99: 55 and 72 years) as well as extensive data on lifestyle and health from the follow‐up questionnaires. The association between cannabis use and age‐related cognitive decline was investigated in linear regression models.
Results
Men with a history of cannabis use had less cognitive decline from early adulthood to late midlife compared to men without a history of cannabis use. Among cannabis users, neither age of initiation of cannabis use nor frequent use was significantly associated with a greater age‐related cognitive decline.
Discussion and Conclusions
In a sample of more than 5000 men followed for a mean of 44 years, we found no significant harmful effects of cannabis use on age‐related cognitive decline.
... In these mutants, early onset of cognitive decline is associated with heightened neuroinflammation and neuronal loss in the hippocampus, suggesting neuroprotective effects of intrinsic CB 1 receptor activity (Albayram et al., 2012). In reverse, prolonged low-grade pharmacological activation of CB 1 receptors is beneficial in preserving cognitive ability in aged rodents (Marchalant et al., 2008(Marchalant et al., , 2009a(Marchalant et al., , 2009b(Marchalant et al., , 2009cBilkei-Gorzo et al., 2017). Consequently, elevating ECB signaling, or normalizing disease-associated deficits of the ECB system in GWI found with age, may prove effective in alleviating neuroinflammation and brain dysfunction. ...
... By using the NOLRT, we assessed short-term non-associative memory in which the amount of time spent in the active exploration of a new object provides an index of spontaneous investigation and formation of hippocampal-sensitive recognition memory (Ennaceur & Delacour, 1988;Squire et al, 2007). NORLT was implemented in a 44 × 44 cm (25-cm walls) quadratic Plexiglas arena with a white covered with saw-dust as described (Bilkei-Gorzo et al, 2017). Briefly, mice were acquainted with the arena daily three times with a 5-min session. ...
The endocannabinoid N -arachidonoylethanolamine (AEA) is a pro-homeostatic bioactive lipid known for its anti-inflammatory, anti-oxidative, immunomodulatory, and neuroprotective properties, which may contrast/mitigate Alzheimer’s disease (AD) pathology. This study explores the therapeutic potential of targeting fatty acid amide hydrolase (FAAH), the major enzyme degrading AEA, in mouse models of amyloidosis APP/PS1 and Tg2576. Enhancing AEA signaling by genetic deletion of FAAH delayed cognitive deficits in APP/PS1 mice and improved cognitive symptoms in 12-month-old AD-like mice. Chronic pharmacological FAAH inhibition fully reverted neurocognitive decline, attenuated neuroinflammation, and promoted neuroprotective mechanisms in Tg2576 mice. Additionally, pharmacological FAAH inactivation robustly suppressed β-amyloid production and accumulation, associated with decreased expression of β-site amyloid precursor protein cleaving enzyme 1 (BACE1), possibly through a cannabinoid receptor 1-dependent epigenetic mechanism. These findings improve our understanding of AEA signaling in AD pathogenesis, and provide proof-of-concept that selective targeting of FAAH activity could be a promising therapeutic strategy against AD.
... Тому в Україні медичний канабіс може бути корисним приблизно для 1 млн онкохворих після хіміотерапії. Канабісу також потребують хворі на епілепсію, розсіяний склероз, боковий амніоторофічний склероз, фіброміалгію, артрит, ВІЛ/СНІД, глаукому, хвороби Альцгеймера, Паркінсона, синдроми Ту-ретта, Леннокса-Госте, Драве, подразненого кишечника, хворі із болем у спині, хронічними болями внаслідок травм спинного мозку, діабетичної нейропатії, постгерпетичної невралгії, хворі із Пост-Травматичним Стресовим Розладом (ПТСР), із анорексією, нудотою та блюванням [4][5][6][7][8][9][10][11][12][13][14][15][16]. ...
In Ukraine, the procedure for the legalization of medical cannabis, which is needed for approximately 6 million patients with cancer in the palliative stages, multiple sclerosis, epilepsy, lateral amniotic sclerosis, fibromyalgia, arthritis, HIV/AIDS, glaucoma, post-traumatic stress disorder, Alzheimer's, Parkinson's disease, Tourette, Lennox-Gastaut, Dravet syndromes, irritable bowel, back pain, chronic pain due to spinal cord injuries, diabetic neuropathy, postherpetic neuralgia, is being completed. Cannabis is necessary for such patients to overcome spasticity, chronic pain, nausea, vomiting, anorexia, increased eye pressure. It can be a supplement to treatment with other pharmaceuticals or an alternative to them. On the eve of the entry into force of the relevant law, it is necessary to determine the main directions for the rapid development of the necessary by-laws (clinical protocols, instructions, etc.) for the rapid start of the wide use of cannabis in clinical practice, in particular in palliative medicine. Using the methods of systematic analysis and bibliosemantic, a study of scientific literary sources in Google Scholar and PubMed was conducted to study the main properties of medical cannabis, the medical and social risks of its use, in particular side effects, the increase in illegal recreational use of herbal cannabis. The experience of other countries where medical cannabis has already been legalized (USA, Canada, Australia, Denmark, Germany, Israel, Switzerland) has been studied. The list of normative legal acts of Ukraine that can regulate the use of medical cannabis has been defined: 27 evidence-based clinical guidelines; 27 standards and protocols of medical care. Possible scenarios are identified and the necessary measures are proposed for the adoption of legal acts for the final decriminalization of cannabis, the determination and forecasting of the need for palliative patients, the creation of conditions for the cultivation of Ukrainian herbal cannabis and the manufacture of domestic pharmaceuticals, reimbursement of their cost to patients. Keywords: chronic pain, narcotic painkillers, marijuana, PTSD, anorexia.
... The antianxiolytic-like effects of SR against SB and VA which were further counteracted by CZ, as well as the antimemory improving-like effects of CZ which were further counteracted by SR, may reflect some mediatory roles of histone acetylation in the interplay between the ECB and TRPV1 systems. A number of studies have suggested the contribution of reduced histone acetylation to both stress (or drug)-related impaired emotional/cognitive behaviours and disturbed function of either the ECB or TRPV1 system.[118][119][120][121][122][123][124] Nevertheless, few studies have discussed the role of HDAC inhibitor-induced histone acetylation in the interacting behavioural influence of the ECB and TRPV1 systems.125 ...
The addictive use of nicotine contained in tobacco is associated with stressor‐like emotional and cognitive effects such as anxiety and working memory impairment, and the involvement of epigenetic mechanisms such as histone acetylation has recently been reported. Although the precise nature of behavioural plasticity remains unclear, both anxiogenic‐ and working memory impairment‐like effects were observed in the present experimental model of mice treated with repeated subcutaneous nicotine and/or immobilization stress, and these effects were commonly attenuated by the histone deacetylase (HDAC) inhibitors that induce histone acetylation. Such HDAC inhibitor‐induced resilience was mimicked by ligands for the endocannabinoid (ECB) system, a neurotransmitter system that is closely associated with nicotine‐induced addiction‐related behaviours: the anxiogenic‐like effects were mitigated by the cannabinoid type 1 (CB1) agonist arachidonylcyclopropylamide (ACPA), whereas the working memory impairment‐like effects were mitigated by the CB1 antagonist SR 141716A. Moreover, the effects of the HDAC inhibitors were also mimicked by ligands for the endovanilloid (transient receptor potential vanilloid 1 [TRPV1]) system, a system that shares common characteristics with the ECB system: the anxiogenic‐like effects were mitigated by the TRPV1 antagonist capsazepine, whereas the working memory impairment‐like effects were mitigated by the TRPV1 agonist olvanil. Notably, the HDAC inhibitor‐induced anxiolytic‐like effects were attenuated by SR 141716A, which were further counteracted by capsazepine, whereas the working memory improvement‐like effects were attenuated by capsazepine, which were further counteracted by SR 141716A. These results suggest the contribution of interrelated control of the ECB/TRPV1 systems and epigenetic processes such as histone acetylation to novel therapeutic approaches.
... The results showed, however, that THC administration neither exacerbated nor improved anxiety and memory impairments associated with SCD. These findings should be interpreted in the context of previous evidence suggesting that THC treatment may have both detrimental and beneficial effects on mood and memory function in wild-type mice (Bilkei-Gorzo et al., 2017;Braida et al., 2007;Rubino et al., 2007;Sarne et al., 2018;Schramm-Sapyta et al., 2007). It is plausible that a different dosage or regimen of THC might have led to different outcomes, but further research is needed to test this possibility. ...
People with sickle cell disease (SCD) often experience chronic pain as well as unpredictable episodes of acute pain, which significantly affect their quality of life and life expectancy. Current treatment strategies for SCD-associated pain primarily rely on opioid analgesics, which have limited efficacy and cause serious adverse effects. Cannabis has emerged as a potential alternative, yet its efficacy remains uncertain. In this study, we investigated the antinociceptive effects of Δ9-tetrahydrocannabinol (THC), cannabis' intoxicating constituent, in male HbSS mice, which express >99% human sickle hemoglobin, and male HbAA mice, which express normal human hemoglobin A, as a control. Acute THC administration (0.1-3 mg-kg-1, intraperitoneal, i.p.) dose-dependently reduced mechanical and cold hypersensitivity in HbSS, but not HbAA mice. In the tail-flick assay, THC (1 and 3 mg-kg-1, i.p.) produced substantial antinociceptive effects in HbSS mice. By contrast, THC (1 mg-kg-1, i.p.) did not alter anxiety-like behavior (elevated plus maze) or long-term memory (24-h novel object recognition). Subchronic THC treatment (1 and 3 mg-kg-1, i.p.) provided sustained relief of mechanical hypersensitivity but led to tolerance in cold hypersensitivity in HbSS mice. Together, the findings identify THC as a possible therapeutic option for the management of chronic pain in SCD. Further research is warranted to elucidate its mechanism of action and possible interaction with other cannabis constituents. Significance Statement The study explores THC's efficacy in alleviating pain in sickle cell disease (SCD) using a humanized mouse model. Findings indicate that acute THC administration reduces mechanical and cold hypersensitivity in SCD mice without impacting emotional and cognitive dysfunction. Subchronic THC treatment offers sustained relief of mechanical hypersensitivity but leads to cold hypersensitivity tolerance. These results offer insights into THC's potential as an alternative pain management option in SCD, highlighting both its benefits and limitations.
... AdoTHC rats learned a visually cued instrumental response rule quicker than AdoVEH-treated controls, and this effect was most robust in females. This finding adds to the growing literature on potentially pro-learning/cognitive effects of AdoTHC (Bilkei-Gorzo et al., 2017;Sarne, 2019;Hernandez et al., 2021;Stringfield and Torregrossa, 2021a). This said, previous studies using other adolescent cannabinoid exposure models have not found analogous increases in initial rule discrimination learning (Gomes et al., 2015;Hernandez et al., 2021;Freels et al., 2024), though this might be due to the fact that few studies included female subjects, and the THC administration protocols employed were quite different. ...
Rationale
Adolescent cannabis use is linked to later-life changes in cognition, learning, and memory. Rodent experimental studies suggest Δ ⁹ -tetrahydrocannabinol (THC) influences development of circuits underlying these processes, especially in the prefrontal cortex, which matures during adolescence.
