Category Archives: Alzheimer’s Disease (AD)

The Memory Benefit to Aged APP/PS1 Mice from Long-Term Intranasal Treatment of Low-Dose THC

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“THC has been used as a promising treatment approach for neurological disorders, but the highly psychoactive effects have largely warned off many scientists from pursuing it further. We conducted an intranasal treatment using low-dose THC on 12-month-old APP/PS1 mice daily for 3 months to overcome any potential psychoactive response induced by the systemic delivery.

Our results demonstrate that the THC nasal treatment at 0.002 and 0.02 mg/kg significantly slowed the memory decline compared to that in the vehicle-treated transgenic mouse control group.

An enzyme-linked immunosorbent assay showed that the Aβ1-40 and 1-42 peptides decreased in the THC-treated groups. The Western blot data indicate that long-term low-dose THC intranasal administration promoted p-tau level reduction and mitochondrial function marker redistribution. The blood biochemical parameter data demonstrate some insignificant changes in cytokine, immunoglobulin, and immune cell profiles during intranasal THC treatment.

Intranasal delivery is a non-invasive and convenient method that rapidly targets therapeutics to the brain, minimizing systemic exposure to avoid unwanted adverse effects. Our study provides new insights into the role of low-dose THC intranasal treatment as a pharmacological strategy to counteract alterations in Alzheimer’s disease-related cognitive performance.”

https://pubmed.ncbi.nlm.nih.gov/35457070/

https://www.mdpi.com/1422-0067/23/8/4253

“Low-Dose Delta-9-Tetrahydrocannabinol as Beneficial Treatment for Aged APP/PS1 Mice.  In conclusion, treatment with THC at 0.2 and 0.02 mg/kg improved the spatial learning of aged APP/PS1 mice, suggesting low-dose THC is a safe and effective treatment for AD.”

https://pubmed.ncbi.nlm.nih.gov/35269905/

Cannabinoid extract in microdoses ameliorates mnemonic and nonmnemonic Alzheimer’s disease symptoms: a case report

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“Background: Cannabinoid-based therapy has been shown to be promising and is emerging as crucial for the treatment of cognitive deficits, mental illnesses, and many diseases considered incurable. There is a need to find an appropriate therapy for Alzheimer’s disease, and cannabinoid-based therapy appears to be a feasible possibility.

Case presentation: This report addresses the beneficial effect of cannabinoids in microdoses on improving memory and brain functions of a patient with mild-stage Alzheimer’s disease. The patient is a 75-year-old white man presenting with main symptoms of memory deficit, spatial and temporal disorientation, and limited daily activity. The experimental therapeutic intervention was carried out for 22 months with microdoses of a cannabis extract containing cannabinoids. Clinical evaluations using Mini-Mental State Examination and Alzheimer’s Disease Assessment Scale-Cognitive Subscale were performed.

Conclusions: Here we provide original evidence that cannabinoid microdosing could be effective as an Alzheimer’s disease treatment while preventing major side effects. This is an important step toward dissociating cannabinoids’ health-improving effects from potential narcotic-related limitations.”

https://pubmed.ncbi.nlm.nih.gov/35820856/

“In summary, data presented in this case report suggest that cannabinoid microdosing is a potential therapeutic for AD, with no significant side effects, although placebo-controlled clinical trials are needed to confirm and extend these data.”

https://jmedicalcasereports.biomedcentral.com/articles/10.1186/s13256-022-03457-w

Cannabis: Chemistry, extraction and therapeutic applications

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“Cannabis, a genus of perennial indigenous plants is well known for its recreational and medicinal activities. Cannabis and its derivatives have potential therapeutic activities to treat epilepsy, anxiety, depression, tumors, cancer, Alzheimer’s disease, Parkinson’s disease, to name a few.

This article reviews some recent literature on the bioactive constituents of Cannabis, commonly known as phytocannabinoids, their interactions with the different cannabinoids and non-cannabinoid receptors as well as the significances of these interactions in treating various diseases and syndromes.

The biochemistry of some notable cannabinoids such as tetrahydrocannabinol, cannabidiol, cannabinol, cannabigerol, cannabichromene and their carboxylic acid derivatives is explained in the context of therapeutic activities.

The medicinal features of Cannabis-derived terpenes are elucidated for treating several neuro and non-neuro disorders. Different extraction techniques to recover cannabinoids are systematically discussed. Besides the medicinal activities, the traditional and recreational utilities of Cannabis and its derivatives are presented. A brief note on the legalization of Cannabis-derived products is provided.

