cannabidiol and Alzheimer-Disease

Cannabidiol (CBD) is one of the major phytocannabinoids present in the cannabis plant, with no acute psychotropic effects and a favorable safety and abuse liability profile. Animal and limited controlled human studies have demonstrated CBD to have analgesic, anxiolytic, anti-inflammatory, antipsychotic, and anticonvulsant effects, to name a few possible indications. There is growing evidence for the use of CBD to treat neurological disorders such as epilepsy, multiple sclerosis, Parkinson's disease, and Alzheimer's disease. It has been suggested that CBD improves cognition and neurogenesis. Cognitive impairment is associated with numerous disorders and can involve deficits in learning, memory, executive functioning, and attention. The purpose of this review will be to evaluate the available preclinical and clinical data on CBD for the treatment of the cognitive impairment associated with several disorders including schizophrenia, epilepsy, Alzheimer's disease, and others. Preclinical, but not clinical, studies found evidence for an improvement in cognitive performance after treatment with CBD. More research is needed to determine whether CBD can be effectively used as a monotherapy to treat cognitive dysfunction. (PsycInfo Database Record (c) 2023 APA, all rights reserved).

Topics: Alzheimer Disease; Animals; Cannabidiol; Cognitive Dysfunction; Epilepsy; Humans; Schizophrenia

Depression and Alzheimer´s disease (AD) are two disorders highly prevalent worldwide. Depression affects more than 300 million people worldwide while AD affects 60-80% of the 55 million cases of dementia. Both diseases are affected by aging with high prevalence in elderly and share not only the main brain affected areas but also several physiopathological mechanisms. Depression disease is already ascribed as a risk factor to the development of AD. Despite the wide diversity of pharmacological treatments currently available in clinical practice for depression management, they remain associated to a slow recovery process and to treatment-resistant depression. On the other hand, AD treatment is essentially based in symptomatology relieve. Thus, the need for new multi-target treatments arises. Herein, we discuss the current state-of-art regarding the contribution of the endocannabinoid system (ECS) in synaptic transmission processes, synapses plasticity and neurogenesis and consequently the use of exogenous cannabinoids in the treatment of depression and on delaying the progression of AD. Besides the well-known imbalance of neurotransmitter levels, including serotonin, noradrenaline, dopamine and glutamate, recent scientific evidence highlights aberrant spine density, neuroinflammation, dysregulation of neurotrophic factor levels and formation of amyloid beta (Aβ) peptides, as the main physiopathological mechanisms compromised in depression and AD. The contribution of the ECS in these mechanisms is herein specified as well as the pleiotropic effects of phytocannabinoids. At the end, it became evident that Cannabinol, Cannabidiol, Cannabigerol, Cannabidivarin and Cannabichromene may act in novel therapeutic targets, presenting high potential in the pharmacotherapy of both diseases.

Topics: Aged; Alzheimer Disease; Amyloid beta-Peptides; Brain; Cannabidiol; Depression; Humans

Cannabidiol (CBD), derived from Cannabis sativa, has gained remarkable attention for its potential therapeutic applications. This thorough analysis explores the increasing significance of CBD in treating neurological conditions including epilepsy, multiple sclerosis, Parkinson's disease, and Alzheimer's disease, which present major healthcare concerns on a worldwide scale. Despite the lack of available therapies, CBD has been shown to possess a variety of pharmacological effects in preclinical and clinical studies, making it an intriguing competitor. This review brings together the most recent findings on the endocannabinoid and neurotransmitter systems, as well as anti-inflammatory pathways, that underlie CBD's modes of action. Synthesized efficacy and safety assessments for a range of neurological illnesses are included, covering human trials, in vitro studies, and animal models. The investigation includes how CBD could protect neurons, control neuroinflammation, fend off oxidative stress, and manage neuronal excitability. This study emphasizes existing clinical studies and future possibilities in CBD research, addressing research issues such as regulatory complications and contradicting results, and advocates for further investigation of therapeutic efficacy and ideal dose methodologies. By emphasizing CBD's potential to improve patient well-being, this investigation presents a revised viewpoint on its suitability as a therapeutic intervention for neurological illnesses.

Topics: Alzheimer Disease; Animals; Cannabidiol; Epilepsy; Humans

The use of cannabinoids (substances contained specifically in hemp plants) for therapeutic purposes has received increased attention in recent years. Presently, attention is paid to two main cannabinoids: delta-9-tetrahydrocannabinol (THC) and cannabidiol (CBD). With respect to the psychotropic effects and dependence potential of THC (though it is very mild), its use is associated with certain restrictions, and thus the therapeutic properties of CBD are frequently emphasized because there are no limitations associated with the risk of dependence. Therefore, this review covers the main pharmacodynamic and pharmacokinetic features of CBD (including characteristics of endocannabinoidome) with respect to its possible beneficial effects on selected diseases in clinical practice. A substantial part of the text deals with the main effects of CBD on aging, including Alzheimer's disease and related underlying mechanisms.

Topics: Alzheimer Disease; Cannabidiol; Cannabinoids; Dronabinol; Humans

Alzheimer's Disease (AD) is one of the most common neurodegenerative diseases with chronic, progressive, and irreversible characteristics, affecting nearly 50 million older adults worldwide. The pathogenesis of AD includes the formation of senile plaques, the abnormal aggregation of tau protein and the gradual degeneration and death of cerebral cortical cells. The main symptoms are memory loss, cognitive decline and behavioral disorders. Studies indicate that cannabidiol (CBD) possesses various pharmacological activities, including anti-inflammatory, anti-oxidation and neuroprotective activities. It has been suggested as a potential multi-target medicine for the treatment of AD. In this review, we aim to summarize the underlying mechanisms and protective effects of CBD on signaling pathways and central receptors involved in the pathogenesis of AD, including the endocannabinoid system (eCBs), the Transient receptor potential vanilloid type 1(TRPV1) receptor, and the Peroxisome Proliferator-Activated Receptor (PPAR) receptor.

