The gut microbiota in neurodegenerative diseases: revisiting possible therapeutic targets for cannabidiol

Posted on December 23, 2022 by David

Heliyon | Journal | ScienceDirect.com by Elsevier

“Understanding the pathophysiology of Alzheimer’s disease (AD) is essential to improve the efficacy of treatments and, consequently, patients’ lives. Unfortunately, traditional therapeutic strategies have not been effective. There is therefore an urgent need to discover or develop alternative treatment strategies.

Recently, some pieces of the puzzle appear to emerge: on a hand, the gut microbiota (GM) has gained attention since intestinal dysbiosis aggravates and generates some of the pathological processes of AD; on the other hand, cannabidiol (CBD), a phytocannabinoid, attenuates intestinal inflammation and possesses neuroprotective properties.

Intestinal dysbiosis (increased population of proinflammatory bacteria) in AD increases plasma lipopolysaccharide and Aβ peptide levels, both responsible for increasing the permeability of the blood-brain barrier (BBB). A leaky BBB may facilitate the entry of peripheral inflammatory mediators into the central nervous system and ultimately aggravate neuroinflammation and neuronal death due to chronic activation of glial cells. Studies investigating the GM reported a strong relationship between intestinal dysbiosis and AD. In this review we conjecture that the GM is a promising therapeutic target for CBD in the context of AD.”

https://pubmed.ncbi.nlm.nih.gov/36544841/

https://www.cell.com/heliyon/fulltext/S2405-8440(22)03460-0?_returnURL=https%3A%2F%2Flinkinghub.elsevier.com%2Fretrieve%2Fpii%2FS2405844022034600%3Fshowall%3Dtrue

Cannabidiol Protects Striatal Neurons by Attenuating Endoplasmic Reticulum Stress

Posted on December 3, 2022 by David

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“Introduction: The aggregation of misfolded proteins in the endoplasmic reticulum (ER) is a pathological trait shared by many neurodegenerative disorders. This aggregation leads to the persistent activation of the unfolded protein response (UPR) and ultimately apoptosis as a result of ER stress. Cannabidiol (CBD) has been demonstrated to be neuroprotective in various cellular and animal models of neurodegeneration, which has been attributed to its antioxidant and anti-inflammatory properties. However, little is known about the role of CBD in the context of protein folding and ER stress. The purpose of this study was to investigate whether CBD is neuroprotective against an in vitro model of ER stress.

Materials and Methods: Using different exposure models, mouse striatal STHdh^Q7/Q7 cells were exposed to either the ER stress inducer thapsigargin (TG) and/or CBD. Cell viabilities assays were used to investigate the effect of CBD pre-treatment, co-treatment, and post-treatment on TG-induced cell death. Real-time quantitative polymerase chain reaction was used to measure changes in ER stress regulators and UPR genes such as glucose-regulated protein-78 (GRP78), mesencephalic astrocyte-derived neurotrophic factor (MANF), B cell lymphoma 2 (BCL-2), BCL-2 interacting mediator of cell death (BIM), and caspase-12.

Results: Cell viability increased significantly when cells were pre-treated with CBD before TG exposure. An increase in the gene expression of pro-survival ER chaperone GRP78 and ER-resident neurotrophic factor MANF coincided with this effect and decreased ER-mediated pro-apoptotic markers such as BIM, and caspase-12 was observed.

Conclusions: These data suggest that CBD pre-treatment is neuroprotective against TG-induced cell death. Understanding the role of ER stress in CBD-driven neuroprotection provides insight into the therapeutic potential of CBD and the role of ER dysfunction in neurodegenerative disorders.”