This review provides comprehensive knowledge about the medicinal properties, recreational usage, extraction techniques, legalization and some prospects of cannabinoids and terpenes extracted from Cannabis.”

https://pubmed.ncbi.nlm.nih.gov/34838836/

“Cannabinoids have therapeutic effects against various health disorders.•

Medicinal effects are due to the interactions of cannabinoids with bio-receptors.•

Cannabinoids can be extracted from Cannabis plant products by eco-friendly extraction methods.”

https://www.sciencedirect.com/science/article/abs/pii/S0045653521034846?via%3Dihub

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Phytocannabinoids and Cannabis-Based Products as Alternative Pharmacotherapy in Neurodegenerative Diseases: From Hypothesis to Clinical Practice

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“Historically, Cannabis is one of the first plants to be domesticated and used in medicine, though only in the last years the amount of Cannabis-based products or medicines has increased worldwide.

Previous preclinical studies and few published clinical trials have demonstrated the efficacy and safety of Cannabis-based medicines in humans. Indeed, Cannabis-related medicines are used to treat multiple pathological conditions, including neurodegenerative disorders.

In clinical practice, Cannabis products have already been introduced to treatment regimens of Alzheimer’s disease, Parkinson’s disease and Multiple Sclerosis’s patients, and the mechanisms of action behind the reported improvement in the clinical outcome and disease progression are associated with their anti-inflammatory, immunosuppressive, antioxidant, and neuroprotective properties, due to the modulation of the endocannabinoid system.

In this review, we describe the role played by the endocannabinoid system in the physiopathology of Alzheimer, Parkinson, and Multiple Sclerosis, mainly at the neuroimmunological level. We also discuss the evidence for the correlation between phytocannabinoids and their therapeutic effects in these disorders, thus describing the main clinical studies carried out so far on the therapeutic performance of Cannabis-based medicines.”

https://pubmed.ncbi.nlm.nih.gov/35707521/

“Based on scientific evidence, the use of Cannabis-based products or Cannabis-based medicine (CBM) has been growing among patients diagnosed with neurodegenerative diseases. Most reports of clinical trials also describe significant improvement in disease-related primary and/or secondary symptoms, besides general improvement in life quality.”

https://www.frontiersin.org/articles/10.3389/fncel.2022.917164/full


Inhibitory Effects of Cannabinoids on Acetylcholinesterase and Butyrylcholinesterase Enzyme Activities

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“Acetylcholinesterase (AChE) and butyrylcholinesterase (BChE) are two cholinergic enzymes catalyzing the reaction of cleaving acetylcholine into acetate and choline at the neuromuscular junction. Abnormal hyperactivity of AChE and BChE can lead to cholinergic deficiency, which is associated with several neurological disorders including cognitive decline and memory impairments.

Preclinical studies support that some cannabinoids including cannabidiol (CBD) and tetrahydrocannabinol (THC) may exert pharmacological effects on the cholinergic system, but it remains unclear whether cannabinoids can inhibit AChE and BChE activities.

Herein, we aimed to evaluate the inhibitory effects of a panel of cannabinoids including CBD, Δ8-THC, cannabigerol (CBG), cannabigerolic acid (CBGA), cannabicitran (CBT), cannabidivarin (CBDV), cannabichromene (CBC), and cannabinol (CBN) on AChE and BChE activities.

Results: Cannabinoids including CBD, Δ8-THC, CBG, CBGA, CBT, CBDV, CBC, and CBN (at 200 µM) inhibited the activities of AChE and BChE by 70.8, 83.7, 92.9, 76.7, 66.0, 79.3, 13.7, and 30.5%, and by 86.8, 80.8, 93.2, 87.1, 77.0, 78.5, 27.9, and 22.0%, respectively. The inhibitory effects of these cannabinoids (with IC50 values ranging from 85.2 to >200 µM for AChE and 107.1 to >200 µM for BChE) were less potent as compared to the positive control galantamine (IC50 1.21 and 6.86 µM for AChE and BChE, respectively). In addition, CBD, as a representative cannabinoid, displayed a competitive type of inhibition on both AChE and BChE. Data from the molecular docking studies suggested that cannabinoids interacted with several amino acid residues on the enzyme proteins, which supported their overall inhibitory effects on AChE and BChE.

Conclusion: Cannabinoids showed moderate inhibitory effects on the activities of AChE and BChE enzymes, which may contribute to their modulatory effects on the cholinergic system. Further studies using cell-based and in vivo models are warranted to evaluate whether cannabinoids’ neuroprotective effects are associated with their anti-cholinesterase activities.”

https://pubmed.ncbi.nlm.nih.gov/35702400/

“Previously published work from our group has shown that medicinal plants and their derived natural products show neuroprotective and anti-inflammatory properties.

Notably, cannabinoids from Cannabis sativa (C. sativa) have been increasingly evaluated in studies to treat chronic pain, inflammation, multiple sclerosis, post-traumatic stress disorder, and neurological diseases, specifically AD.