Topics: Aged; Alzheimer Disease; Cannabidiol; Endocannabinoids; Humans

Dementia is a common chronic condition, mainly affecting older adults, characterised by a progressive decline in cognitive and functional abilities. Medical treatments for dementia are limited. Cannabinoids are being investigated for the treatment of dementia.. To determine the efficacy and safety of cannabinoids for the treatment of dementia.. We searched ALOIS - the Cochrane Dementia and Cognitive Improvement Group's Specialised Register - on 8 July 2021, using the terms cannabis or cannabinoid or endocannabinoid or cannabidiol or THC or CBD or dronabinol or delta-9-tetrahydrocannabinol or marijuana or marihuana or hashish. The register contains records from all major healthcare databases (the Cochrane Library, MEDLINE, Embase, PsycINFO, CINAHL, LILACS), as well as from many clinical trials registries and grey literature sources.. We included all randomised controlled trials (RCTs) of cannabinoids for the treatment of dementia. We included participants of any age and of either sex with diagnosed dementia of any subtype, or with unspecified dementia of any severity, from any setting. We considered studies of cannabinoids administered by any route, at any dose, for any duration, compared with placebo, no treatment, or any active control intervention.. Two review authors independently screened and selected studies for inclusion, extracted data, and assessed the risk of bias in included studies. When necessary, other review authors were involved in reaching consensus decisions. We conducted meta-analyses using a generic inverse variance fixed-effect model to derive estimates of effect size. We used GRADE methods to assess our confidence in the effect estimates.. We included four studies (126 participants) in this review. Most participants had Alzheimer's disease; a few had vascular dementia or mixed dementia. Three studies had low risk of bias across all domains; one study had unclear risk of bias for the majority of domains.  The included studies tested natural delta-9-tetrahydrocannabinol (THC) (Namisol) and two types of synthetic THC analogue (dronabinol and nabilone). Three trials had a cross-over design. Interventions were applied over 3 to 14 weeks; one study reported adverse events over 70 weeks of follow-up. One trial was undertaken in the USA, one in Canada, and two in The Netherlands. Two studies reported non-commercial funding, and two studies were conducted with the support of both commercial and non-commercial funding. Primary outcomes in this review were changes in global and specific cognitive function, overall behavioural and psychological symptoms of dementia (BPSD), and adverse events. We found very low-certainty evidence suggesting there may be little or no clinically important effect of a synthetic THC analogue on cognition assessed with the standardised Mini-Mental State Examination (sMMSE) (mean difference (MD) 1.1 points, 95% confidence interval (CI) 0.1 to 2.1; 1 cross-over trial, 28 participants).  We found low-certainty evidence suggesting there may be little or no clinically important effect of cannabinoids on overall behavioural and psychological symptoms of dementia assessed with the Neuropsychiatric Inventory (or its modified nursing home version) (MD -1.97, 95% CI -3.87 to -0.07; 1 parallel group and 2 cross-over studies, 110 participants). All included studies reported data on adverse events. However, the total number of adverse events, the total numbers of mild and moderate adverse events, and the total number of serious adverse events (SAEs) were not reported in a way that permitted meta-analysis.  There were no clear differences between groups in numbers of adverse events, with the exception of sedation (including lethargy), which was more frequent among participants taking nabilone (N = 17) than placebo (N = 6) (odds ratio (OR) 2.83, 95% CI 1.07 to 7.48; 1 cross-over study, 38 participants). We judged the certainty of evidence for adverse event outcomes to be low or very low due to serious concerns regarding imprecision and indirectness.. Based on data from four small, short, and heterogeneous placebo-controlled trials, we cannot be certain whether cannabinoids have any beneficial or harmful effects on dementia. If there are benefits of cannabinoids for people with dementia, the effects may be too small to be clinically meaningful. Adequately powered, methodologically robust trials with longer follow-up are needed to properly assess the effects of cannabinoids in dementia.

Topics: Activities of Daily Living; Aged; Alzheimer Disease; Cannabidiol; Cannabinoids; Dementia, Vascular; Humans

Herein, 11 general types of natural cannabinoids from Cannabis sativa as well as 50 (-)-CBD analogues with therapeutic potential were described. The underlying molecular mechanisms of CBD as a therapeutic candidate for epilepsy and neurodegenerative diseases were comprehensively clarified. CBD indirectly acts as an endogenous cannabinoid receptor agonist to exert its neuroprotective effects. CBD also promotes neuroprotection through different signal transduction pathways mediated indirectly by cannabinoid receptors. Furthermore, CBD prevents the glycogen synthase kinase 3β (GSK-3β) hyperphosphorylation caused by Aβ and may be developed as a new therapeutic candidate for Alzheimer's disease.

Topics: Alzheimer Disease; Animals; Biological Products; Cannabidiol; Cannabis; Epilepsy; Humans; Neuroprotective Agents

Medicinal use of

Topics: Alzheimer Disease; Anxiety; Bicyclic Monoterpenes; Cannabidiol; Cannabinoid Receptor Agonists; Cannabis; Cognitive Dysfunction; Dronabinol; Humans; Inflammatory Bowel Diseases; Neuralgia; Neuroprotective Agents; Nootropic Agents; Schizophrenia; Sesquiterpenes; Terpenes

Deposition of Amyloid-beta (Aβ) peptide in the brain is the leading source of the onset and progression of Alzheimer's Disease (AD). Recent studies have suggested that anti-amyloidogenic agents may be a suitable therapeutic strategy for AD. The current review was proposed to address the beneficial effects of cannabis-based drugs for the treatment of AD, focusing primarily on Aβ modifications. Keywords related to AD, Aβ, and cannabis-based on MeSH were identified and were searched in PubMed, Google Scholar, Scopus, Ovid-Medline, and Web of Science from inception until 15 March 2020. The full text of identified papers was obtained and assessed based on exclusion and inclusion criteria. The review is based on articles that have focused on AD and the amyloidogenic pathway. A total of 17 studies were identified based on the inclusion criteria; however, nine studies qualified for this systematic review. The maximum and minimum cannabis dosages, mostly CBD and THC in animal studies, were 0.75 and 50 mg/kg, respectively. Cannabis (CBD and THC) was injected for 10 to 21 days. The findings of the 9 articles indicated that cannabis-based drugs might modulate Aβ modifications in several AD models. Our findings establish that cannabis-based drugs inhibited the progression of AD by modulating Aβ modifications.