Objective
We determined how 14 daily THC injections (5mg/kg) during adolescence persistently impacts medial prefrontal cortex (mPFC) dopamine-dependent cognition.
Methods
In adult Long Evans rats treated as adolescents with THC (AdoTHC), we quantify performance on two mPFC dopamine-dependent reward-based tasks—strategy set shifting and probabilistic discounting. We also determined how acute dopamine augmentation with amphetamine (0, 0.25, 0.5 mg/kg), or specific chemogenetic stimulation of ventral tegmental area (VTA) dopamine neurons and their projections to mPFC impacts probabilistic discounting.
Results
AdoTHC sex-dependently impacts acquisition of cue-guided instrumental reward seeking, but has minimal effects on set-shifting or probabilistic discounting in either sex. When we challenged dopamine circuits acutely with amphetamine during probabilistic discounting, we found reduced discounting of improbable reward options, with AdoTHC rats being more sensitive to these effects than controls. In contrast, neither acute chemogenetic stimulation of VTA dopamine neurons nor pathway-specific chemogenetic stimulation of their projection to mPFC impacted probabilistic discounting in control rats, although stimulation of this cortical dopamine projection slightly disrupted choices in AdoTHC rats.
Conclusions
These studies confirm a marked specificity in the cognitive processes impacted by AdoTHC exposure. They also suggest that some persistent AdoTHC effects may alter amphetamine-induced cognitive changes in a manner independent of VTA dopamine projections to mPFC, or via alterations of non-VTA dopamine neurons.
... Further, a small amount of D9-THC has been shown in a study to considerably boost neurogenesis in the hippocampal regions of elderly rats, as demonstrated by Suliman et al., [104]. Recent research in aged mice has also revealed a similar result: a long-term low dosage of D9-THC augmented the density of the hippocampus spine and improved mental function [105]. Additionally, D9-THC can inhibit the inflammatory response and facilitate the elimination of the intraneuronal Aβ buildup [106]. ...
... The notion that gait variability may be a putative marker of cognitive-cortical deterioration in neurodegenerative disorders has diagnostic and prognostic implications. In light of data suggesting chronic ultra-low-dose THC is associated with significant augmentation of memory and other aspects of cognition in animal models and in older adults with dementing illness (Bilkei-Gorzo, 2017 [38]; Sarne et al., 2011 [39] and 2018 [40]; Calabrese & Rubio-Casillas, 2018 [41]), the finding that mobility and gait stability are not likely to acutely deteriorate with THC on board represents reassurance about safety. ...
In this overview, we seek to appraise recent experimental and observational studies investigating THC and its potential role as adjunctive therapy in various medical illnesses. Recent clinical trials are suggestive of the diverse pharmacologic potentials for THC but suffer from small sample sizes, short study duration, failure to address tolerance, little dose variation, ill-defined outcome measures, and failure to identify and/or evaluate confounds, all of which may constitute significant threats to the validity of most trials. However, the existing work underscores the potential therapeutic value of THC and, at the same time, calls attention to the critical need for better-designed protocols to fully explore and demonstrate safety and efficacy. In the most general sense, the present brief review illuminates some intriguing findings about THC, along with the basic threats to the validity of the research that supports those findings. The intent is to highlight existing generic weaknesses in the existing randomized controlled trial literature and, most importantly, provide guidance for improved clinical research.
... Mice with intact short-term memory prefer to explore a novel arm over the familiar arms, whereas mice with impaired spatial memory enter all arms randomly. Thus, the test session represents a classic test for spatial working memory as previously described (27,98,101). ...
Repeat concussions (or repetitive mild traumatic brain injury [rmTBI]) are complex pathological processes consisting of a primary insult and long-term secondary complications and are also a prerequisite for chronic traumatic encephalopathy (CTE). Recent evidence implies a significant role of autophagy-mediated dysfunctional mitochondrial clearance, mitophagy, in the cascade of secondary deleterious events resulting from TBI. C18-ceramide, a bioactive sphingolipid produced in response to cell stress and damage, and its synthesizing enzyme (CerS1) are precursors to selective stress-mediated mitophagy. A transporter, p17, mediates the trafficking of CerS1, induces C18-ceramide synthesis in the mitochondrial membrane, and acts as an elimination signal in cell survival. Whether p17-mediated mitophagy occurs in the brain and plays a causal role in mitochondrial quality control in secondary disease development after rmTBI are unknown. Using a novel repetitive less-than-mild TBI (rlmTBI) injury paradigm, ablation of mitochondrial p17/C18-ceramide trafficking in p17 knockout (KO) mice results in a loss of C18-ceramide–induced mitophagy, which contributes to susceptibility and recovery from long-term secondary complications associated with rlmTBI. Using a ceramide analog with lipid-selenium conjugate drug, LCL768 restored mitophagy and reduced long-term secondary complications, improving cognitive deficits in rlmTBI-induced p17KO mice. We obtained a significant reduction of p17 expression and a considerable decrease of CerS1 and C18-ceramide levels in cortical mitochondria of CTE human brains compared with age-matched control brains. These data demonstrated that p17/C18-ceramide trafficking is an endogenous neuroprotective mitochondrial stress response following rlmTBI, thus suggesting a novel prospective strategy to interrupt the CTE consequences of concussive TBI.
... 48,49 Interestingly, recent studies have shown that treatment with THC restores cognitive function in aging mice; the increased level of Sirtuin1 (an enzyme that has been previously shown to be involved in neuroprotection and neuroplasticity) was elevated in the hippocampus and the frontal cortex of old mice. [50][51][52] Age seems to be of major importance regarding whether there is an improvement or an impairment in cognition when using dronabinol. ...
Background: Cannabis may offer therapeutic benefits to patients with advanced cancer not responding adequately to conventional palliative treatment. However, tolerability is a major concern. Cognitive function is a potential adverse reaction to tetrahydrocannabinol containing regimens. The aim of this study was to test cognitive function in patients being prescribed dronabinol as an adjuvant palliative therapy.
Methods: Adult patients with advanced cancer and severe related pain refractory to conventional palliative treatment were included in this case-series study. Patients were examined at baseline in conjunction with initiation of dronabinol therapy and at a two-week follow-up using three selected Wechsler's adult intelligence scale III neurocognitive tests: Processing Speed Index (PSI), Perceptual Organization Index (POI), and Working Memory Index (WMI). Patients were also assessed using pain visual analog scale, Major Depression Inventory, and Brief Fatigue Inventory.
Results: Eight patients consented to take part in the study. Two patients discontinued dronabinol therapy, one due to a complaint of dizziness and another critical progression of cancer disease, respectively. The remaining six patients were successfully treated with a daily dosage of 12.5 mg dronabinol (p = 0.039). PSI (p = 0.020), POI (p = 0.034.), and WMI (p = 0.039).
Conclusions: Cognitive function improved in this group of patients with advanced cancer in conjunction with low-dose dronabinol therapy. The cause is likely multifactorial including reported relief of cancer-associated symptoms. Further clinical investigation is required.
... Yakhtin et al. showed that activated peritoneal macrophages treated with THC and THC extract have reduced NO, IL6, TNFα, CXCL2, and G-CSF compared to vehicle control [66]. These data point to the advantage of using low or even ultralow doses of THC, in accordance with the reversal of cognitive impairment in old mice and spatial memory tests in old female mice [67,68]. Transcription of TNFα was not affected by pretreatment with THC; this was evident from RTqPCR ( Figure S4A) and transcriptomics. ...
Intestinal inflammation is mediated by a subset of cells populating the intestine, such as enteric glial cells (EGC) and macrophages. Different studies indicate that phytocannabinoids could play a possible role in the treatment of inflammatory bowel disease (IBD) by relieving the symptoms involved in the disease. Phytocannabinoids act through the endocannabinoid system, which is distributed throughout the mammalian body in the cells of the immune system and in the intestinal cells. Our in vitro study analyzed the putative anti-inflammatory effect of nine selected pure cannabinoids in J774A1 macrophage cells and EGCs triggered to undergo inflammation with lipopolysaccharide (LPS). The anti-inflammatory effect of several phytocannabinoids was measured by their ability to reduce TNFα transcription and translation in J774A1 macrophages and to diminish S100B and GFAP secretion and transcription in EGCs. Our results demonstrate that THC at the lower concentrations tested exerted the most effective anti-inflammatory effect in both J774A1 macrophages and EGCs compared to the other phytocannabinoids tested herein. We then performed RNA-seq analysis of EGCs exposed to LPS in the presence or absence of THC or THC-COOH. Transcriptomic analysis of these EGCs revealed 23 differentially expressed genes (DEG) compared to the treatment with only LPS. Pretreatment with THC resulted in 26 DEG, and pretreatment with THC-COOH resulted in 25 DEG. To evaluate which biological pathways were affected by the different phytocannabinoid treatments, we used the Ingenuity platform. We show that THC treatment affects the mTOR and RAR signaling pathway, while THC-COOH mainly affects the IL6 signaling pathway.
... Single-cell transcriptomic profiling identified different immune cell types and their distribution changes with age scRNA-seq was carried out on 19 livers harvested from mice at 4 different periods, namely, 5 newborns and 5 suckling (the 7th day after birth), 3 young (10 weeks), and 6 aged (18 mo) mice ( Figure 1A). [14,15] After qualitative filtering, 112,414 cells were obtained for further analysis, and to focus on the immune microenvironment, we further selected 89,542 immune cells with Ptprc (Cd45) expression. Based on marker gene expression, data from t-distributed Stochastic Neighbor Embedding visualization identified 9 cell types: cycling cells, T/natural killer T (NKT) cells, natural killer (NK) cells, monocytes/macrophages (mono/mac), plasmacytoid dendritic cells, conventional dendritic cells (cDCs), neutrophils, B cells, and plasma cells ( Figure 1B-C and Supplemental Figure S1A, http://links.lww.com/HEP/ ...
Background and aims:
Immune cells play a crucial role in liver aging. However, the impact of dynamic changes in the local immune microenvironment on age-related liver injury remains poorly understood. We aimed to characterize intrahepatic immune cells at different ages to investigate key mechanisms associated with liver aging.
Approach and results:
We carried out single-cell RNA sequencing (scRNA-seq) on mouse liver tissues at four different ages, namely, the newborn, suckling, young, and aged stages. The transcriptomic landscape, cellular classification, and intercellular communication were analyzed. We confirmed the findings by multiplex immunofluorescence staining, flow cytometry, in vitro functional experiments, and chimeric animal models. Nine subsets of 89,542 immune cells with unique properties were identified, of which Cxcl2+ macrophages within the monocyte/macrophage subset were preferentially enriched in the aged liver. Cxcl2+ macrophages presented a senescence-associated secretory phenotype (SASP) and recruited neutrophils to the aged liver through the CXCL2-CXCR2 axis. Through the secretion of IL-1β (interleukin-1 beta) and TNF-α (tumor necrosis factor alpha), Cxcl2+ macrophages stimulated neutrophil extracellular traps (NETs) formation. Targeting the CXCL2-CXCR2 axis limited the neutrophils migration toward the liver and attenuated age-related liver injury. Moreover, the relationship between Cxcl2+ macrophages and neutrophils in age-related liver injury was further validated by human liver transplantation samples.