Furthermore, a study implicated that phytochemicals of C. sativa, including several cannabinoids, are inhibitors of AChE,

In summary, several cannabinoids exhibited moderate inhibitory effects against the activities of cholinesterases including AChE and BChE.”

https://www.karger.com/Article/FullText/524086

“Naturally Occurring Acetylcholinesterase Inhibitors and Their Potential Use for Alzheimer’s Disease Therapy”

https://www.frontiersin.org/articles/10.3389/fphar.2018.01192/full


Cannabinoid CB 2 Receptors Modulate Microglia Function and Amyloid Dynamics in a Mouse Model of Alzheimer’s Disease

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“The distribution and roles of the cannabinoid CB2 receptor in the CNS are still a matter of debate. Recent data suggest that, in addition to its presence in microglial cells, the CB2 receptor may be also expressed at low levels, yet biologically relevant, in other cell types such as neurons. It is accepted that the expression of CB2 receptors in the CNS is low under physiological conditions and is significantly elevated in chronic neuroinflammatory states associated with neurodegenerative diseases such as Alzheimer’s disease. By using a novel mouse model (CB2 EGFP/f/f), we studied the distribution of cannabinoid CB2 receptors in the 5xFAD mouse model of Alzheimer’s disease (by generating 5xFAD/CB2 EGFP/f/f mice) and explored the roles of CB2 receptors in microglial function. We used a novel selective and brain penetrant CB2 receptor agonist (RO6866945) as well as mice lacking the CB2 receptor (5xFAD/CB2 -/-) for these studies. We found that CB2 receptors are expressed in dystrophic neurite-associated microglia and that their modulation modifies the number and activity of microglial cells as well as the metabolism of the insoluble form of the amyloid peptide. These results support microglial CB2 receptors as potential targets for the development of amyloid-modulating therapies.”

https://pubmed.ncbi.nlm.nih.gov/35645832/

“These data thus suggest a role for microglial cannabinoid CB2 receptors in the initiation, maintenance and removal of plaques and open new venues for the microglia-based therapeutic approaches in AD.”

https://www.frontiersin.org/articles/10.3389/fphar.2022.841766/full

Efficacy of Δ9 -Tetrahydrocannabinol (THC) Alone or in Combination With a 1:1 Ratio of Cannabidiol (CBD) in Reversing the Spatial Learning Deficits in Old Mice

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“Decline in cognitive performance, an aspect of the normal aging process, is influenced by the endocannabinoid system (ECS). Cannabinoid receptor 1 (CB1) signaling diminishes with advancing age in specific brain regions that regulate learning and memory and abolishing CB1 receptor signaling accelerates cognitive aging in mice. We recently demonstrated that prolonged exposure to low dose (3 mg/kg/day) Δ9-tetrahydrocannabinol (THC) improved the cognitive performances in old mice on par with young untreated mice. Here we investigated the potential influence of cannabidiol (CBD) on this THC effect, because preclinical and clinical studies indicate that the combination of THC and CBD often exhibits an enhanced therapeutic effect compared to THC alone. We first tested the effectiveness of a lower dose (1 mg/kg/day) THC, and then the efficacy of the combination of THC and CBD in 1:1 ratio, same as in the clinically approved medicine Sativex®. Our findings reveal that a 1 mg/kg/day THC dose still effectively improved spatial learning in aged mice. However, a 1:1 combination of THC and CBD failed to do so. The presence of CBD induced temporal changes in THC metabolism ensuing in a transient elevation of blood THC levels. However, as CBD metabolizes, the inhibitory effect on THC metabolism was alleviated, causing a rapid clearance of THC. Thus, the beneficial effects of THC seemed to wane off more swiftly in the presence of CBD, due to these metabolic effects. The findings indicate that THC-treatment alone is more efficient to improve spatial learning in aged mice than the 1:1 combination of THC and CBD.”

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8435893/

“In conclusion, our observations indicate that 1 mg/kg/day THC dose is still effective in improving the spatial learning in aged mice. With regard to the efficacy, THC-alone has proved to be more efficient in improving spatial learning in aged mice than its 1:1 combination with CBD. However, the possibility of THC/CBD being efficient in other ratios or at the earliest time-points, like immediately after the treatment cease, cannot be negated. Possibly, reducing the dose of CBD may improve the efficacy of the THC/CBD combination.”