Topics: Alzheimer Disease; Amyloid beta-Peptides; Amyloid beta-Protein Precursor; Animals; Brain; Cannabidiol; Humans; Medical Marijuana

Neurodegeneration leading to Parkinson's disease (PD) and Alzheimer's disease (AD) has become a major health burden globally. Current treatments mainly target controlling symptoms and there are no therapeutics available in clinical practice to preventing the neurodegeneration or inducing neuronal repairing. Thus, the demand of novel research for the two disorders is imperative. This literature review aims to provide a collection of published work on PD and AD and current uses of endocannabinoid system (ECS) as a potential drug target for neurodegeneration. PD is frequently treated with L-DOPA and deep brain stimulation. Recent gene modification and remodelling techniques, such as CRISPR through human embryonic stem cells and induced pluripotent stem cells, have shown promising strategy for personalised medicine. AD characterised by extracellular deposits of amyloid β-senile plaques and neurofibrillary tangles of tau protein commonly uses choline acetyltransferase enhancers as therapeutics. The ECS is currently being studied as PD and AD drug targets where overexpression of ECS receptors exerted neuroprotection against PD and reduced neuroinflammation in AD. The delta-9-tetrahydrocannabinoid (Δ

Topics: Alzheimer Disease; Animals; Cannabidiol; Dronabinol; Endocannabinoids; Humans; Inflammation; Parkinson Disease

Alzheimer's disease (AD) is the most common neurodegenerative disorder, characterized by progressive loss of cognition. Over 35 million individuals currently have AD worldwide. Unfortunately, current therapies are limited to very modest symptomatic relief. The brains of AD patients are characterized by the deposition of amyloid-β and hyperphosphorylated forms of tau protein. AD brains also show neurodegeneration and high levels of oxidative stress and inflammation. The phytocannabinoid cannabidiol (CBD) possesses neuroprotective, antioxidant and anti-inflammatory properties and reduces amyloid-β production and tau hyperphosphorylation in vitro. CBD has also been shown to be effective in vivo making the phytocannabinoid an interesting candidate for novel therapeutic interventions in AD, especially as it lacks psychoactive or cognition-impairing properties. CBD treatment would be in line with preventative, multimodal drug strategies targeting a combination of pathological symptoms, which might be ideal for AD therapy. Thus, this review will present a brief introduction to AD biology and current treatment options before outlining comprehensively CBD biology and pharmacology, followed by in-vitro and in-vivo evidence for the therapeutic potential of CBD. We will also discuss the role of the endocannabinioid system in AD before commenting on the potential future of CBD for AD therapy (including safety aspects).

Topics: Alzheimer Disease; Animals; Anti-Inflammatory Agents; Antioxidants; Brain; Cannabidiol; Cognition; Cognition Disorders; Humans; Neuroprotective Agents; Oxidative Stress

Dementia currently affects over 35 million people worldwide. The most common form of dementia is Alzheimer's disease (AD). Currently, treatments for AD do not stop or reverse the progression of the disease and they are accompanied by side effects.. The main features of AD pathology, treatment options currently available, the endocannabinoid system and its functionality in general and its role in AD pathology in detail will be outlined. A particular focus will be on the therapeutic potential of the phytocannabinoid cannabidiol.. Based on the complex pathology of AD, a preventative, multimodal drug approach targeting a combination of pathological AD symptoms appears ideal. Importantly, cannabinoids show anti-inflammatory, neuroprotective and antioxidant properties and have immunosuppressive effects. Thus, the cannabinoid system should be a prime target for AD therapy. The cannabinoid receptor 2 appears to be a promising candidate but its role in AD has to be investigated cautiously. Furthermore, the phytocannabinoid cannabidiol is of particular interest as it lacks the psychoactive and cognition-impairing properties of other cannabinoids. In conclusion, future research should focus on the evaluation of the effects of manipulations to the endocannabinoid system in established animal models for AD, combined with early-phase studies in humans.

Topics: Alzheimer Disease; Animals; Cannabidiol; Cannabinoid Receptor Modulators; Endocannabinoids; Humans; Memory

Neurodegenerative diseases represent, nowadays, one of the main causes of death in the industrialized country. They are characterized by a loss of neurons in particular regions of the nervous system. It is believed that this nerve cell loss underlies the subsequent decline in cognitive and motor function that patients experience in these diseases. A range of mutant genes and environmental toxins have been implicated in the cause of neurodegenerative disorders but the mechanism remains largely unknown. At present, inflammation, a common denominator among the diverse list of neurodegenerative diseases, has been implicated as a critical mechanism that is responsible for the progressive nature of neurodegeneration. Since, at present, there are few therapies for the wide range of neurodegenerative diseases, scientists are still in search of new therapeutic approaches to the problem. An early contribution of neuroprotective and antiinflammatory strategies for these disorders seems particularly desirable because isolated treatments cannot be effective. In this contest, marijuana derivatives have attracted special interest, although these compounds have always raised several practical and ethical problems for their potential abuse. Nevertheless, among Cannabis compounds, cannabidiol (CBD), which lacks any unwanted psychotropic effect, may represent a very promising agent with the highest prospect for therapeutic use.

Topics: Alzheimer Disease; Animals; Cannabidiol; Cytoprotection; Disease Models, Animal; Humans; Huntington Disease; Multiple Sclerosis; Neurodegenerative Diseases; Neuroprotective Agents; Parkinson Disease; Prion Diseases

Human aging involves gradual decline in organ functions leading to organ specific age-related chronic diseases such as Alzheimer's disease (AD). Although advances in the development of new drugs, novel surgical procedures, improved diet and lifestyle, have resulted in doubling of lifespan of humans, the quality of life in many cases remains poor because of increased incidence of age-related chronic diseases. Using experimental models of accelerated aging, several cellular defects associated with aging and AD have been identified. Some cellular defects due to increased oxidative stress, chronic inflammation, autophagy defects, mitochondrial dysfunction, and imbalances in the composition probiotics in favor of harmful bacteria over beneficial bacteria are common to both aging and AD, while others such as telomere attrition, loss of collagen, elastin, and hyaluronic acid, failure of DNA repair system, and impaired immune function are unique to aging; and some such as increased production of beta-amyloids, hyperphosphorylation of tau protein, and abnormal behaviors are unique to AD. It is suggested that supplementation with a micronutrient mixture, probiotics, collagen peptides, CBD, and modifications in the diet and lifestyle may reduce the aging processes, and the development, progression of AD, and improve the treatments of this disease.