Conclusions:
This in-depth study illustrates that the mechanism of Cxcl2+ macrophage-driven neutrophil activation involves the CXCL2-CXCR2 axis, and provide a potential therapeutic strategy for age-related liver injury.
... This is in accordance to the known biphasic effect of THC [89,90]. This data points to the advantage of using low or even ultralow doses of THC, this in accordance with the reversal of cognitive impairment in old mice, and spatial memory test in old female mice [91,92]. Transcription of TNFα was not affected by pretreatment of THC this was evident from RTqPCR ( Figure S4A,) and transcriptomics. ...
Inflammatory bowel diseases (IBD) includes Crohn's disease and ulcerative colitis, are idiopathic chronic relapsing inflammatory disorders of the intestinal tract. Different studies indicate that phytocanna-binoids, could play a possible role in the treatment of IBD by relieving the symptoms involved in the dis-ease. Phytocannabinoids act through the endocannabinoid system, which is distributed throughout the mammalian body in the cells of the immune system and in the intestinal cells. Our in vitro study analyzed the putative-anti-inflammatory effect of nine-selected pure cannabinoids in J774A1 macrophages cells and enteric glial cells (EGC’s) triggered to undergo inflammation with lipopolysaccharide (LPS). The an-ti-inflammatory effect of several phytocannabinoids was measured by their ability to reduce TNF tran-scription and translation in J774A1 macrophages and to diminish S100B and GFAP secretion and tran-scription in EGC’s. Our results demonstrate that THC at the lower concentrations tested exerted the most effective anti- inflammatory effect in both J774A1 macrophages and EGC’s compared to the other phy-tocannabinoids tested herein. We then performed RNA-seq analysis of EGC’s exposed to LPS in the presence or absence of THC or THC-COOH. Transcriptomic analysis of these EGC’s revealed 23 differ-entially expressed genes (DEG) compared to treatment with only LPS. Pretreatment with THC resulted in 26 DEG and pretreatment with THC-COOH resulted in 25 DEG. To evaluate which biological pathways were affected by the different phytocannabinoid treatments we used the Ingenuity platform. We show that THC treatment affected the mTOR and RAR signaling pathway while THC-COOH affected mainly the IL6 signaling pathway.
... Additionally, we showed that AEA treatment is able to improve the neuronal uptake of cholesterol from aged astrocytes. Thus, considering that reduced neuronal cholesterol impacts synaptic receptor function and synaptic plasticity, the fact that cannabinoids are able to restore the cholesterol transport from aged astrocytes to neurons would have important implications in the aging field since it would contribute to explain observations showing improved cognition in old individuals treated with phytocannabinoids [29,30] . ...
Cholesterol is crucial for the proper functioning of eukaryotic cells, especially neurons, which rely on cholesterol to maintain their complex structure and facilitate synaptic transmission. However, brain cells are isolated from peripheral cholesterol by the blood-brain barrier and mature neurons primarily uptake the cholesterol synthesized by astrocytes for proper function. This study aimed to investigate the effect of aging on cholesterol trafficking in astrocytes and its delivery to neurons.
Using in vitro and in vivo models of aging, we found that aged astrocytes accumulated high levels of cholesterol in the lysosomal compartment, and this cholesterol buildup can be attributed to the simultaneous occurrence of two events: decreased levels of the ABCA1 transporter which impairs ApoE-cholesterol export from astrocytes, and reduced expression of NPC1, which hinders cholesterol release from lysosomes. We show that these two events are accompanied by increased microR33 in aged astrocytes, which is known to downregulate ABCA1 and NPC1. In addition, we demonstrate that the microR33 increase is triggered by oxidative stress, one of the hallmarks of aging.
By co-culture experiments we also show that aging in vitro impairs the cholesterol delivery from astrocytes to neurons. Remarkably, we found that this altered transport of cholesterol could be alleviated through treatment with endocannabinoids as well as cannabidiol or CBD. Given that reduced neuronal cholesterol affects synaptic plasticity, the ability of cannabinoids to restore cholesterol transport from aged astrocytes to neurons holds significant implications in the field of aging.
... As mDexos are immune-activating drugs, their immunotherapeutic effects are best when the immune system is intact, and the mouse immune system tends to mature after 6 weeks of age; thus, 6-week-old C57BL/6J mice were selected for construction of the melanoma mouse model in the current study. 34,35 The TGI rate of the siBRAF-mDexo group was the highest, indicating that siBRAF-mDexos had the strongest antimelanoma activity. However, the TGI rate of the siBRAF group was the lowest, indicating that the in vivo antimelanoma activity of siBRAF was limited, due to the instability of free siRNA in vivo after administration, the ease with which free siRNA is decomposed by nucleases in vivo, and the difficulty with which free siRNA crosses the biofilm barrier into cells to reach the site of action. ...
Purpose
Malignant melanoma (MM), the most lethal skin cancer, is highly invasive and metastatic. These qualities are related to not only genetic mutations in MM itself but also the interaction of MM cells with the immune system and microenvironment. This study aimed to construct a combined immunotherapy and gene therapy drug delivery system for the effective treatment of MM.
Methods
Mature dendritic cell (mDC) exosomes (mDexos) with immune induction functions were used as carriers. BRAF siRNA (siBRAF) with the ability to silence mutated BRAF in MM was encapsulated in mDexos by electroporation to construct a biomimetic nanosystem for the codelivery of immunotherapy and gene therapy drugs (siBRAF-mDexos) to the MM microenvironment. Then, we investigated the nanosystem’s serum stability and biocompatibility, uptake efficiency in mouse melanoma cells (B16-F10 cells), cytotoxicity against B16-F10 cells and inhibitory effect on BRAF expression. Furthermore, we evaluated its antimelanoma activity and safety in vivo.
Results
SiBRAF-mDexos were nanosized. Compared to siBRAF, siBRAF-mDexos displayed significantly increased serum stability, biocompatibility, uptake efficiency in B16-F10 cells, and cytotoxicity to B16-F10 melanoma cells; they also had a significantly greater inhibitory effect on BRAF expression and induced T-lymphocyte proliferation. Moreover, compared with siBRAF, siBRAF-mDexos showed significantly enhanced anti-MM activity and a high level of safety in vivo.
Conclusion
The study suggests that the siBRAF-mDexo biomimetic drug codelivery system can be used to effectively treat MM, which provides a new strategy for combined gene therapy and immunotherapy for MM.
... Importantly, aging is considered the main risk factor for several neurodegenerative disorders (Hou et al., 2019), and surprisingly, we do not fully understand how the ECS evolve during aging. Indeed, just a handful of studies have looked into how aging shape the ECS signaling, but current data indicates that older people respond differently to exogenous cannabinoids (Bilkei-Gorzo et al., 2017;Mueller et al., 2021). Thus, it is recommended to apply with care the current knowledge about the ECS in young adulthood into the neurodegenerative disorders research, especially in AD and PD in which aging is a strong risk factor. ...
Neurodegenerative disorders are debilitating conditions that impair patient quality of life and that represent heavy social-economic burdens to society. Whereas the root of some of these brain illnesses lies in autosomal inheritance, the origin of most of these neuropathologies is scantly understood. Similarly, the cellular and molecular substrates explaining the progressive loss of brain functions remains to be fully described too. Indeed, the study of brain neurodegeneration has resulted in a complex picture, composed of a myriad of altered processes that include broken brain bioenergetics, widespread neuroinflammation and aberrant activity of signaling pathways. In this context, several lines of research have shown that the endocannabinoid system (ECS) and its main signaling hub, the type-1 cannabinoid (CB1) receptor are altered in diverse neurodegenerative disorders. However, some of these data are conflictive or poorly described. In this review, we summarize the findings about the alterations in ECS and CB1 receptors signaling in three representative brain illnesses, the Alzheimer's, Parkinson's and Huntington's diseases, and we discuss the relevance of these studies in understanding neurodegeneration development and progression, with a special focus on astrocyte function. Noteworthy, the analysis of ECS defects in neurodegeneration warrant much more studies, as our conceptual understanding of ECS function has evolved quickly in the last years, which now include glia cells and the subcellular-specific CB1 receptors signaling as critical players of brain functions.
... For mouse studies, early THC exposure led to notable memory deficits, 40 while older mice exposed to THC showed improved cognitive performance on par with younger cohorts. [41][42][43] Few studies have examined the global effect of cannabinoids on longevity. Zebra fish given low-dose CBD or THC during development showed a significant survival increase. ...
Introduction: The legalization of cannabis products has increased their usage in the United States. Among the ∼500 active compounds, this is especially true for cannabidiol (CBD)-based products, which are being used to treat a range of ailments. Research is ongoing regarding the safety, therapeutic potential, and molecular mechanism of cannabinoids. Drosophila (fruit flies) are widely used to model a range of factors that impact neural aging, stress responses, and longevity. Materials and Methods: Adult wild-type Drosophila melanogaster cohorts (w1118/+) were treated with different Δ9-tetrahydrocannabinol (THC) and CBD dosages and examined for neural protective properties using established neural aging and trauma models. The therapeutic potential of each compound was assessed using circadian and locomotor behavioral assays and longevity profiles. Changes to NF-κB pathway activation were assessed by measuring expression levels of downstream targets using quantitative real-time polymerase chain reaction analysis of neural cDNAs. Results: Flies exposed to different CBD or THC dosages showed minimal effects to sleep and circadian-based behaviors or the age-dependent decline in locomotion. The 2-week CBD (3 μM) treatment did significantly enhance longevity. Flies exposed to different CBD and THC dosages were also examined under stress conditions, using the Drosophila mild traumatic brain injury (mTBI) model (10×). Pretreatment with either compound did not alter baseline expression of key inflammatory markers (NF-κB targets), but did reduce neural mRNA profiles at a key 4-h time point following mTBI exposure. Locomotor responses were also significantly improved 1 and 2 weeks following mTBI. After mTBI (10×) exposure, the 48-h mortality rate improved for CBD (3 μM)-treated flies, as were global average longevity profiles for other CBD doses tested. While not significant, THC (0.1 μM)-treated flies show a net positive impact on acute mortality and longevity profiles following mTBI (10×) exposure. Conclusions: This study shows that the CBD and THC dosages examined had at most a modest impact on basal neural function, while demonstrating that CBD treatments had significant neural protective properties for flies following exposure to traumatic injury.
... Evidence from animal studies and investigation of the human body's natural endocannabinoid system show that cannabinoids (e.g. chronic low dose THC) demonstrate anti-inflammatory and neuroprotective effects [24,25]. While there is no research in humans to suggest cannabis compounds decrease risk for cognitive decline, there is interest in examining the therapeutic potential of cannabinoid products on brain function under conditions of high inflammation [26]. ...
