Category Archives: Alzheimer’s Disease (AD)

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


Recent Advances in the Potential of Cannabinoids for Neuroprotection in Alzheimer’s, Parkinson’s, and Huntington’s Diseases

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“Three prevalent neurodegenerative diseases, Parkinson’s, Alzheimer’s, and Huntington’s are in need of symptomatic relief of slowing disease progression or both. This chapter focuses on the potential of cannabinoids to afford neuroprotection, i.e. avoid or retard neuronal death. The neuroprotective potential of cannabinoids is known from the work in animal models and is mediated by the two cannabinoid receptors (CB1/CB2) and eventually, by their heteromers, GPR55, orphan receptors (GPR3/GPR6/GPR12/GPR18), or PPARγ. Now, there is the time to translate the findings into patients. The chapter takes primarily into account advances since 2016 and addresses the issue of proving neuroprotection in humans. One recent discovery is the existence of activated microglia with neuroprotective phenotype; cannabinoids are good candidates to skew phenotype, especially via glial CB2 receptors (CB2R), whose targeting has, a priori, less side effects those targeting the CBs1 receptor (CB1R), which are expressed in both neurons and glia. The fact that a cannabis extract (SativexTM) is approved for human therapy, such that cannabis use will likely be legalized in many countries and different possibilities that cannabinoid pharmacology suggests a successful route of cannabinoids (natural or synthetic) all the way to be approved and used in the treatment of neurodegeneration.”

https://pubmed.ncbi.nlm.nih.gov/33332005/

https://link.springer.com/chapter/10.1007/978-3-030-57369-0_6

Analogues of cannabinoids as multitarget drugs in the treatment of Alzheimer’s disease

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“Given that neuronal degeneration in Alzheimer’s disease (AD) is caused by the combination of multiple neurotoxic insults, current directions in the research of novel therapies to treat this disease attempts to design multitarget strategies that could be more effective than the simply use of acetylcholinesterase inhibitors; currently, the most used therapy for AD. One option, explored recently, is the synthesis of new analogues of cannabinoids that could competitively inhibit the acetylcholinesterase (AChE) enzyme and showing the classic neuroprotective profile of cannabinoid compounds. In this work, molecular docking has been used to design some cannabinoid analogues with such multitarget properties, based on the similarities of donepezil and Δ9-tetrahydrocannabinol. The analogues synthesized, compounds 1 and 2, demonstrated to have two interesting characteristics in different in vitro assays: competitive inhibition of AChE and competitive antagonism at the CB1/CB2 receptors. They are highly lipophilic, highlighting that they could easily reach the CNS, and apparently presented a low toxicity. These results open the door to the synthesis of new compounds for a more effective treatment of AD.”

https://pubmed.ncbi.nlm.nih.gov/33460612/

https://www.sciencedirect.com/science/article/abs/pii/S0014299921000285?via%3Dihub

The Neuroprotective Properties, Functions, and Roles of Cannabis sativa in Selected Diseases Related to the Nervous System

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“Background: Cannabis and its extracts are now being explored due to their huge health benefits. Although, the effect they elicit, whether on humans or rodents, may vary based on the age of the animal/subject and or the time in which the extract is administered. However, several debates exist concerning the various medical applications of these compounds. Nonetheless, their applicability as therapeutics should not be clouded based on their perceived negative biological actions.

Methods: Articles from reliable databases such as Science Direct, PubMed, Google Scholar, Scopus, and Ovid were searched. Specific search methods were employed using multiple keywords: ”Medicinal Cannabis; endocannabinoid system; cannabinoids receptors; cannabinoids and cognition; brain disorders; neurodegenerative diseases”. For the inclusion/exclusion criteria, only relevant articles related to medicinal Cannabis and its various compounds were considered.

Results: The current review highlights the role, effects, and involvement of Cannabis, cannabinoids, and endocannabinoids in preventing selected neurodegenerative diseases and possible amelioration of cognitive impairments. Furthermore, it also focuses on Cannabis utilization in many disease conditions such as Alzheimer’s and Parkinson’s disease among others.