Topics: Aging; Alzheimer Disease; Amyloid beta-Peptides; Cannabidiol; Diet; Humans; Micronutrients; Probiotics; Quality of Life

Topics: Alzheimer Disease; Amyloid beta-Peptides; Animals; Astrocytes; Caenorhabditis elegans; Cannabidiol; Humans; Reactive Oxygen Species; Ubiquitin-Protein Ligases

Most studies related to hemp are focused on Cannabidiol (CBD) and Tetrahydrocannabinol (THC); however, up to 120 types of phytocannabinoids are present in hemp. Hemp leaves contain large amounts of Cannabidiolic acid (CBDA) and Tetrahydrocannabinolic acid (THCA), which are acidic variants of CBD and THC and account for the largest proportion of CBDA. In recent studies, CBDA exhibited anti-hyperalgesia and anti-inflammatory effects. THCA also showed anti-inflammatory and neuroprotective effects that may be beneficial for treating neurodegenerative diseases. CBDA and THCA can penetrate the blood-brain barrier (BBB) and affect the central nervous system. The purpose of this study was to determine whether CBDA and THCA ameliorate Alzheimer's disease (AD)-like features in vitro and in vivo. The effect of CBDA and THCA was evaluated in the Aβ

Topics: Alzheimer Disease; Amyloid beta-Peptides; Animals; Cannabidiol; Cannabinoids; Cannabis; Dronabinol; Memory Disorders; Mice; Neuroprotective Agents

Cannabidiol (CBD), a major non-psychoactive component of the cannabis plant, has shown therapeutic potential in Alzheimer's disease (AD). In this study, we identified potential CBD targets associated with AD using a drug-target binding affinity prediction model and generated CBD analogs using a genetic algorithm combined with a molecular docking system. As a result, we identified six targets associated with AD: Endothelial NOS (ENOS), Myeloperoxidase (MPO), Apolipoprotein E (APOE), Amyloid-beta precursor protein (APP), Disintegrin and metalloproteinase domain-containing protein 10 (ADAM10), and Presenilin-1 (PSEN1). Furthermore, we generated CBD analogs for each target that optimize for all desired drug-likeness properties and physicochemical property filters, resulting in improved pIC50 values and docking scores compared to CBD. Molecular dynamics (MD) simulations were applied to analyze each target's CBD and highest-scoring CBD analogs. The MD simulations revealed that the complexes of ENOS, MPO, and ADAM10 with CBD exhibited high conformational stability, and the APP and PSEN1 complexes with CBD analogs demonstrated even higher conformational stability and lower interaction energy compared to APP and PSEN1 complexes with CBD. These findings demonstrated the capable binding of the six identified targets with CBD and the enhanced binding stability achieved with the developed CBD analogs for each target.

Topics: Alzheimer Disease; Amyloid beta-Protein Precursor; Cannabidiol; Humans; Molecular Docking Simulation; Molecular Dynamics Simulation

Using nanoparticle (NP) drugs can have better effects on the target tissue in various diseases. Alzheimer's disease (AD) is one of the degenerative neurological diseases that due to its high prevalence, requires the use of more appropriate treatments. Therefore, the aim of this study was consideration of the effect of cannabidiol (CBD) coated by nano-chitosan on learning and memory, hippocampal cannabinoid receptor type 1 (CB1) and cannabinoid receptor type 1 (CB2) levels, and amyloid plaques in an AD rat model.. Thirty-five male Wistar rats were randomly divided into 5 groups (n = 7 in each): control, Alzheimer's disease model that received the beta-amyloid (Aβ) peptide (Alz), Alz + nano-chitosan (NP) Alz + CBD, and Alz + NP + CBD. Alz was induced by injection of the Aβ1-42 peptide into the hippocampal area cornu ammonis1. After confirmation of Alz, 1 μL of CBD and NP + CBD were administered by oral gavage daily in rats for 1 month. The Morris water maze (MWM) test was used to assess learning and memory of animals. Cresyl violet staining was used for consideration of dead cells. Gene and protein expression of CB1 and CB2 was performed by real-time PCR and immunohistochemistry methods.. Induction of Alz significantly increased Aβ plaques and dead cells compared to the control group (p < 0.001). Results of MWM in the day test show that Alz + NP + CBD significantly decrease escape latency (p < 0.01), travelled distance (p < 0.001), and significantly increased spending time (p < 0.001) compared to the Alz group. Protein expression of CB1 and CB2 significantly increased in Alz + CBD and Alz + NP + CBD compared to the Alz group (p < 0.05).. It seems that CBD coated by nano-chitosan has good potential for reducing Aβ plaques, increasing brain CB1 and levels CB2, and improving learning and memory in Alz rats.

Topics: Alzheimer Disease; Amyloid beta-Peptides; Animals; Cannabidiol; Chitosan; Hippocampus; Humans; Male; Plaque, Amyloid; Rats; Rats, Wistar; Receptors, Cannabinoid

Alzheimer's disease (AD) is a neurodegenerative disease characterized by cascading changes in cognition and behavior. G-protein-coupled receptor 55 (GPR55) has been used as a promising target for the treatment of diabetes, but its function in AD is unclear. The objective of this study was to investigate the neuroprotective effects of O-1602, a GPR55 agonist, on the streptozotocin (STZ)-induced AD mouse model. A single intracerebroventricular (i.c.v.) injection of STZ into the brains of mice significantly induced cognitive impairment. In contrast, O-1602 (2.0 or 4.0 μg/mouse, i.c.v.) can improve the cognitive dysfunction caused by STZ in the Morris water maze (MWM) and novel object recognition (NOR) tests. Importantly, O-1602 treatment reversed STZ-induced GPR55 down-regulation, reduced the activity of β-secretase 1 (BACE1) and the level of Aβ

Topics: Acetylcholinesterase; Alzheimer Disease; Amyloid Precursor Protein Secretases; Animals; Aspartic Acid Endopeptidases; Cannabidiol; Cognitive Dysfunction; Disease Models, Animal; Maze Learning; Mice; Neuroprotective Agents; Oxidative Stress; Receptors, Cannabinoid; Streptozocin; Synapses