Cannabis use is rapidly increasing among older adults in the United States, in part to treat symptoms of common health conditions (e.g., chronic pain, sleep problems). Longitudinal studies of cannabis use and cognitive decline in aging populations living with chronic disease are lacking. We examined different levels of cannabis use and cognitive and everyday function over time among 297 older adults with HIV (ages 50–84 at baseline). Participants were classified based on average cannabis use: frequent (> weekly) (n = 23), occasional (≤ weekly) (n = 83), and non-cannabis users (n=191) and were followed longitudinally for up to 10 years (average years of follow-up = 3.9). Multi-level models examined the effects of average and recent cannabis use on global cognition, global cognitive decline, and functional independence. Occasional cannabis users showed better global cognitive performance overall compared to non-cannabis users. Rates of cognitive decline and functional problems did not vary by average cannabis use. Recent cannabis use was linked to worse cognition at study visits when participants had THC+ urine toxicology—this short-term decrement in cognition was driven by worse memory and did not extend to reports of functional declines. Occasional (≤ weekly) cannabis use was associated with better global cognition over time in older adults with HIV, a group vulnerable to chronic inflammation and cognitive impairment. Recent THC exposure may have a temporary adverse impact on memory. To inform safe and efficacious medical cannabis use, the effects of specific cannabinoid doses on cognition and biological mechanisms must be investigated in older adults.
... This is true with respect to THC, but only with certain doses (Sarne, 2019). Ultra-low (0.002 mg/kg; i.p) and low (3 mg/kg; i.p) doses of THC resulted in improved cognitive function in old mice (24 and 18-month-old, respectively), whereas the same dose induced cognitive impairments in adult mice (2-months-old; Bilkei-Gorzo et al., 2017;Sarne et al., 2018). However, higher doses of THC have the reverse effect (Calabrese and Rubio-Casillas, 2018). ...
Consumption of cannabis is on the rise as public opinion trends toward acceptance and its consequent legalization. Specifically, the senior population is one of the demographics increasing their use of cannabis the fastest, but research aimed at understanding cannabis' impact on the aged brain is still scarce. Aging is characterized by many brain changes that slowly alter cognitive ability. One process that is greatly impacted during aging is axonal myelination. The slow degradation and loss of myelin (i.e., demyelination) in the brain with age has been shown to associate with cognitive decline and, furthermore, is a common characteristic of numerous neurological diseases experienced in aging. It is currently not known what causes this age-dependent degradation, but it is likely due to numerous confounding factors (i.e., heightened inflammation, reduced blood flow, cellular senescence) that impact the many cells responsible for maintaining overall homeostasis and myelin integrity. Importantly, animal studies using non-human primates and rodents have also revealed demyelination with age, providing a reliable model for researchers to try and understand the cellular mechanisms at play. In rodents, cannabis was recently shown to modulate the myelination process. Furthermore, studies looking at the direct modulatory impact cannabis has on microglia, astrocytes and oligodendrocyte lineage cells hint at potential mechanisms to prevent some of the more damaging activities performed by these cells that contribute to demyelination in aging. However, research focusing on how cannabis impacts myelination in the aged brain is lacking. Therefore, this review will explore the evidence thus far accumulated to show how cannabis impacts myelination and will extrapolate what this knowledge may mean for the aged brain.
... Such conditions may facilitate the detection of augmented contingency degradation learning after drug exposure. This finding may relate to previous reports that chronic low-dose THC exposure can promote neurogenesis (Cao et al. 2014;Jiang et al. 2005;Suliman et al. 2018) and improve cognition and memory in mature and aged, but not young, mice (Bilkei-Gorzo et al. 2017;Sarne et al. 2018). Such findings have raised the possibility that late-life cannabis use may have neuroprotective effects (Weinstein and Sznitman 2020). ...
Rationale
The endocannabinoid system makes critical contributions to reward processing, motivation, and behavioral control. Repeated exposure to THC or other cannabinoid drugs can cause persistent adaptions in the endocannabinoid system and associated neural circuitry. It remains unclear how such treatments affect the way rewards are processed and pursued.
Objective and methods
We examined if repeated THC exposure (5 mg/kg/day for 14 days) during adolescence or adulthood led to long-term changes in rats’ capacity to flexibly encode and use action-outcome associations for goal-directed decision making. Effects on hedonic feeding and progressive ratio responding were also assessed.
Results
THC exposure had no effect on rats’ ability to flexibly select actions following reward devaluation. However, instrumental contingency degradation learning, which involves avoiding an action that is unnecessary for reward delivery, was augmented in rats with a history of adult but not adolescent THC exposure. THC-exposed rats also displayed more vigorous instrumental behavior in this study, suggesting a motivational enhancement. A separate experiment found that while THC exposure had no effect on hedonic feeding behavior, it increased rats’ willingness to work for food on a progressive ratio schedule, an effect that was more pronounced when THC was administered to adults. Adolescent and adult THC exposure had opposing effects on the CB1 receptor dependence of progressive ratio performance, decreasing and increasing sensitivity to rimonabant-induced behavioral suppression, respectively.
Conclusions
Our findings reveal that exposure to a translationally relevant THC exposure regimen induces long-lasting, age-dependent alterations in cognitive and motivational processes that regulate the pursuit of rewards.
... Consistently, the age of cannabis users affects human brain function, as observed by comparing adolescents, adults, and healthy controls [214]. Accordingly, while chronic exposure to low doses of THC restores cognitive functions, such as memory deficits and learning capacity in old mice (12-18 months), in young adult mice (2 months old) the same THC dose induces cognitive deficits [215]. Moreover, in rodents, THC exposure in adolescence induces memory impairment in the novel object recognition (NOR) test in adulthood [216][217][218][219][220][221][222][223], while milder or non-significant deficits have been observed with THC exposure in adulthood [223][224][225][226]. Taken together, this evidence suggests that THC-induced cognitive impairments may be due to its effects on the adolescent brain. ...
Cannabis is the most used drug of abuse worldwide. It is well established that the most abundant phytocannabinoids in this plant are Δ9-tetrahydrocannabinol (THC) and cannabidiol (CBD). These two compounds have remarkably similar chemical structures yet vastly different effects in the brain. By binding to the same receptors, THC is psychoactive, while CBD has anxiolytic and antipsychotic properties. Lately, a variety of hemp-based products, including CBD and THC, have become widely available in the food and health industry, and medical and recreational use of cannabis has been legalized in many states/countries. As a result, people, including youths, are consuming CBD because it is considered “safe”. An extensive literature exists evaluating the harmful effects of THC in both adults and adolescents, but little is known about the long-term effects of CBD exposure, especially in adolescence. The aim of this review is to collect preclinical and clinical evidence about the effects of cannabidiol.
... For example, 1.5 mg/kg THC (i.p. for 1 or 3 weeks) administered to adult male Sprague Dawley rats resulted in improved learning and memory in the novel object recognition task, a result that was associated with enhanced expression of neurogenesis markers in the hippocampus (Suliman et al., 2018). Furthermore, a dose of 3 mg/kg/day THC (subcutaneous via osmotic pump, 4 weeks) demonstrated the ability to improve the learning and memory performance of aged male mice (12-and 18-month-old C57BL/6J mice) in the Morris water maze (MWM) test, novel object recognition test and social recogni-tion test through restoration of CB1 signalling (Bilkei-Gorzo et al., 2017). These effects were associated with hippocampal gene transcription patterns in the 12-month-old mice being restored to the levels of 2-month-old non-aged mice. ...
Alzheimer's disease (AD) is the most common form of dementia, and currently there is no cure. New therapeutic strategies that have the potential to address the complex pathophysiology of AD are urgently required; medicinal cannabis offers this possibility. Several potential leads can be extracted from Cannabis sativa (cannabis) that can target AD pathophysiology and alleviate symptoms, making it a prime candidate for AD drug discovery research. To date, most cannabis and AD research has focused on the major cannabinoids Δ9-tetrahydrocannabinol (THC) and cannabidiol (CBD), paying little attention to other plant constituents with therapeutic properties for AD. This chapter will highlight emerging evidence on the therapeutic potential of medicinal cannabis going beyond CBD and THC to discuss cannabinol (CBN), cannabigerol (CBG), cannabichromene (CBC), cannabinoid acids, and other cannabinoid homologs, terpenes, and flavonoids that may have relevance to AD therapy. Further, the entourage effect, clinical implications, and directions for future research will be discussed.
... Here we could demonstrate that prolonged WIN 55,212-2 treatment caused severe cognition memory and spatial reference memory deficits. In line with the present findings, longterm THC and WIN 55,212-2 administration has previously been described to cause persistent memory impairments in adolescent and adult rodents (Tomas-Roig et al. 2017;Abush and Akirav 2010;Bilkei-Gorzo et al. 2017). However, most studies analyzed the effects of cannabinoids on cognition during intoxication or a short washout period (Gorey et al. 2019). ...
In recent years, there has been growing evidence that cannabinoids have promising medicinal and pharmacological effects. However, the growing interest in medical cannabis highlights the need to better understand brain alterations linking phytocannabinoids or synthetic cannabinoids to clinical and behavioral phenotypes. Therefore, the aim of this study was to investigate the effects of long-term WIN 55,212-2 treatment—with and without prolonged abstinence—on cerebral metabolism and memory function in healthy wildtype mice. Adult C57BI/6J mice were divided into two treatment groups to study the acute effects of WIN 55,212-2 treatment as well the effects of WIN 55,212-2 treatment after an extended washout phase. We could demonstrate that 3 mg/kg WIN 55,212-2 treatment in early adulthood leads to a hypometabolism in several brain regions including the hippocampus, cerebellum, amygdala and midbrain, even after prolonged abstinence. Furthermore, prolonged acute WIN 55,212-2 treatment in 6-months-old mice reduced the glucose metabolism in the hippocampus and midbrain. In addition, Win 55,212-2 treatment during adulthood lead to spatial memory and recognition memory deficits without affecting anxiety behavior. Overall we could demonstrate that treatment with the synthetic CB1/CB2 receptor aganist Win 55,212-2 during adulthood causes persistent memory deficits, especially when mice were treated in early adulthood. Our findings highlight the risks of prolonged WIN 55,212-2 use and provide new insights into the mechanisms underlying the effects of chronic cannabinoid exposure on the brain and behavior.