https://pubmed.ncbi.nlm.nih.gov/36454179/

https://www.liebertpub.com/doi/10.1089/can.2022.0090

Cannabidiol for neurodegenerative disorders: A comprehensive review

Posted on November 18, 2022 by David

“Despite the significant advances in neurology, the cure for neurodegenerative conditions remains a formidable task to date. Among various factors arising from the complex etiology of neurodegenerative diseases, neuroinflammation and oxidative stress play a major role in pathogenesis. To this end, some phytocannabinoids isolated from Cannabis sativa (widely known as marijuana) have attracted significant attention as potential neurotherapeutics. The profound effect of ∆⁹-tetrahydrocannabinol (THC), the major psychoactive component of cannabis, has led to the discovery of the endocannabinoid system as a molecular target in the central nervous system (CNS). Cannabidiol (CBD), the major non-psychoactive component of cannabis, has recently emerged as a potential prototype for neuroprotective drug development due to its antioxidant and anti-inflammatory properties and its well-tolerated pharmacological behavior. This review briefly discusses the role of inflammation and oxidative stress in neurodegeneration and demonstrates the neuroprotective effect of cannabidiol, highlighting its general mechanism of action and disease-specific pathways in Parkinson’s disease (PD) and Alzheimer’s disease (AD). Furthermore, we have summarized the preclinical and clinical findings on the therapeutic promise of CBD in PD and AD, shed light on the importance of determining its therapeutic window, and provide insights into identifying promising new research directions.”

https://pubmed.ncbi.nlm.nih.gov/36386183/

https://www.frontiersin.org/articles/10.3389/fphar.2022.989717/full

Virtual Screening and In Vitro Experiments Highlight Cannabidiol as a Drug-like Phosphodiesterase 9 Inhibitor

Posted on November 16, 2022 by David

“The growing interest on the therapeutic potential against neurodegeneration of Cannabis sativa extracts, and of phytocannabinoids in particular, is paralleled by a limited understanding of the undergoing biochemical pathways in which these natural compounds may be involved. Computational tools are nowadays commonly enrolled in the drug discovery workflow and can guide the investigation of macromolecular targets for such molecules. In this contribution, in silico techniques have been applied to the study of C. sativa constituents at various extents, and a total of 7 phytocannabinoids and 4 terpenes were considered. On the side of ligand-based virtual screening, physico-chemical descriptors were computed and evaluated, highlighting the phytocannabinoids possessing suitable drug-like properties to potentially target the central nervous system. Our previous findings and literature data prompted us to investigate the interaction of these molecules with phosphodiesterases (PDEs), a family of enzymes being studied for the development of therapeutic agents against neurodegeneration. Among the compounds, structure-based techniques such as docking and molecular dynamics (MD), highlighted cannabidiol (CBD) as a potential and selective PDE9 ligand, since a promising calculated binding energy value (-9.1 kcal/mol) and a stable interaction in the MD simulation timeframe were predicted. Additionally, PDE9 inhibition assay confirmed the computational results, and showed that CBD inhibits the enzyme in the nanomolar range in vitro, paving the way for further development of this phytocannabinoid as a therapeutic option against neurodegeneration.”

https://pubmed.ncbi.nlm.nih.gov/36382587/

https://onlinelibrary.wiley.com/doi/10.1111/ejn.15869

Promising Action of Cannabinoids on ER Stress-Mediated Neurodegeneration: An In Silico Investigation

Posted on November 15, 2022 by David

“Neurodegeneration has been recognized as a clinical episode characterized by neuronal death, including dementia, cognitive impairment and movement disorder. Most of the neurodegenerative deficits, via clinical symptoms, includes common pathogenic features as protein misfolding and aggregation. Therefore, the focus highlights the cellular organelle endoplasmic reticulum (ER) critically linked with the quality control and protein homeostasis. Unfolded protein response (UPR) or ER stress have also been considered as hallmarks for neurodegenerative disorders. It has been implicated that the levels of endocannabinoids (ECB) could rise at the platform of neurodegeneration. In addition, phytocannabinoids (PCB) including cannabidiol (CBD) could also initiate the IRE1, PERK, XBP-1, and ATF6, pathways that could lead to the degradation of the misfolded proteins and termination of protein translation. Thus, our aim was to determine if cannabinoids bind to these ER arm proteins involved in UPR by molecular docking and therefore determine its drug resemblance through ADME analysis. In our study, three cannabinoid receptors (CB1, CB2, and CB3) were considered to demonstrate their neuroprotective actions. The chosen ligands were screened as PCB (Δ9-tetrahydrocannabinol or THC), CBD, and two ECB, anandamide (AEA) and 2-arachidonoylglycerol (2-AG). The current findings have advocated that the cannabinoids and their molecular targets have shown considerable binding and their ADME properties also reveals that they possess moderate drug-like properties making it as a valuable option for the treatment and management of neurodegenerative diseases.”