Recent discoveries have implicated the potential of Cannabidiol (CBD) in the prevention of Alzheimer's disease (AD). However, how CBD affects such neurodegenerative disorders remains unclear. Herein, Caenorhabditis elegans (C. elegans) was used as the model organism to elucidate the mechanism by which CBD ameliorates AD in vivo. CBD was found to alleviate the progression of Aβ-induced AD but not tau protein-induced AD or α-syn-induced Parkinson's disease. CBD inhibited the aggregation of Aβ in C. elegans. However, CBD failed to prevent the formation of β-sheet aggregation in vitro. Moreover, CBD was found to scavenge reactive oxygen species (ROS) in vivo without inducing the overexpression of antioxidative genes. In addition, CBD treatment enhanced the worm resistance to oxidative stress, which was independent of the classical transcription factors DAF-16 and SKN-1. These results supported that the in vivo antioxidative activity of CBD was most likely due to its intrinsic antioxidative property. Furthermore, the phenolic hydroxyl groups of CBD were found to be critical for scavenging ROS in vitro and in vivo, alleviating the aggregation of Aβ in vivo, and ameliorating Aβ-associated neurotoxicity. These studies show that CBD protects against AD in C. elegans via the ROS scavenging activity of its phenolic hydroxyl groups, which provides insight for further structure-activity relationship studies of CBD as an AD therapeutic.

Topics: Alzheimer Disease; Animals; Caenorhabditis elegans; Cannabidiol; Free Radical Scavengers; Oxidative Stress; Reactive Oxygen Species; Structure-Activity Relationship

Frontotemporal dementia (FTD) and Alzheimer's disease (AD) share the pathological hallmark of intracellular neurofibrillary tangles, which result from the hyperphosphorylation of microtubule associated protein tau. The P301S mutation in human tau carried by TAU58/2 transgenic mice results in brain pathology and behavioural deficits relevant to FTD and AD. The phytocannabinoid cannabidiol (CBD) exhibits properties beneficial for multiple pathological processes evident in dementia. Therefore, 14-month-old female TAU58/2 transgenic and wild type-like (WT) littermates were treated with 100 mg/kg CBD or vehicle i.p. starting three weeks prior to conducting behavioural paradigms relevant to FTD and AD. TAU58/2 females exhibited impaired motor function, reduced bodyweight and less anxiety behaviour compared to WT. Impaired spatial reference memory of vehicle-treated transgenic mice was restored by chronic CBD treatment. Chronic CBD also reduced anxiety-like behaviours and decreased contextual fear-associated freezing in all mice. Chronic remedial CBD treatment ameliorated several disease-relevant phenotypes in 14-month-old TAU58/2 transgenic mice, suggesting potential for the treatment of tauopathy-related behavioural impairments including cognitive deficits.

Topics: Alzheimer Disease; Animals; Cannabidiol; Disease Models, Animal; Female; Frontotemporal Dementia; Memory Disorders; Mice; Mice, Transgenic; Spatial Memory; tau Proteins; Tauopathies

Cannabidiol is a nonpsychoactive phytocannabinoid produced by the

Topics: Alzheimer Disease; Animals; Antioxidants; Caenorhabditis elegans; Caenorhabditis elegans Proteins; Cannabidiol; Lactoylglutathione Lyase; Longevity; Pyruvaldehyde

Alzheimer's disease (AD) is associated with the accumulation and aggregation of amyloid in the brain. The cation channel TRPV2 may mediate the pathological changes in mild cognitive impairment. A high-affinity agonist of TRPV2 named cannabidiol is one of the candidate drugs for AD. However, the molecular mechanism of cannabidiol via TRPV2 in AD remains unknown. The present study investigated whether cannabidiol enhances the phagocytosis and clearance of microglial Aβ via the TRPV2 channel. We used a human dataset, mouse primary neuron and microglia cultures, and AD model mice to evaluate TRPV2 expression and the ability of microglial amyloid-β phagocytosis in vivo and in vitro. The results revealed that TRPV2 expression was reduced in the cortex and hippocampus of AD model mice and AD patients. Cannabidiol enhanced microglial amyloid-β phagocytosis through TRPV2 activation, which increased the mRNA expression of the phagocytosis-related receptors, but knockdown of TRPV2 or Trem2 rescued the expression. TRPV2-mediated effects were also dependent on PDK1/Akt signaling, a pathway in which autophagy was indispensable. Furthermore, cannabidiol treatment successfully attenuated neuroinflammation while simultaneously improving mitochondrial function and ATP production via TRPV2 activation. Therefore, TRPV2 is proposed as a potential therapeutic target in AD, while CBD is a promising drug candidate for AD.

Topics: Alzheimer Disease; Amyloid beta-Peptides; Animals; Calcium Channels; Cannabidiol; Humans; Membrane Glycoproteins; Mice; Microglia; Phagocytosis; Receptors, Immunologic; TRPV Cation Channels

Cannabidiol (CBD) and rivastigmine have been launched as drugs for treating dementia and cholinesterases (ChEs) are ideal drug targets. This study focused on developing novel ChE inhibitors as drug leads against dementia through molecular modeling and fragment reassembly approaches. A potent carbamate fragment binding to active site gorge of BuChE was found via a docking-based structural splicing approach, thus, 17 novel compounds were designed by structural reassembly. Compound C16 was identified as a highly selective potent BuChE inhibitor (IC

Topics: Acetylcholinesterase; Alzheimer Disease; Animals; Binding Sites; Blood-Brain Barrier; Butyrylcholinesterase; Cannabidiol; Carbamates; Cell Line, Tumor; Cell Survival; Cholinesterase Inhibitors; Drug Design; Humans; Kinetics; Maze Learning; Mice; Mice, Inbred ICR; Molecular Docking Simulation; Neuroprotective Agents; Structure-Activity Relationship

Topics: Alzheimer Disease; Benzothiazoles; Brain; Cannabidiol; Humans; Kinetics; Microscopy, Atomic Force; Neurons; Protein Aggregation, Pathological; Protein Isoforms; tau Proteins

Alzheimer's disease (AD) is a central nervous system disease characterized by dementia, which has now become a major threat to global health. Cannabidiol (CBD) is a natural component extracted from the hemp plant and exhibits multiple mechanisms to improve the pathological process of AD in vitro and in vivo. However, its underlying molecular mechanism is still unclear. This study attempts to reveal its common mechanism through transcriptome sequence. We performed transcriptome sequence in the hippocampus of 6 month old APP/PS1 mice chronically treated with CBD for one month or 30 days. In addition, Aβ plaques were investigated by Immunohistochemistry. Autophagosomes were observed by transmission electron microscopy and the expression of autophagy related proteins was examined by Western blot. GO_BP and KEGG enriched analysis showed that the immune system response was up-regulation significantly. Both KEGG pathway analysis and GSEA analysis showed that autophagy was significantly up-regulated. Finally, the autophagy of hippocampal neurons in APP/PS1 mice treated with CBD was significantly enhanced by transmission electron microscopy. This study illustrated that CBD may improve the pathological process of AD by enhancing immune system response and autophagy pathway.