การวิจัยนี้ มีวัตถุประสงค์เพื่อศึกษาประสิทธิผลของน้ำมันกัญชา (ตำรับหมอเดชา) ต่อการเพิ่มความจำขณะทำงานของผู้ที่มีภาวะนอนไม่หลับ กลุ่มตัวอย่างแบ่งออกเป็น 2 กลุ่มเท่ากัน โดยกลุ่มทดลองได้รับน้ำมันกัญชาร่วมกับการปฏิบัติตามสุขอนามัยการนอนหลับที่ดี ส่วนกลุ่มควบคุมได้รับยาหลอกร่วมกับการปฏิบัติตามสุขอนามัยการนอนหลับที่ดี ประเมินความจำขณะทำงานด้วยการวัดคลื่นไฟฟ้าสมองขณะทำกิจกรรมการวัดความจำตัวเลขย้อนกลับ ผลการวิจัยพบว่า 1) ค่า ERD% ของคลื่นแอลฟาระดับสูงก่อนการทดลอง ระหว่างกลุ่มใช้น้ำมันกัญชากับกลุ่มใช้ยาหลอกไม่แตกต่างกัน 2) ในกลุ่มใช้น้ำมันกัญชา หลังการทดลองมีค่า ERD% ของคลื่นแอลฟาระดับสูงเพิ่มขึ้นอย่างมีนัยสำคัญทางสถิติ เมื่อเทียบกับก่อนทดลองที่ตำแหน่ง AF4 (p = 0.001), F3 (p = 0.002), F4 (p = 0.048), F7 (p = 0.001), F8 (p = 0.002), P7 (p = 0.007) และ P8 (p = 0.005) และ 3) ภายหลังการทดลองกลุ่มใช้น้ำมันกัญชา มีค่า ERD% ของคลื่นแอลฟาระดับสูงเพิ่มขึ้นอย่างมีนัยสำคัญทางสถิติ เมื่อเทียบกับกลุ่มใช้ยาหลอกที่ตำแหน่ง AF4 (p = 0.013), F3 (p = 0.035), F4 (p = 0.031), F8 (p = 0.014), P7 (p = 0.008) และ P8 (p = 0.008) ดังนั้น การใช้น้ำมันกัญชา (ตำรับหมอเดชา) ร่วมกับการปฏิบัติตามสุขอนามัยการนอนหลับที่ดีเพื่อรักษาผู้ที่มีภาวะนอนไม่หลับ สามารถเพิ่มความจำขณะทำงานของสมองได
Cannabinoids and the endocannabinoid system (ECS) have been intensively studied for their neuroregulatory roles in the central nervous system (CNS), especially in regulating learning and memory. However, many experimental and clinical studies obtained conflicting results indicating a complex network of interaction underlying the regulation of learning and memory by different cannabinoids and the ECS. The ECS influences neuronal synaptic communications, and therefore may exert different regulation via their different impact on other neurotransmitters. The monoaminergic system includes a variety of neurotransmitters, such as dopamine, norepinephrine, and serotonin, which play important roles in regulating mood, cognition, and reward. The interaction among cannabinoids, ECS and the monoaminergic system has drawn particular attention, especially their contributions to learning and memory. In this review, we summarized the current understanding of how cannabinoids, ECS and the monoaminergic system contribute to the process of learning and memory, and discussed the influences of monoaminergic neurotransmission by cannabinoids and ECS during this process.
Cannabinoids (the endocannabinoids, the synthetic cannabinoids, and the phytocannabinoids) are well known for their various pharmacological properties, including neuroprotective and anti-inflammatory features, which are fundamentally important for the treatment of neurodegenerative diseases. The aging of the global population is causing an increase in these diseases that require the development of effective drugs to be even more urgent. Taking into account the unavailability of effective drugs for neurodegenerative diseases, it seems appropriate to consider the role of cannabinoids in the treatment of these diseases. To our knowledge, few reviews are devoted to cannabinoids’ impact on modulating central and peripheral immunity in neurodegenerative diseases. The objective of this review is to provide the best possible information about the cannabinoid receptors and immuno-modulation features, peripheral immune modulation by cannabinoids, cannabinoid-based therapies for the treatment of neurological disorders, and the future development prospects of making cannabinoids versatile tools in the pursuit of effective drugs.
Cholesterol is crucial for the proper functioning of eukaryotic cells, especially neurons, which rely on cholesterol to maintain their complex structure and facilitate synaptic transmission. However, brain cells are isolated from peripheral cholesterol by the blood–brain barrier and mature neurons primarily uptake the cholesterol synthesized by astrocytes for proper function. This study aimed to investigate the effect of aging on cholesterol trafficking in astrocytes and its delivery to neurons. We found that aged astrocytes accumulated high levels of cholesterol in the lysosomal compartment, and this cholesterol buildup can be attributed to the simultaneous occurrence of two events: decreased levels of the ABCA1 transporter, which impairs ApoE-cholesterol export from astrocytes, and reduced expression of NPC1, which hinders cholesterol release from lysosomes. We show that these two events are accompanied by increased microR-33 in aged astrocytes, which targets ABCA1 and NPC1. In addition, we demonstrate that the microR-33 increase is triggered by oxidative stress, one of the hallmarks of aging. By coculture experiments, we show that cholesterol accumulation in astrocytes impairs the cholesterol delivery from astrocytes to neurons. Remarkably, we found that this altered transport of cholesterol could be alleviated through treatment with endocannabinoids as well as cannabidiol or CBD. Finally, according to data demonstrating that aged astrocytes develop an A1 phenotype, we found that cholesterol buildup is also observed in reactive C3+ astrocytes. Given that reduced neuronal cholesterol affects synaptic plasticity, the ability of cannabinoids to restore cholesterol transport from aged astrocytes to neurons holds significant implications in aging and inflammation.
Cannabis is one of the oldest and widely used substances in the world. Cannabinoids within the cannabis plant, known as phytocannabinoids, mediate cannabis' effects through interactions with the body's endogenous cannabinoid system. This endogenous system, the endocannabinoid system, has important roles in physical and mental health. These roles point to the potential to develop cannabinoids as therapeutic agents, while underscoring the risks related to interfering with the endogenous system during non-medical use. This scoping narrative review synthesizes the current evidence for both the therapeutic and adverse effects of the major (i.e., Δ9-tetrahydrocannabinol and cannabidiol) and lesser studied minor phytocannabinoids, from nonclinical to clinical research. We pay particular attention to the areas where evidence is well-established, including analgesic effects after acute exposures and neurocognitive risks after acute and chronic use. In addition, drug development considerations for cannabinoids as therapeutic agents within the United States are reviewed. The proposed clinical study design considerations encourage methodological standards for greater scientific rigor and reproducibility, ultimately, to extend our knowledge of the risks and benefits of cannabinoids for patients and providers. Significance Statement This work provides a review of prior research related to phytocannabinoids, including therapeutic potential and known risks in the context of drug development within the United States. We also provide study design considerations for future cannabinoid drug development.
Purpose of Review
To examine the acute and long-term effects of cannabis use on cognitive functioning across the lifespan, and to evaluate the evidence for the hypothesis of developmental sensitivity to cannabis effects.
Recent Findings
Acute cannabis intoxication impairs cognitive functioning, and frequent cannabis use is associated with subtle cognitive deficits after intoxication has passed, in adolescence, young adulthood, and midlife. Longitudinal studies show that more frequent and longer-term cannabis use are associated with cognitive decline, though associations are small and inconsistent in studies of adolescents and young adults and small-moderate in studies of longer-term use to midlife. Older adults are understudied. Findings on prenatal and early postnatal cannabis exposure and cognitive functioning, though mixed, caution against use during pregnancy.
Summary
It seems likely that cannabis use is associated with cognitive deficits across the lifespan. However, the very young and the old are understudied, and there are few within-study comparisons of age differences in cognitive effects. The evidence on age-related differences in sensitivity to cannabis effects on cognitive functioning in humans is inconclusive.
Background
Cannabis use has increased in recent years. However, the long-term implications of cannabis use on brain health remain unknown. We explored the associations of cannabis use with volumetric brain magnetic resonance imaging (MRI) measures in dementia-free older adults.
Methods
This cross-sectional and longitudinal study included dementia-free participants of the UK Biobank aged ≥60 years. Linear regression models were used to evaluate the association of cannabis use and patterns of use with volumetric brain MRI measures. The association between cannabis use and change in brain MRI measures over time was also tested. All models were adjusted for potential confounders.
Results
The sample included 19,932 participants (mean age 68 ± 5 years, 48% men), 3,800 (19%) reported lifetime use of cannabis. Cannabis use was associated with smaller total, white, grey and peripheral cortical grey matter volumes (B = −6,690 ± 1,157; P < 0.001, B = −4,396 ± 766; P < 0.001, B = −2,140 ± 690; P = 0.002 and B = −2,451 ± 606; P < 0.001, respectively). Among cannabis users, longer duration of use was associated with smaller total brain, grey and cortical grey matter volumes (B = −7,878 ± 2,396; P = 0.001, B = −5,411 ± 1,430; P < 0.001, B = −5,396 ± 1,254; P < 0.001, respectively), and with increased white matter hyperintensity volume (B = 0.09 ± 0.03; P = 0.008). Additionally, current vs. former users (B = −10,432 ± 4,395; P = 0.020) and frequent versus non-frequent users (B = −2,274 ± 1,125; P = 0.043) had smaller grey and cortical grey matter volumes, respectively. No significant associations were observed between cannabis use and change in brain MRI measures.
Discussion
Our findings suggest that cannabis use, particularly longer duration and frequent use, may be related to smaller grey and white matter volumes in older ages, but not to late-life changes in these measures over time.
Recent research connecting choline-containing lipids to basal forebrain cholinergic neurons (BFCN) degeneration in neuropathological states highlights a challenge for balancing lipid integrity with optimal acetylcholine (ACh) levels. Warranting an adequate choline source to maintain ACh levels in this pathway is crucial for preserving memory. The endocannabinoid (eCB) system plays a role in modulating learning and memory processes controlled by cholinergic neurotransmission. Consequently, we propose that activation of this system is neuroprotective against cholinergic degeneration. In the present study, we investigated the neuroprotective effect of a subchronic treatment with the CB1 cannabinoid agonist, WIN55,212-2, using both ex vivo and in vivo 192IgG-Saporin models of specific cholinergic damage. Degeneration of baso-cortical cholinergic pathways induced memory deficits and a downregulation of saturated and mono-unsaturated lysophosphatidylcholines (LPC) cortical levels. WIN55,212-2 not only restored memory deficits but also increased cortical ACh levels and modified cortical choline-containing lipids such as sphingomyelins (SM) and LPCs, which are essential for correct memory functioning, in lesioned animals. Given these results, we propose that WIN55,212-2 generates an alternative choline source through the breakdown of SMs, which is enough to increase cortical ACh levels and LPCs. These findings suggest that modification of choline-containing lipids by the activation of CB1 receptors is a promising therapy for dementia associated with cholinergic dysfunction, such as in Alzheimer`s disease (AD).
Background: There is an urgent need for novel therapies to treat Alzheimer's disease. Among others, the use of cannabinoids such as delta-9-tetrahydrocannabinol (THC) and cannabidiol (CBD) has been proposed as a putative approach based on their anti-inflammatory effects. Methods: The present work was designed to explore the effects of chronic (28 days) treatment with low doses of cannabinoids: CBD (0.273 mg/kg), THC (0.205 mg/kg) or a combination of both (CBD:THC; 0.273 mg/kg:0.205 mg/kg) in the 5xFAD mouse model of AD. Results: Our data revealed that THC-treated 5xFAD mice (but not other treatment groups) exhibited anxiogenic and depressant-like behavior. A significant improvement in spatial memory was observed only in the CBD:THC-treated group. Interestingly, all cannabinoid-treated groups showed significantly increased cortical levels of the insoluble form of beta amyloid 1-42. These effects were not accompanied by changes in molecular parameters of inflammation at the mRNA or protein level. Conclusions: These data reveal differential effects of chronic, low-dose cannabinoids and point to a role of these cannabinoids in the processing of amyloid peptides in the brains of 5xFAD mice.