https://pubmed.ncbi.nlm.nih.gov/36374961/

https://dl.begellhouse.com/journals/0ff459a57a4c08d0,6b57eefe5f7fdc1a,560f019e6ae36432.html

The Therapeutic Potential of the Endocannabinoid System in Age-Related Diseases

Posted on October 28, 2022 by David

“The endocannabinoid system (ECS) dynamically regulates many aspects of mammalian physiology. ECS has gained substantial interest since growing evidence suggests that it also plays a major role in several pathophysiological conditions due to its ability to modulate various underlying mechanisms. Furthermore, cannabinoids, as components of the cannabinoid system (CS), have proven beneficial effects such as anti-inflammatory, immunomodulatory, neuromodulatory, antioxidative, and cardioprotective effects. In this comprehensive review, we aimed to describe the complex interaction between CS and most common age-related diseases such as neuro-degenerative, oncological, skeletal, and cardiovascular disorders, together with the potential of various cannabinoids to ameliorate the progression of these disorders. Since chronic inflammation is postulated as the pillar of all the above-mentioned medical conditions, we also discuss in this paper the potential of CS to ameliorate aging-associated immune system dysregulation.”

https://pubmed.ncbi.nlm.nih.gov/36289755/

“The cannabinoid system has the potential to ameliorate different underlying mechanism involved in the progression of aging-related diseases. Additionally, ECS may represent a promising approach not only for the treatment, but also for the alleviation of age-related disorder-associated symptoms and/or for increasing the efficacy of existing drugs. Moreover, our findings show that cannabinoids may be able to modulate various mechanisms rather than targeting a single dysregulated pathway in age-related diseases. Natural as well as synthetic cannabinoids ameliorate the balance between neurodegeneration and neuroinflammation in neurodegenerative diseases. In addition, they may play an important role in modulating the complex physio-pathology of MS and may be used as immune modulators, neuroprotectors, or remyelination promoters. The modulation of pro-inflammatory cytokines through the endogenous cannabinoid system may have beneficial effects on MS, AD, PD, aging-related musculoskeletal changes, and CVDs. On the other hand, it is clearly now that targeting the ECS with various natural or synthetic compounds may have the theoretical potential of an improved control of cancer progression.”

https://www.mdpi.com/2227-9059/10/10/2492/htm

Effect of Cannabidiolic Acid, N- Trans-Caffeoyltyramine and Cannabisin B from Hemp Seeds on microRNA Expression in Human Neural Cells

Posted on October 27, 2022 by David

“Given the increasing interest in bioactive dietary components that can modulate gene expression enhancing human health, three metabolites isolated from hemp seeds-cannabidiolic acid, N–trans-caffeoyltyramine, and cannabisin B-were examined for their ability to change the expression levels of microRNAs in human neural cells. To this end, cultured SH-SY5Y cells were treated with the three compounds and their microRNA content was characterized by next-generation small RNA sequencing. As a result, 31 microRNAs underwent major expression changes, being at least doubled or halved by the treatments. A computational analysis of the biological pathways affected by these microRNAs then showed that some are implicated in neural functions, such as axon guidance, hippocampal signaling, and neurotrophin signaling. Of these, miR-708-5p, miR-181a-5p, miR-190a-5p, miR-199a-5p, and miR-143-3p are known to be involved in Alzheimer’s disease and their expression changes are expected to ameliorate neural function. Overall, these results provide new insights into the mechanism of action of hemp seed metabolites and encourage further studies to gain a better understanding of their biological effects on the central nervous system.”

https://pubmed.ncbi.nlm.nih.gov/36286061/

https://www.mdpi.com/1467-3045/44/10/347/htm

Targeting the cannabinoid system to counteract the deleterious effects of stress in Alzheimer’s disease