Topics: Alzheimer Disease; Amyloid beta-Protein Precursor; Animals; Autophagy; Cannabidiol; Computational Biology; Disease Models, Animal; Gene Expression Profiling; Gene Library; Hippocampus; Immune System; Male; Mice; Mice, Inbred C57BL; Mice, Transgenic; Microscopy, Electron, Transmission; Neurons; Protein Interaction Mapping; Quality Control; RNA-Seq; Transcriptome; Up-Regulation

With the increasing popularity of CBD-based products, especially CBD oil, it is increasingly important to understand what motivates caregivers of individuals with Alzheimer's disease (AD) to use CBD oil as part of treatment. The purpose of this study was to identify the attitudes and beliefs of caregivers of individuals with AD toward CBD oil in Poland, to identify factors that might be associated with the decision to use CBD oil among caregivers, and to explore whether such a decision was discussed with a healthcare professional.. A cross-sectional online survey was conducted in Poland. Participation in the study was entirely voluntary and completely anonymous. Caregivers (n = 73) were asked about their practices and attitudes regarding CBD oil.. The most common source of knowledge about CBD oil was an online support group for caregivers. The vast majority of caregivers found CBD to be effective in managing behavioral symptoms of AD and believed that healthcare professionals should offer CBD oil as a part of treatment. However, only 63 % (n = 46) reported consulting with their physician about using CBD oil. The study also demonstrated that some caregivers thought that CBD oil use was illegal in Poland and that their care-recipient may develop a dependence and withdrawal symptoms if they stopped using it.. The results of the study highlight the positive and negative perceptions among caregivers of people with AD. The study also emphasizes the importance of enhancing communication between caregivers and healthcare professionals to discuss the use of CBD oil in the treatment of individuals with AD.

Topics: Alzheimer Disease; Attitude; Cannabidiol; Caregivers; Cross-Sectional Studies; Humans

There is a dire need for due innovative therapeutic modalities to improve outcomes of AD patients. In this study, we tested whether cannabidiol (CBD) improves outcomes in a translational model of familial AD and to investigate if CBD regulates interleukin (IL)-33 and triggering receptor expressed on myeloid cells 2 (TREM2), which are associated with improved cognitive function. CBD was administered to 5xFAD mice, which recapitulate early onset, familial AD. Behavioral tests and immunoassays were used to evaluate cognitive and motor outcomes. Our findings suggest that CBD treatment enhanced IL-33 and TREM2 expression, ameliorated the symptoms of AD, and retarded cognitive decline.

Topics: Alzheimer Disease; Animals; Cannabidiol; Cognition; Disease Models, Animal; Humans; Interleukin-33; Male; Membrane Glycoproteins; Mice; Mice, Transgenic; Receptors, Immunologic; Up-Regulation

Alzheimer's disease (AD) is characterized by progressive cognitive decline and pathologically by the accumulation of amyloid-β (Aβ) and tau hyperphosphorylation causing neurodegeneration and neuroinflammation. Current AD treatments do not stop or reverse the disease progression, highlighting the need for more effective therapeutics. The phytocannabinoid cannabidiol (CBD) has demonstrated antioxidant, anti-inflammatory, and neuroprotective properties. Furthermore, chronic CBD treatment (20 mg/kg) reverses social and object recognition memory deficits in the AβPPxPS1 transgenic mouse model with only limited effects on AD-relevant brain pathology. Importantly, studies have indicated that CBD works in a dose-dependent manner. Thus, this study determined the chronic effects of 50 mg/kg CBD in male AβPPxPS1 mice. 12-month-old mice were treated with 50 mg/kg CBD or vehicle via daily intraperitoneal injections for 3 weeks prior to behavioral testing. A variety of cognitive domains including object and social recognition, spatial and fear-associated memory were evaluated. Pathological brain analyses for AD-relevant markers were conducted using ELISA and western blot. Vehicle-treated male AβPPxPS1 mice demonstrated impaired social recognition memory and reversal spatial learning. These deficits were restored after CBD treatment. Chronic CBD tended to reduce insoluble Aβ40 levels in the hippocampus of AβPPxPS1 mice but had no effect on neuroinflammation, neurodegeneration, or PPARγ markers in the cortex. This study demonstrates that therapeutic-like effects of 50 mg/kg CBD on social recognition memory and spatial learning deficits in AβPPxPS1 mice are accompanied by moderate brain region-specific reductions in insoluble Aβ40 levels. The findings emphasize the clinical relevance of CBD treatment in AD; however, the underlying mechanisms involved require further investigation.