Cannabis sativa L. produces a wide variety of volatile secondary metabolites that contribute to its unique aroma. The major volatile constituents include monoterpenes, sesquiterpenes, and their oxygenated derivates. In particular, the compounds ß-myrcene, D-(+)-limonene, ß-caryophyllene, and terpinolene are often found in greatest amounts, which has led to their use in chemotaxonomic classification schemes and legal Cannabis sativa L. product labeling. While these compounds contribute to the characteristic aroma of Cannabis sativa L. and may help differentiate varieties on a broad level, their importance in producing specific aromas is not well understood. Here, we show that across Cannabis sativa L. varieties with divergent aromas, terpene expression remains remarkably similar, indicating their benign contribution to these unique, specific scents. Instead, we found that many minor, nonterpenoid compounds correlate strongly with nonprototypical sweet or savory aromas produced by Cannabis sativa L. Coupling sensory studies to our chemical analysis, we derive correlations between groups of compounds, or in some cases, individual compounds, that produce many of these diverse scents. In particular, we identified a new class of volatile sulfur compounds (VSCs) containing the 3-mercaptohexyl functional group responsible for the distinct citrus aromas in certain varieties and skatole (3-methylindole) as the key source of the chemical aroma in others. Our results provide not only a rich understanding of the chemistry of Cannabis sativa L. but also highlight how the importance of terpenes in the context of the aroma of Cannabis sativa L. has been overemphasized.
Background:
Phytocannabinoids have been shown to inhibit the aggregation and neurotoxicity of the neurotoxic Alzheimer's disease protein beta amyloid (Aβ). We characterised the capacity of six phytocannabinoids: cannabichromene, cannabigerol, cannabinol, cannabidivarin, cannabidiol and Δ9 -tetrahydrocannabinol, to disrupt Aβ aggregation and protect against Aβ-evoked neurotoxicity in PC12 cells.
Methods:
Neuroprotection against lipid peroxidation and Aβ-induced cytotoxicity was assessed using the MTT assay. Transmission electron microscopy was used to visualise phytocannabinoid effects on Aβ aggregation and fluorescence microscopy, with morphometrics and principal component analysis to assess PC12 cell morphology.
Results:
Cannabidiol inhibited lipid peroxidation with no significant effect on Aβ toxicity, while cannabinol, cannabidivarin and cannabigerol provided neuroprotection. Cannabichromene, cannabigerol and cannabinol inhibited Aβ1-42 -induced neurotoxicity in PC12 cells, as did Δ9 -tetrahydrocannabinol, cannabidiol and cannabidivarin. Cannabichromene, cannabinol and cannabidivarin inhibited Aβ aggregation, while Δ9 -tetrahydrocannabinol reduced aggregate density. Aβ1-42 induced morphological changes in PC12 cells, including a reduction in neuritic projections and rounded cell morphology. Cannabichromene and cannabigerol inhibited this effect, while Δ9 -tetrahydrocannabinol, cannabidiol and cannabidivarin did not alter Aβ1-42 effects on cell morphology.
Conclusions:
These findings highlight the neuroprotective activity of cannabichromene, cannabigerol and cannabinol as novel phytocannabinoids associated with variable effects on Aβ-evoked neurite damage and inhibition of amyloid β aggregation.
Cannabis products and Cannabis use are inherently variable. Given the difficulty in standardizing Cannabis products and Cannabis use patterns, studies are often impacted by differences in the participants’ exposure to Cannabis or even specific cannabinoids, especially in medical use. Although it is clear that chronic recreational use impacts brain function, albeit subtly, future researches exploring moderating factors, including the age of onset, recovery of function after abstinence, frequency and magnitude of Cannabis use, high- versus low-potency products, mode of use, and the unique effects of specific cannabinoids, are all needed to understand the impact of Cannabis fully. As legalization efforts expand, overall use rates continue to rise, and questions regarding Cannabis and public policy measures remain crucial.
Cannabis sativa is widely used as a folk medicine in many parts of the globe and has been reported to be a treasure trove of phytoconstituents, including cannabinoids, terpenoids, and flavonoids. Accumulating evidence from various pre-clinical and clinical studies revealed the therapeutic potential of these constituents in various pathological conditions, including chronic pain, inflammation, neurological disorders, and cancer. However, the psychoactive effect and addiction potential associated with cannabis use limited its clinical application. In the past two decades, extensive research on cannabis has led to a resurgence of interest in the clinical application of its constituents, particularly cannabinoids. This review summarizes the therapeutic effect and molecular mechanism of various phytoconstituents of cannabis. Furthermore, recently developed nanoformulations of cannabis constituents have also been reviewed. Since cannabis is often associated with illicit use, regulatory aspects are of vital importance and this review therefore also documented the regulatory aspects of cannabis use along with clinical data and commercial products of cannabis.
There are general inhibitory effects of exo-cannabinoids on dopamine-mediated behaviors. Many studies suggested the interaction between cannabinoid receptors and dopamine receptors in the brain that affect cognition behaviors. In this paper, we investigate the effects of marijuana on 6-OHDA-induced cognitive impairments and the expression of dopamine and cannabinoid receptors in the hippocampus of male rats. 42 rats were divided into six groups. 6-hydroxy dopamine (6-OHDA) was administrated into the substantia nigra. Marijuana (60 mg/kg; i.p.) was administered 28 days, one week after the 6-OHDA injection. Morris water maze (MWM) and novel object recognition tests were performed. The hippocampal expression levels of cannabinoid receptors and D1 and D2 dopamine receptors evaluate by real-time PCR. The results showed marijuana improved the spatial learning and memory disorders caused by 6-OHDA in the MVM task and novel object recognition test. Additionally, the level of both D1 and D2 mRNA was decreased in 6-OHDA-treated animals and marijuana consumption only increased the hippocampal level of D1 mRNA. Moreover, the level of hippocampal CB1 mRNA in 6-OHDA- treated rats was higher than in control rats. However, the hippocampal level of CB2 mRNA was decreased in 6-OHDA- treated rats. Marijuana consumption caused a significant decrease in CB1 mRNA level and an increase in CB2 mRNA level in 6-OHDA + marijuana group. Therefore, marijuana may be helpful for learning & memory disorders, D1, and D2 dopamine receptors, and cannabinoid receptor alteration in patients with Parkinson’s disease.
Unlabelled:
Aging weakens memory functions. Exposing healthy rodents or pathological rodent models to environmental enrichment (EE) housing improves their cognitive functions by changing neuronal levels of excitation, cellular signaling, and plasticity, notably in the hippocampus. At the molecular level, brain derived-neurotrophic factor (BDNF) represents an important player that supports EE-associated changes. EE facilitation of learning was also shown to correlate with chromatin acetylation in the hippocampus. It is not known, however, whether such mechanisms are still into play during aging. In this study, we exposed a cohort of aged rats (18-month-old) to either a 6 month period of EE or standard housing conditions and investigated chromatin acetylation-associated events [histone acetyltranferase activity, gene expression, and histone 3 (H3) acetylation] and epigenetic modulation of the Bdnf gene under rest conditions and during learning. We show that EE leads to upregulation of acetylation-dependent mechanisms in aged rats, whether at rest or following a learning challenge. We found an increased expression of Bdnf through Exon-I-dependent transcription, associated with an enrichment of acetylated H3 at several sites of Bdnf promoter I, more particularly on a proximal nuclear factor κB (NF-κB) site under learning conditions. We further evidenced p65/NF-κB binding to chromatin at promoters of genes important for plasticity and hippocampus-dependent learning (e.g., Bdnf, CamK2D). Altogether, our findings demonstrate that aged rats respond to a belated period of EE by increasing hippocampal plasticity, together with activating sustained acetylation-associated mechanisms recruiting NF-κB and promoting related gene transcription. These responses are likely to trigger beneficial effects associated with EE during aging.
Significance statement:
Aging weakens memory functions. Optimizing the neuronal circuitry required for normal brain function can be achieved by increasing sensory, motor, and cognitive stimuli resulting from interactions with the environment (behavioral therapy). This can be experimentally modeled by exposing rodents to environmental enrichment (EE), as with large cages, numerous and varied toys, and interaction with other rodents. However, EE effects in aged rodents has been poorly studied, and it is not known whether beneficial mechanisms evidenced in the young adults can still be recruited during aging. Our study shows that aged rats respond to a belated period of EE by activating specific epigenetic and transcriptional signaling that promotes gene expression likely to facilitate plasticity and learning behaviors.
The Klotho protein is a β-glucuronidase, and its overexpression is associated with life extension. Its mechanism of action is not fully understood, although it has been recently reported that αKlotho improves synaptic and cognitive functions, and it may also influence a variety of structures and functions during CNS maturation and aging. The αKlotho gene has two transcripts, one encoding a transmembrane isoform (m-KL), and the other a putative secreted isoform (s-KL). Unfortunately, little is known about the secreted αKlotho isoform, since available antibodies cannot discriminate s-KL from the KL1 domain cleaved from the transmembrane isoform. This study shows, for the first time, that the klotho transcript produced by alternative splicing generates a stable protein (70 kDa), and that in contrast to the transmembrane Klotho isoform, it is ten times more abundant in the brain than in the kidney suggesting that the two isoforms may have different functions. We also studied whether klotho expression in the CNS was influenced by aging, Alzheimer's disease (AD), or a healthy lifestyle, such as voluntary moderate continuous exercise. We observed a strong correlation between high expression levels of the two klotho transcripts and the healthy status of the animals. Expression of Klotho in brain areas decayed more rapidly in the 3xTg-AD model of AD than in healthy animals, whilst moderate continuous exercise in adulthood prevents the decline in expression of both klotho transcripts.
Aging is the primary risk factor for cognitive decline, an emerging health threat to aging societies worldwide. Whether anti-aging factors such as klotho can counteract cognitive decline is unknown. We show that a lifespan-extending variant of the human KLOTHO gene, KL-VS, is associated with enhanced cognition in heterozygous carriers. Because this allele increased klotho levels in serum, we analyzed transgenic mice with systemic overexpression of klotho. They performed better than controls in multiple tests of learning and memory. Elevating klotho in mice also enhanced long-term potentiation, a form of synaptic plasticity, and enriched synaptic GluN2B, an N-methyl-D-aspartate receptor (NMDAR) subunit with key functions in learning and memory. Blockade of GluN2B abolished klotho-mediated effects. Surprisingly, klotho effects were evident also in young mice and did not correlate with age in humans, suggesting independence from the aging process. Augmenting klotho or its effects may enhance cognition and counteract cognitive deficits at different life stages.
As human lifespan increases, a greater fraction of the population is suffering from age-related cognitive impairments, making it important to elucidate a means to combat the effects of aging. Here we report that exposure of an aged animal to young blood can counteract and reverse pre-existing effects of brain aging at the molecular, structural, functional and cognitive level. Genome-wide microarray analysis of heterochronic parabionts-in which circulatory systems of young and aged animals are connected-identified synaptic plasticity-related transcriptional changes in the hippocampus of aged mice. Dendritic spine density of mature neurons increased and synaptic plasticity improved in the hippocampus of aged heterochronic parabionts. At the cognitive level, systemic administration of young blood plasma into aged mice improved age-related cognitive impairments in both contextual fear conditioning and spatial learning and memory. Structural and cognitive enhancements elicited by exposure to young blood are mediated, in part, by activation of the cyclic AMP response element binding protein (Creb) in the aged hippocampus. Our data indicate that exposure of aged mice to young blood late in life is capable of rejuvenating synaptic plasticity and improving cognitive function.