Conclusion: In conclusion, the usage of Cannabis should be further explored as accumulating evidence suggests that it could be effective and somewhat safe, especially when adhered to the recommended dosage. Furthermore, in-depth studies should be conducted in order to unravel the specific mechanism underpinning the involvement of cannabinoids at the cellular level and their therapeutic applications.”

https://pubmed.ncbi.nlm.nih.gov/33504317/

https://www.eurekaselect.com/article/113707

Roles of Cannabidiol in the Treatment and Prevention of Alzheimer’s Disease by Multi-target Actions

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“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.”

https://pubmed.ncbi.nlm.nih.gov/33797364/

https://www.eurekaselect.com/article/115117

Cannabidiol Treatment Improves Glucose Metabolism and Memory in Streptozotocin-Induced Alzheimer’s Disease Rat Model: A Proof-of-Concept Study

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“An early and persistent sign of Alzheimer’s disease (AD) is glucose hypometabolism, which can be evaluated by positron emission tomography (PET) with 18F-2-fluoro-2-deoxy-D-glucose ([18F]FDG). Cannabidiol has demonstrated neuroprotective and anti-inflammatory properties but has not been evaluated by PET imaging in an AD model. Intracerebroventricular (icv) injection of streptozotocin (STZ) is a validated model for hypometabolism observed in AD. This proof-of-concept study evaluated the effect of cannabidiol treatment in the brain glucose metabolism of an icv-STZ AD model by PET imaging. Wistar male rats received 3 mg/kg of STZ and [18F]FDG PET images were acquired before and 7 days after STZ injection. Animals were treated with intraperitoneal cannabidiol (20 mg/kg-STZ-cannabidiol) or saline (STZ-saline) for one week. Novel object recognition was performed to evaluate short-term and long-term memory. [18F]FDG uptake in the whole brain was significantly lower in the STZ-saline group. Voxel-based analysis revealed a hypometabolism cluster close to the lateral ventricle, which was smaller in STZ-cannabidiol animals. The brain regions with more evident hypometabolism were the striatum, motor cortex, hippocampus, and thalamus, which was not observed in STZ-cannabidiol animals. In addition, STZ-cannabidiol animals revealed no changes in memory index. Thus, this study suggests that cannabidiol could be an early treatment for the neurodegenerative process observed in AD.”

https://pubmed.ncbi.nlm.nih.gov/35163003/

https://www.mdpi.com/1422-0067/23/3/1076

Understanding the Modulatory Effects of Cannabidiol on Alzheimer’s Disease

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“Alzheimer’s disease (AD), the most common neurodegenerative disease, is characterized by progressive cognitive impairment. The deposition of amyloid beta (Aβ) and hyperphosphorylated tau is considered the hallmark of AD pathology. Many therapeutic approaches such as Food and Drug Administration-approved cholinesterase inhibitors and N-methyl-D-aspartate receptor antagonists have been used to intervene in AD pathology. However, current therapies only provide limited symptomatic relief and are ineffective in preventing AD progression. Cannabidiol (CBD), a phytocannabinoid devoid of psychoactive responses, provides neuroprotective effects through both cannabinoid and noncannabinoid receptors. Recent studies using an AD mouse model have suggested that CBD can reverse cognitive deficits along with Aβ-induced neuroinflammatory, oxidative responses, and neuronal death. Furthermore, CBD can reduce the accumulation of Aβ and hyperphosphorylation of tau, suggesting the possibility of delaying AD progression. Particularly, the noncannabinoid receptor, peroxisome proliferator-activated receptor gamma, has been suggested to be involved in multiple functions of CBD. Therefore, understanding the underlying mechanisms of CBD is necessary for intervening in AD pathology in depth and for the translation of preclinical studies into clinical settings. In this review, we summarize recent studies on the effect of CBD in AD and suggest problems to be overcome for the therapeutic use of CBD.”

https://pubmed.ncbi.nlm.nih.gov/34573232/

https://www.mdpi.com/2076-3425/11/9/1211