Topics: Alzheimer Disease; Amyloid beta-Peptides; Amyloid beta-Protein Precursor; Animals; Brain; Cannabidiol; Cognition; Dose-Response Relationship, Drug; Fear; Humans; Male; Mice; Mice, Inbred C3H; Mice, Inbred C57BL; Mice, Transgenic; Peptide Fragments; Presenilin-1; Recognition, Psychology; Social Behavior; Space Perception

Alzheimer's disease (AD) is a neurodegenerative disease, in which the primary etiology remains unknown. AD presents amyloid beta (Aβ) protein aggregation and neurofibrillary plaque deposits. AD shows oxidative stress and chronic inflammation. In AD, canonical Wingless-Int (Wnt)/β-catenin pathway is downregulated, whereas peroxisome proliferator-activated receptor γ (PPARγ) is increased. Downregulation of Wnt/β-catenin, through activation of glycogen synthase kinase-3β (GSK-3β) by Aβ, and inactivation of phosphatidylinositol 3-kinase/Akt signaling involve oxidative stress in AD. Cannabidiol (CBD) is a non-psychotomimetic phytocannabinoid from Cannabis sativa plant. In PC12 cells, Aβ-induced tau protein hyperphosphorylation is inhibited by CBD. This inhibition is associated with a downregulation of p-GSK-3β, an inhibitor of Wnt pathway. CBD may also increase Wnt/β-catenin by stimulation of PPARγ, inhibition of Aβ and ubiquitination of amyloid precursor protein. CBD attenuates oxidative stress and diminishes mitochondrial dysfunction and reactive oxygen species generation. CBD suppresses, through activation of PPARγ, pro-inflammatory signaling and may be a potential new candidate for AD therapy.

Topics: Alzheimer Disease; Amyloid beta-Peptides; Animals; Cannabidiol; Glycogen Synthase Kinase 3 beta; Inflammation; Models, Biological; Neurofibrillary Tangles; Oxidative Stress; PC12 Cells; Phosphorylation; PPAR gamma; Rats; tau Proteins; Wnt Signaling Pathway

The endogenous cannabinoid system represents a promising therapeutic target to modify neurodegenerative pathways linked to Alzheimer's disease (AD). The aim of the present study was to evaluate the specific contribution of CB2 receptor to the progression of AD-like pathology and its role in the positive effect of a cannabis-based medicine (1:1 combination of Δ9-tetrahidrocannabinol and cannabidiol) previously demonstrated to be beneficial in the AβPP/PS1 transgenic model of the disease. A new mouse strain was generated by crossing AβPP/PS1 transgenic mice with CB2 knockout mice. Results show that lack of CB2 exacerbates cortical Aβ deposition and increases the levels of soluble Aβ40. However, CB2 receptor deficiency does not affect the viability of AβPP/PS1 mice, does not accelerate their memory impairment, does not modify tau hyperphosphorylation in dystrophic neurites associated to Aβ plaques, and does not attenuate the positive cognitive effect induced by the cannabis-based medicine in these animals. These findings suggest a minor role for the CB2 receptor in the therapeutic effect of the cannabis-based medicine in AβPP/PS1 mice, but also constitute evidence of a link between CB2 receptor and Aβ processing.

Topics: Alzheimer Disease; Amyloid beta-Peptides; Animals; Brain; Cannabidiol; Cognition; Disease Models, Animal; Dronabinol; Humans; Male; Medical Marijuana; Memory; Mice, Inbred C57BL; Mice, Transgenic; Nootropic Agents; Presenilin-1; Random Allocation; Receptor, Cannabinoid, CB2; tau Proteins; Treatment Outcome

Mesenchymal stem cells (MSCs) have emerged as a promising tool for the treatment of several neurodegenerative disorders, including Alzheimer's disease (AD). The main neuropathological hallmarks of AD are senile plaques, composed of amyloid beta (Aβ), and neurofibrillary tangles, formed by hyperphosphorylated tau. However, current therapies for AD have shown limited efficacy. In this study, we evaluated whether pre-treatment with cannabidiol (CBD), at 5 μM concentration, modulated the transcriptional profile of MSCs derived from gingiva (GMSCs) in order to improve their therapeutic potential, by performing a transcriptomic analysis by the next-generation sequencing (NGS) platform. By comparing the expression profiles between GMSCs treated with CBD (CBD-GMSCs) and control GMSCs (CTR-GMSCs), we found that CBD led to the downregulation of genes linked to AD, including genes coding for the kinases responsible of tau phosphorylation and for the secretases involved in Aβ generation. In parallel, immunocytochemistry analysis has shown that CBD inhibited the expression of GSK3β, a central player in AD pathogenesis, by promoting PI3K/Akt signalling. In order to understand through which receptor CBD exerted these effects, we have performed pre-treatments with receptor antagonists for the cannabinoid receptors (SR141716A and AM630) or for the vanilloid receptor 1 (TRPVI). Here, we have proved that TRPV1 was able to mediate the modulatory effect of CBD on the PI3K/Akt/GSK3β axis. In conclusion, we have found that pre-treatment with CBD prevented the expression of proteins potentially involved in tau phosphorylation and Aβ production in GMSCs. Therefore, we suggested that GMSCs preconditioned with CBD possess a molecular profile that might be more beneficial for the treatment of AD.

Topics: Alzheimer Disease; Amyloid beta-Peptides; Cannabidiol; Cells, Cultured; Glycogen Synthase Kinase 3 beta; Humans; Male; Mesenchymal Stem Cells; Phosphatidylinositol 3-Kinases; Proto-Oncogene Proteins c-akt; tau Proteins; Transcriptome; TRPV Cation Channels

The amyloidogenic cascade is regarded as a key factor at the basis of Alzheimer's disease (AD) pathogenesis. The aberrant cleavage of amyloid precursor protein (APP) induces an increased production and a subsequent aggregation of beta amyloid (Aβ) peptide in limbic and association cortices. As a result, altered neuronal homeostasis and oxidative injury provoke tangle formation with consequent neuronal loss. Cannabidiol (CBD), a Cannabis derivative devoid of psychotropic effects, has attracted much attention because it may beneficially interfere with several Aβ-triggered neurodegenerative pathways, even though the mechanism responsible for such actions remains unknown. In the present research, the role of CBD was investigated as a possible modulating compound of APP processing in SHSY5Y(APP+) neurons. In addition, the putative involvement of peroxisome proliferator-activated receptor-γ (PPARγ) was explored as a candidate molecular site responsible for CBD actions. Results indicated the CBD capability to induce the ubiquitination of APP protein which led to a substantial decrease in APP full length protein levels in SHSY5Y(APP+) with the consequent decrease in Aβ production. Moreover, CBD promoted an increased survival of SHSY5Y(APP+) neurons, by reducing their long-term apoptotic rate. Obtained results also showed that all, here observed, CBD effects were dependent on the selective activation of PPARγ.