Significance
The Creb-binding protein (CBP) transcriptional coactivator contains a histone acetyl transferase domain and a bromodomain. Bromodomains bind to acetylated lysines, and their function as previously understood was limited to mediating recruitment to chromatin via binding to acetylated proteins. Here we show that the acetyl lysine-binding activity of the CBP bromodomain has unexpected roles in CBP-mediated acetylation of nonchromatin bound histones, and we show that the interaction between a bromodomain and acetyl lysine is stimulated by autoacetylation. Furthermore, we find that the histone chaperone anti-silencing function 1 binds to the bromodomain of CBP to present free histones correctly for efficient acetylation. Through a combination of structural, biochemical, and cell-based analyses, these studies enhance our understanding of bromodomain function and regulation.
The role of endocannabinoids as inhibitory retrograde transmitters is now widely known and intensively studied. However, endocannabinoids also influence neuronal activity by exerting neuroprotective effects and regulating glial responses. This review centres around this less-studied area, focusing on the cellular and molecular mechanisms underlying the protective effect of the cannabinoid system in brain ageing. The progression of ageing is largely determined by the balance between detrimental, pro-ageing, largely stochastic processes, and the activity of the homeostatic defence system. Experimental evidence suggests that the cannabinoid system is part of the latter system. Cannabinoids as regulators of mitochondrial activity, as anti-oxidants and as modulators of clearance processes protect neurons on the molecular level. On the cellular level, the cannabinoid system regulates the expression of brain-derived neurotrophic factor and neurogenesis. Neuroinflammatory processes contributing to the progression of normal brain ageing and to the pathogenesis of neurodegenerative diseases are suppressed by cannabinoids, suggesting that they may also influence the ageing process on the system level. In good agreement with the hypothesized beneficial role of cannabinoid system activity against brain ageing, it was shown that animals lacking CB1 receptors show early onset of learning deficits associated with age-related histological and molecular changes. In preclinical models of neurodegenerative disorders, cannabinoids show beneficial effects, but the clinical evidence regarding their efficacy as therapeutic tools is either inconclusive or still missing.
Exogenous cannabinoids, such as delta9-tetrahydrocannabinol (THC), as well as the modulation of endogenous cannabinoids, affect cognitive function through the activation of cannabinoid receptors. Indeed, these compounds modulate a number of signalling pathways critically implicated in the deleterious effect of cannabinoids on learning and memory. Thus, the involvement of the mammalian target of rapamycin pathway and extracellular signal-regulated kinases, together with their consequent regulation of cellular processes such as protein translation, play a critical role in the amnesic-like effects of cannabinoids. In this study, we summarize the cellular and molecular mechanisms reported in the modulation of cognitive function by the endocannabinoid system.
The analysis of the contributions to synaptic plasticity and memory of cAMP, PKA, CRE, CREB-1, CREB-2, and CPEB has recruited the efforts of many laboratories all over the world. These are six key steps in the molecular biological delineation of short-term memory and its conversion to long-term memory for both implicit (procedural) and explicit (declarative) memory. I here first trace the background for the clinical and behavioral studies of implicit memory that made a molecular biology of memory storage possible, and then detail the discovery and early history of these six molecular steps and their roles in explicit memory.
Impairment of working memory is one of the most important deleterious effects of marijuana intoxication in humans, but its underlying mechanisms are presently unknown. Here, we demonstrate that the impairment of spatial working memory (SWM) and in vivo long-term depression (LTD) of synaptic strength at hippocampal CA3-CA1 synapses, induced by an acute exposure of exogenous cannabinoids, is fully abolished in conditional mutant mice lacking type-1 cannabinoid receptors (CB(1)R) in brain astroglial cells but is conserved in mice lacking CB(1)R in glutamatergic or GABAergic neurons. Blockade of neuronal glutamate N-methyl-D-aspartate receptors (NMDAR) and of synaptic trafficking of glutamate α-amino-3-hydroxy-5-methyl-isoxazole propionic acid receptors (AMPAR) also abolishes cannabinoid effects on SWM and LTD induction and expression. We conclude that the impairment of working memory by marijuana and cannabinoids is due to the activation of astroglial CB(1)R and is associated with astroglia-dependent hippocampal LTD in vivo.
Normal ageing is associated with impairments in cognitive function, including memory. These impairments are linked, not to a loss of neurons in the forebrain, but to specific and relatively subtle synaptic alterations in the hippocampus and prefrontal cortex. Here, we review studies that have shed light on the cellular and synaptic changes observed in these brain structures during ageing that can be directly related to cognitive decline in young and aged animals. We also discuss the influence of the hormonal status on these age-related alterations and recent progress in the development of therapeutic strategies to limit the impact of ageing on memory and cognition in humans.
Calorie restriction delays brain senescence and prevents neurodegeneration, but critical regulators of these beneficial responses other than the NAD(+)-dependent histone deacetylase Sirtuin-1 (Sirt-1) are unknown. We report that effects of calorie restriction on neuronal plasticity, memory and social behavior are abolished in mice lacking cAMP responsive-element binding (CREB)-1 in the forebrain. Moreover, CREB deficiency drastically reduces the expression of Sirt-1 and the induction of genes relevant to neuronal metabolism and survival in the cortex and hippocampus of dietary-restricted animals. Biochemical studies reveal a complex interplay between CREB and Sirt-1: CREB directly regulates the transcription of the sirtuin in neuronal cells by binding to Sirt-1 chromatin; Sirt-1, in turn, is recruited by CREB to DNA and promotes CREB-dependent expression of target gene peroxisome proliferator-activated receptor-γ coactivator-1α and neuronal NO Synthase. Accordingly, expression of these CREB targets is markedly reduced in the brain of Sirt KO mice that are, like CREB-deficient mice, poorly responsive to calorie restriction. Thus, the above circuitry, modulated by nutrient availability, links energy metabolism with neurotrophin signaling, participates in brain adaptation to nutrient restriction, and is potentially relevant to accelerated brain aging by overnutrition and diabetes.
Since the mid-1990's a trickle of publications from scattered independent laboratories have presented data suggesting that the systemic amyloid precursor transthyretin (TTR) could interact with the amyloidogenic β-amyloid (Aβ) peptide of Alzheimer's disease (AD). The notion that one amyloid precursor could actually inhibit amyloid fibril formation by another seemed quite far-fetched. Further it seemed clear that within the CNS, TTR was only produced in choroid plexus epithelial cells, not in neurons. The most enthusiastic of the authors proclaimed that TTR sequestered Aβ in vivo resulting in a lowered TTR level in the cerebrospinal fluid (CSF) of AD patients and that the relationship was salutary. More circumspect investigators merely showed in vitro interaction between the two molecules. A single in vivo study in Caenorhabditis elegans suggested that wild type human TTR could suppress the abnormalities seen when Aβ was expressed in the muscle cells of the worm. Subsequent studies in human Aβ transgenic mice, including those from our laboratory, also suggested that the interaction reduced the Aβ deposition phenotype. We have reviewed the literature analyzing the relationship including recent data examining potential mechanisms that could explain the effect. We have proposed a model which is consistent with most of the published data and current notions of AD pathogenesis and can serve as a hypothesis which can be tested.
Investigations of long-term changes in brain structure and function that accompany chronic exposure to drugs of abuse suggest that alterations in gene regulation contribute substantially to the addictive phenotype. Here, we review multiple mechanisms by which drugs alter the transcriptional potential of genes. These mechanisms range from the mobilization or repression of the transcriptional machinery - including the transcription factors ΔFOSB, cyclic AMP-responsive element binding protein (CREB) and nuclear factor-κB (NF-κB) - to epigenetics - including alterations in the accessibility of genes within their native chromatin structure induced by histone tail modifications and DNA methylation, and the regulation of gene expression by non-coding RNAs. Increasing evidence implicates these various mechanisms of gene regulation in the lasting changes that drugs of abuse induce in the brain, and offers novel inroads for addiction therapy.
Epigenetic mechanisms integrate signals from diverse intracellular transduction cascades and in turn regulate genetic readout. Accumulating evidence has revealed that these mechanisms are critical components of ongoing physiology and function in the adult nervous system, and are essential for many cognitive processes, including learning and memory. Moreover, a number of psychiatric disorders and syndromes that involve cognitive impairments are associated with altered epigenetic function. In this review, we will examine how epigenetic mechanisms contribute to cognition, consider how changes in these mechanisms may lead to cognitive impairments in a range of disorders and discuss the potential utility of therapeutic treatments that target epigenetic machinery. Finally, we will comment on a number of caveats associated with interpreting epigenetic changes and using epigenetic treatments, and suggest future directions for research in this area that will expand our understanding of the epigenetic changes underlying cognitive disorders.
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.
The hippocampus shrinks in late adulthood, leading to impaired memory and increased risk for dementia. Hippocampal and medial temporal lobe volumes are larger in higher-fit adults, and physical activity training increases hippocampal perfusion, but the extent to which aerobic exercise training can modify hippocampal volume in late adulthood remains unknown. Here we show, in a randomized controlled trial with 120 older adults, that aerobic exercise training increases the size of the anterior hippocampus, leading to improvements in spatial memory. Exercise training increased hippocampal volume by 2%, effectively reversing age-related loss in volume by 1 to 2 y. We also demonstrate that increased hippocampal volume is associated with greater serum levels of BDNF, a mediator of neurogenesis in the dentate gyrus. Hippocampal volume declined in the control group, but higher preintervention fitness partially attenuated the decline, suggesting that fitness protects against volume loss. Caudate nucleus and thalamus volumes were unaffected by the intervention. These theoretically important findings indicate that aerobic exercise training is effective at reversing hippocampal volume loss in late adulthood, which is accompanied by improved memory function.
As the human life span increases, the number of people suffering from cognitive decline is rising dramatically. The mechanisms
underlying age-associated memory impairment are, however, not understood. Here we show that memory disturbances in the aging
brain of the mouse are associated with altered hippocampal chromatin plasticity. During learning, aged mice display a specific
deregulation of histone H4 lysine 12 (H4K12) acetylation and fail to initiate a hippocampal gene expression program associated
with memory consolidation. Restoration of physiological H4K12 acetylation reinstates the expression of learning-induced genes
and leads to the recovery of cognitive abilities. Our data suggest that deregulated H4K12 acetylation may represent an early
biomarker of an impaired genome-environment interaction in the aging mouse brain.