https://www.frontiersin.org/articles/10.3389/fnagi.2021.718850/full

Cannabidiol Inhibits Tau Aggregation In Vitro

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“A hallmark of Alzheimer’s disease (AD) is the accumulation of tau protein in the brain. Compelling evidence indicates that the presence of tau aggregates causes irreversible neuronal destruction, eventually leading to synaptic loss. So far, the inhibition of tau aggregation has been recognized as one of the most effective therapeutic strategies. Cannabidiol (CBD), a major component found in Cannabis sativa L., has antioxidant activities as well as numerous neuroprotective features. Therefore, we hypothesize that CBD may serve as a potent substance to hamper tau aggregation in AD. In this study, we aim to investigate the CBD effect on the aggregation of recombinant human tau protein 1N/4R isoform using biochemical methods in vitro and in silico. Using Thioflavin T (ThT) assay, circular dichroism (CD), and atomic force microscopy (AFM), we demonstrated that CBD can suppress tau fibrils formation. Moreover, by quenching assay, docking, and job’s plot, we further demonstrated that one molecule of CBD interacts with one molecule of tau protein through a spontaneous binding. Experiments performed by quenching assay, docking, and Thioflavin T assay further established that the main forces are hydrogen Van der Waals and some non-negligible hydrophobic forces, affecting the lag phase of tau protein kinetics. Taken together, this study provides new insights about a natural substance, CBD, for tau therapy which may offer new hope for the treatment of AD.”

https://pubmed.ncbi.nlm.nih.gov/34944028/

https://www.mdpi.com/2073-4409/10/12/3521


Tetrahydrocannabinol-Rich Extracts From Cannabis Sativa L. Improve Glucose Consumption and Modulate Metabolic Complications Linked to Neurodegenerative Diseases in Isolated Rat Brains

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“Reduced brain glucose consumption arising from impaired glucose uptake and utilization has been linked to the pathogenesis and complications of neurodegenerative diseases. The ability of Cannabis sativa L. tetrahydrocannabinol (THC)-rich extracts to stimulate brain glucose uptake and utilization as well as its modulatory effect on gluconeogenesis, antioxidative, purinergic and cholinergic activities were investigated in isolated rats’ brains. C. sativa leaves were sequentially extracted to yield the hexane and dichloromethane extracts. The extracts were incubated at 37°C with freshly harvested brains in the presence of glucose for 2 h. The control consisted of incubation without the extracts, while brains without the extracts and glucose served as the normal control. Metformin was used as the standard drug. C. sativa extracts caused a significant (p < 0.05) increase in brain glucose uptake, with concomitant elevation of glutathione level, superoxide dismutase, catalase, and ecto-nucleoside triphosphate diphosphohydrolase activities compared to the controls. Incubation with C. sativa extracts also led to depletion in malondialdehyde and nitric oxide levels, acetylcholinesterase, butyrylcholinesterase, glucose 6-phosphatase and fructose-1,6-biphosphatase activities. GC-MS analysis of the extracts revealed the presence of THC. In silico analysis predicted THC to be permeable across the blood-brain-barrier. THC was also predicted to have an oral LD50 and toxicity class values of 482 mg/kg and 4 respectively. These results indicate that C. sativa improves glucose consumption with concomitant suppression of oxidative stress and cholinergic dysfunction, and modulation of purinergic and gluconeogenic activities in brain tissues.”

https://pubmed.ncbi.nlm.nih.gov/33390972/

“As portrayed by these results, C. sativa improves glucose consumption with concomitant suppression of oxidative stress and cholinergic dysfunction, and modulation of purinergic and gluconeogenic activities in brain tissues. Further studies are recommended to decipher the molecular mechanisms that may be involved in these neuroprotective activities in in vivo studies.”

https://www.frontiersin.org/articles/10.3389/fphar.2020.592981/full

Neuroprotection by Cannabinoids in Neurodegenerative Diseases

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“The cannabinoids are found to have particular application as neuroprotectants for mental and motor dysfuction in neurodegenerative diseases. The neuroprotective properties of cannabinoids suggest their therapeutic use for limiting neurological damage. The cannabinoids treatments should not only aim to alleviate specific symptoms but also attempt to delay/arrest disease progression and to repair the damaged structures. The author conducted a review of studies published between 1974 and 2011. The search was performed using the following PubMed search terms: “Cannabinoids” and “Neurodegenerative Diseases” and 287 papers were detected. The articles were examined and the overlapping or insufficiently clear works were excluded. Finally we chose 117 articles regarding the latest international guidelines, the pathophysiology of neurodegenerative diseases and the various therapeutic choices. The studies reported in the present review support the view that the cannabinoid signalling system is a key modulatory element in the activity of the basal ganglia. This idea is supported by different anatomical, electrophysiological, pharmacological and biochemical data. Furthermore, these studies indicate that the cannabinoid system is impaired in different neurological disorders that directly or indirectly affect the basal ganglia, which supports the idea of developing novel pharmacotherapies with compounds that selectively target specific elements of the cannabinoid system.”

https://www.oatext.com/neuroprotection-by-cannabinoids-in-neurodegenerative-diseases.php#Article