Topics: Alzheimer Disease; Amyloid beta-Peptides; Amyloid beta-Protein Precursor; Apoptosis; Cannabidiol; Cell Line; Humans; Neurons; PPAR gamma; Ubiquitination; Up-Regulation

Patients suffering from Alzheimer's disease (AD) exhibit a decline in cognitive abilities including an inability to recognise familiar faces. Hallmark pathological changes in AD include the aggregation of amyloid-β (Aβ), tau protein hyperphosphorylation as well as pronounced neurodegeneration, neuroinflammation, neurotoxicity and oxidative damage.. The non-psychoactive phytocannabinoid cannabidiol (CBD) exerts neuroprotective, anti-oxidant and anti-inflammatory effects and promotes neurogenesis. CBD also reverses Aβ-induced spatial memory deficits in rodents.. Thus we determined the therapeutic-like effects of chronic CBD treatment (20 mg/kg, daily intraperitoneal injections for 3 weeks) on the APPswe/PS1∆E9 (APPxPS1) transgenic mouse model for AD in a number of cognitive tests, including the social preference test, the novel object recognition task and the fear conditioning paradigm. We also analysed the impact of CBD on anxiety behaviours in the elevated plus maze.. Vehicle-treated APPxPS1 mice demonstrated impairments in social recognition and novel object recognition compared to wild type-like mice. Chronic CBD treatment reversed these cognitive deficits in APPxPS1 mice without affecting anxiety-related behaviours.. This is the first study to investigate the effect of chronic CBD treatment on cognition in an AD transgenic mouse model. Our findings suggest that CBD may have therapeutic potential for specific cognitive impairments associated with AD.

Topics: Alzheimer Disease; Amyloid beta-Protein Precursor; Animals; Anxiety; Cannabidiol; Conditioning, Psychological; Disease Models, Animal; Exploratory Behavior; Fear; Humans; Male; Mice, Inbred C57BL; Mice, Transgenic; Neuropsychological Tests; Nootropic Agents; Presenilin-1; Recognition, Psychology; Social Perception

Impairments in cognitive ability and widespread pathophysiological changes caused by neurotoxicity, neuroinflammation, oxidative damage, and altered cholesterol homeostasis are associated with Alzheimer's disease (AD). Cannabidiol (CBD) has been shown to reverse cognitive deficits of AD transgenic mice and to exert neuroprotective, anti-oxidative, and anti-inflammatory properties in vitro and in vivo. Here we evaluate the preventative properties of long-term CBD treatment in male AβPPSwe/PS1ΔE9 (AβPP × PS1) mice, a transgenic model of AD. Control and AD transgenic mice were treated orally from 2.5 months of age with CBD (20 mg/kg) daily for 8 months. Mice were then assessed in the social preference test, elevated plus maze, and fear conditioning paradigms, before cortical and hippocampal tissues were analyzed for amyloid load, oxidative damage, cholesterol, phytosterols, and inflammation. We found that AβPP × PS1 mice developed a social recognition deficit, which was prevented by CBD treatment. CBD had no impact on anxiety or associative learning. The prevention of the social recognition deficit was not associated with any changes in amyloid load or oxidative damage. However, the study revealed a subtle impact of CBD on neuroinflammation, cholesterol, and dietary phytosterol retention, which deserves further investigation. This study is the first to demonstrate CBD's ability to prevent the development of a social recognition deficit in AD transgenic mice. Our findings provide the first evidence that CBD may have potential as a preventative treatment for AD with a particular relevance for symptoms of social withdrawal and facial recognition.

Topics: Alzheimer Disease; Amyloid beta-Protein Precursor; Animals; Cannabidiol; Cerebral Cortex; Disease Models, Animal; Hippocampus; Humans; Male; Memory Disorders; Mice, Inbred C3H; Mice, Inbred C57BL; Mice, Transgenic; Mutation; Neuroimmunomodulation; Nootropic Agents; Presenilin-1; Recognition, Psychology; Social Behavior

Microglial activation is an invariant feature of Alzheimer's disease (AD). It is noteworthy that cannabinoids are neuroprotective by preventing β-amyloid (Aβ)-induced microglial activation both in vitro and in vivo. On the other hand, the phytocannabinoid cannabidiol (CBD) has shown anti-inflammatory properties in different paradigms. In the present study, we compared the effects of CBD with those of other cannabinoids on microglial cell functions in vitro and on learning behavior and cytokine expression after Aβ intraventricular administration to mice. CBD, (R)-(+)-[2,3-dihydro-5-methyl-3-(4-morpholinylmethyl) pyrrolo-[1,2,3-d,e]-1,4-benzoxazin-6-yl]-1-naphthalenyl-methanone [WIN 55,212-2 (WIN)], a mixed CB(1)/CB(2) agonist, and 1,1-dimethylbutyl-1-deoxy-Δ(9)-tetrahydrocannabinol [JWH-133 (JWH)], a CB(2)-selective agonist, concentration-dependently decreased ATP-induced (400 μM) increase in intracellular calcium ([Ca(2+)](i)) in cultured N13 microglial cells and in rat primary microglia. In contrast, 4-[4-(1,1-dimethylheptyl)-2,6-dimethoxyphenyl]-6,6-dimethyl-bicyclo[3.1.1]hept-2-ene-2-methanol [HU-308 (HU)], another CB(2) agonist, was without effect. Cannabinoid and adenosine A(2A) receptors may be involved in the CBD action. CBD- and WIN-promoted primary microglia migration was blocked by CB(1) and/or CB(2) antagonists. JWH and HU-induced migration was blocked by a CB(2) antagonist only. All of the cannabinoids decreased lipopolysaccharide-induced nitrite generation, which was insensitive to cannabinoid antagonism. Finally, both CBD and WIN, after subchronic administration for 3 weeks, were able to prevent learning of a spatial navigation task and cytokine gene expression in β-amyloid-injected mice. In summary, CBD is able to modulate microglial cell function in vitro and induce beneficial effects in an in vivo model of AD. Given that CBD lacks psychoactivity, it may represent a novel therapeutic approach for this neurological disease.

Topics: Alzheimer Disease; Animals; Base Sequence; Cannabidiol; Cannabinoids; Cells, Cultured; DNA Primers; Humans; Immunohistochemistry; In Vitro Techniques; Mice; Microglia; Nitric Oxide; Polymerase Chain Reaction; Rats; RNA, Messenger