Molecular Psychiatry publishes work aimed at elucidating biological mechanisms underlying psychiatric disorders and their treatment
Polycomb proteins are epigenetic regulators of gene expression. Human central nervous system (CNS) malformations are congenital defects of the brain and spinal cord. One example of a human CNS malformation is Chiari malformation (CM), which presents as abnormal brainstem growth and cerebellar herniation, sometimes accompanied by spina bifida and cortical defects; it can occur in families. Clinically, CM ranges from an asymptomatic condition to one with incapacitating or lethal symptoms, including neural tube defects and hydrocephalus. However, no genes that are causally involved in any manifestation of CM or similar malformations have been identified. Here, we show that a pathway that involves Zac1 (also known as Plagl1 or Lot1) and controls neuronal proliferation is altered in mice that are heterozygous for the polycomb gene Suz12, resulting in a phenotype that overlaps with some clinical manifestations of the CM spectrum. Suz12 heterozygotes show cerebellar herniation and an enlarged brainstem, accompanied by occipital cortical alterations and spina bifida. Downward displacement of the cerebellum causes hydrocephalus in the most severely impaired cases. Although the involvement of polycomb genes in human disease is starting to be recognized, this is the first demonstration of their role in nervous system malformations. Our work strongly suggests that brain malformations such as CM can result from altered epigenetic regulation of genes involved in cell proliferation in the brain.
Background
Correlation networks are increasingly being used in bioinformatics applications. For example, weighted gene co-expression network analysis is a systems biology method for describing the correlation patterns among genes across microarray samples. Weighted correlation network analysis (WGCNA) can be used for finding clusters (modules) of highly correlated genes, for summarizing such clusters using the module eigengene or an intramodular hub gene, for relating modules to one another and to external sample traits (using eigengene network methodology), and for calculating module membership measures. Correlation networks facilitate network based gene screening methods that can be used to identify candidate biomarkers or therapeutic targets. These methods have been successfully applied in various biological contexts, e.g. cancer, mouse genetics, yeast genetics, and analysis of brain imaging data. While parts of the correlation network methodology have been described in separate publications, there is a need to provide a user-friendly, comprehensive, and consistent software implementation and an accompanying tutorial.
Results
The WGCNA R software package is a comprehensive collection of R functions for performing various aspects of weighted correlation network analysis. The package includes functions for network construction, module detection, gene selection, calculations of topological properties, data simulation, visualization, and interfacing with external software. Along with the R package we also present R software tutorials. While the methods development was motivated by gene expression data, the underlying data mining approach can be applied to a variety of different settings.
Conclusion
The WGCNA package provides R functions for weighted correlation network analysis, e.g. co-expression network analysis of gene expression data. The R package along with its source code and additional material are freely available at .
Neuronal expression of familial Alzheimer's disease-mutant human amyloid precursor protein (hAPP) and hAPP-derived amyloid-beta (Abeta) peptides causes synaptic dysfunction, inflammation and abnormal cerebrovascular tone in transgenic mice. Fatty acids may be involved in these processes, but their contribution to Alzheimer's disease pathogenesis is uncertain. We used a lipidomics approach to generate a broad profile of fatty acids in brain tissues of hAPP-expressing mice and found an increase in arachidonic acid and its metabolites, suggesting increased activity of the group IV isoform of phospholipase A(2) (GIVA-PLA(2)). The levels of activated GIVA-PLA(2) in the hippocampus were increased in individuals with Alzheimer's disease and in hAPP mice. Abeta caused a dose-dependent increase in GIVA-PLA(2) phosphorylation in neuronal cultures. Inhibition of GIVA-PLA(2) diminished Abeta-induced neurotoxicity. Genetic ablation or reduction of GIVA-PLA(2) protected hAPP mice against Abeta-dependent deficits in learning and memory, behavioral alterations and premature mortality. Inhibition of GIVA-PLA(2) may be beneficial in the treatment and prevention of Alzheimer's disease.
Delta9-Tetrahydrocannabinol, the main active component of marijuana, induces apoptosis of transformed neural cells in culture. Here, we show that intratumoral administration of Delta9-tetrahydrocannabinol and the synthetic cannabinoid agonist WIN-55,212-2 induced a considerable regression of malignant gliomas in Wistar rats and in mice deficient in recombination activating gene 2. Cannabinoid treatment did not produce any substantial neurotoxic effect in the conditions used. Experiments with two subclones of C6 glioma cells in culture showed that cannabinoids signal apoptosis by a pathway involving cannabinoid receptors, sustained ceramide accumulation and Raf1/extracellular signal-regulated kinase activation. These results may provide the basis for a new therapeutic approach for the treatment of malignant gliomas.
Plasticity is a remarkable feature of the brain, allowing neuronal structure and function to accommodate to patterns of electrical activity. One component of these long-term changes is the activity-driven induction of new gene expression, which is required for both the long-lasting long-term potentiation of synaptic transmission associated with learning and memory, and the activity dependent survival events that help to shape and wire the brain during development. We have characterized molecular mechanisms by which neuronal membrane depolarization and subsequent calcium influx into the cytoplasm lead to the induction of new gene transcription. We have identified three points within this cascade of events where the specificity of genes induced by different types of stimuli can be regulated. By using the induction of the gene that encodes brain-derived neurotrophic factor (BDNF) as a model, we have found that the ability of a calcium influx to induce transcription of this gene is regulated by the route of calcium entry into the cell, by the pattern of phosphorylation induced on the transcription factor cAMP-response element (CRE) binding protein (CREB), and by the complement of active transcription factors recruited to the BDNF promoter. These results refine and expand the working model of activity-induced gene induction in the brain, and help to explain how different types of neuronal stimuli can activate distinct transcriptional responses.
The expansion of a CAG repeat coding for polyglutamine in otherwise unrelated gene products is central to eight neurodegenerative disorders including Huntington's disease. It has been well documented that expanded polyglutamine fragments, cleaved from their respective full-length proteins, form microscopically visible aggregates in affected individuals and in transgenic mice. The contribution of polyglutamine oligomers to neurodegeneration, however, is controversial. The azo-dye Congo red binds preferentially to beta-sheets containing amyloid fibrils and can specifically inhibit oligomerization and disrupt preformed oligomers. Here we show that inhibition of polyglutamine oligomerization by Congo red prevents ATP depletion and caspase activation, preserves normal cellular protein synthesis and degradation functions, and promotes the clearance of expanded polyglutamine repeats in vivo and in vitro. Infusion of Congo red into a transgenic mouse model of Huntington's disease, well after the onset of symptoms, promotes the clearance of expanded repeats in vivo and exerts marked protective effects on survival, weight loss and motor function. We conclude that oligomerization is a crucial determinant in the biochemical properties of expanded polyglutamine that are central to their chronic cytotoxicity.
Cannabinoids and ethanol can activate the same reward pathways, which could suggest endocannabinoid involvement in the rewarding effects of ethanol. The high ethanol preference of young (6-10 weeks) C57BL6J mice is reduced by the cannabinoid receptor 1 (CB1) antagonist SR141716A to levels observed in their CB1 knockout littermates or in old (26-48 weeks) wild-type mice, in both of which ethanol preference is unaffected by SR141716A. Similarly, SR141716A inhibits food intake in food-restricted young, but not old, wild-type mice. There are no age-dependent differences in the tissue levels of the endocannabinoids anandamide and 2-arachidonoylglycerol or the density of CB1 in the hypothalamus, limbic forebrain, amygdala, and cerebellum. CB1-stimulated guanosine 5'-[gamma-thio]triphosphate (GTP[gammaS]) binding is selectively reduced in the limbic forebrain of old compared with young wild-type mice. There is no age-dependent difference in G(i) or G(o) subunit protein expression in the limbic forebrain, and the selective reduction in GTP[gammaS] labeling in tissue from old mice is maintained in a receptorG protein reconstitution assay by using functional bovine brain G protein. These findings suggest that endocannabinoids acting at CB1 contribute to ethanol preference, and decreased coupling of CB1 to G proteins in the limbic forebrain by mechanisms other than altered receptor or G protein levels may be involved in the age-dependent decline in the appetite for both ethanol and food.
Endocannabinoids form a novel class of intercellular messengers, the functions of which include retrograde signaling in the brain and mediation or modulation of several types of synaptic plasticity. Yet, the signaling mechanisms and long-term effects of the stimulation of CB1 cannabinoid receptors (CB1-R) are poorly understood. We show that anandamide, 2-arachidonoyl-glycerol, and Delta9-tetrahydrocannabinol (THC) activated extracellular signal-regulated kinase (ERK) in hippocampal slices. In living mice, THC activated ERK in hippocampal neurons and induced its accumulation in the nuclei of pyramidal cells in CA1 and CA3. Both effects were attributable to stimulation of CB1-R and activation of MAP kinase/ERK kinase (MEK). In hippocampal slices, the stimulation of ERK was independent of phosphatidyl-inositol-3-kinase but was regulated by cAMP. The endocannabinoid-induced stimulation of ERK was lost in Fyn knock-out mice, in slices and in vivo, although it was insensitive to inhibitors of Src-family tyrosine kinases in vitro, suggesting a noncatalytic role of Fyn. Finally, the effects of cannabinoids on ERK activation were dependent on the activity of glutamate NMDA receptors in vivo, but not in hippocampal slices, indicating the existence of several pathways linking CB1-R to the ERK cascade. In vivo THC induced the expression of immediate-early genes products (c-Fos protein, Zif268, and BDNF mRNAs), and this induction was prevented by an inhibitor of MEK. The strong potential of cannabinoids for inducing long-term alterations in hippocampal neurons through the activation of the ERK pathway may be important for the physiological control of synaptic plasticity and for the general effects of THC in the context of drug abuse.
A defect in Klotho gene expression in mice accelerates the degeneration of multiple age-sensitive traits. Here, we show that overexpression
of Klotho in mice extends life span. Klotho protein functions as a circulating hormone that binds to a cell-surface receptor and represses
intracellular signals of insulin and insulin-like growth factor 1 (IGF1), an evolutionarily conserved mechanism for extending
life span. Alleviation of aging-like phenotypes in Klotho-deficient mice was observed by perturbing insulin and IGF1 signaling,
suggesting that Klotho-mediated inhibition of insulin and IGF1 signaling contributes to its anti-aging properties. Klotho
protein may function as an anti-aging hormone in mammals.
Alpha-linolenic acid (ALA) is a major precursor of the essential n-3 polyunsaturated fatty acid (PUFA), whose deficiency alters the structure and function of membranes and induces cerebral dysfunctions. The major purpose of this study was to investigate the protective effect of prolonged ALA intake on cognitive function during natural aging. Female Sprague-Dawley rats aged 6 months were chronically treated with ALA and/or lard per day for 12 months. Regular diet-treated rats, both young and old (4 and 18 months old, respectively) served as controls. Rats fed on regular diet during aging showed memory deficits in Morris water maze, which were further exacerbated by lard intake. However, supplementation with ALA for 12 months dose-dependently improved the performance in spatial working memory tasks. Memory performance correlated well with the activation of cAMP response element-binding protein (CREB) and increases in both levels of brain-derived neurotrophic factor (BDNF) and its specific receptor tyrosine kinase B (TrkB) phosphorylation in the hippocampus. Further study identified that hippocampal extracellular signal-related kinase (ERK) and Akt rather than calcium calmodulin kinase IV (CaMKIV) and protein kinase A (PKA), the upstream signalings of CREB, were also activated by ALA supplement. Moreover, memory improvement was accompanied with alterations of hippocampal synaptic structure and number, suggestive of enhancement in synaptic plasticity. Together, these results suggest that long-term dietary intake of ALA enhances CREB/BDNF/TrkB pathway through the activation of ERK and Akt signalings in hippocampus, which contributes to its ameliorative effects on cognitive deficits in natural aging.