Posted on October 22, 2022 by David

“Alzheimer’s disease is a progressive neurodegenerative disorder characterized histologically in postmortem human brains by the presence of dense protein accumulations known as amyloid plaques and tau tangles. Plaques and tangles develop over decades of aberrant protein processing, post-translational modification, and misfolding throughout an individual’s lifetime. We present a foundation of evidence from the literature that suggests chronic stress is associated with increased disease severity in Alzheimer’s patient populations. Taken together with preclinical evidence that chronic stress signaling can precipitate cellular distress, we argue that chronic psychological stress renders select circuits more vulnerable to amyloid- and tau- related abnormalities. We discuss the ongoing investigation of systemic and cellular processes that maintain the integrity of protein homeostasis in health and in degenerative conditions such as Alzheimer’s disease that have revealed multiple potential therapeutic avenues. For example, the endogenous cannabinoid system traverses the central and peripheral neural systems while simultaneously exerting anti-inflammatory influence over the immune response in the brain and throughout the body. Moreover, the cannabinoid system converges on several stress-integrative neuronal circuits and critical regions of the hypothalamic-pituitary-adrenal axis, with the capacity to dampen responses to psychological and cellular stress. Targeting the cannabinoid system by influencing endogenous processes or exogenously stimulating cannabinoid receptors with natural or synthetic cannabis compounds has been identified as a promising route for Alzheimer’s Disease intervention. We build on our foundational framework focusing on the significance of chronic psychological and cellular stress on the development of Alzheimer’s neuropathology by integrating literature on cannabinoid function and dysfunction within Alzheimer’s Disease and conclude with remarks on optimal strategies for treatment potential.”

https://pubmed.ncbi.nlm.nih.gov/36268196/

https://www.frontiersin.org/articles/10.3389/fnagi.2022.949361/full

Evaluation of cannabinoid type 2 receptor expression and pyridine-based radiotracers in brains from a mouse model of Alzheimer’s disease

Posted on October 17, 2022 by David

“Neuroinflammation plays an important role in the pathophysiology of Alzheimer’s disease. The cannabinoid type 2 receptor (CB₂R) is an emerging target for neuroinflammation and therapeutics of Alzheimer’s disease. Here, we aim to assess the alterations in brain CB₂R levels and evaluate novel CB₂R imaging tracers in the arcAß mouse model of Alzheimer’s disease amyloidosis. Immunohistochemical staining for amyloid-ß deposits (6E10), microgliosis (anti-Iba1 and anti-CD68 antibodies), astrocytes (GFAP) and the anti-CB₂R antibody was performed on brain slices from 17-month-old arcAß mice. Autoradiography using the CB₂R imaging probes [¹⁸F]RoSMA-18-d6, [¹¹C]RSR-056, and [¹¹C]RS-028 and mRNA analysis were performed in brain tissue from arcAß and non-transgenic littermate (NTL) mice at 6, 17, and 24 months of age. Specific increased CB₂R immunofluorescence intensities on the increased number of GFAP-positive astrocytes and Iba1-positive microglia were detected in the hippocampus and cortex of 17-month-old arcAß mice compared to NTL mice. CB₂R immunofluorescence was higher in glial cells inside 6E10-positive amyloid-ß deposits than peri-plaque glial cells, which showed low background immunofluorescence in the hippocampus and cortex of 17-month-old arcAß mice. Ex vivo autoradiography showed that the specific binding of [¹⁸F]RoSMA-18-d6 and [¹¹C]RSR-056 was comparable in arcAß and NTL mice at 6, 17, and 24 months of age. The level of Cnr2 mRNA expression in the brain was not significantly different between arcAß and NTL mice at 6, 17, or 24 months of age. In conclusion, we demonstrated pronounced specific increases in microglial and astroglial CB₂R expression levels in a mouse model of AD-related cerebral amyloidosis, emphasizing CB₂R as a suitable target for imaging neuroinflammation.”

https://pubmed.ncbi.nlm.nih.gov/36248003/

https://www.frontiersin.org/articles/10.3389/fnagi.2022.1018610/full

Effect of long-term cannabidiol on learning and anxiety in a female Alzheimer’s disease mouse model

Posted on October 14, 2022 by David

“Cannabidiol is a promising potential therapeutic for neurodegenerative diseases, including Alzheimer’s disease (AD).

Our laboratory has shown that oral CBD treatment prevents cognitive impairment in a male genetic mouse model of AD, the amyloid precursor protein 1 x presenilin 1 hemizygous (APPxPS1) mouse. However, as sex differences are evident in clinical populations and in AD mouse models, we tested the preventive potential of CBD therapy in female APPxPS1 mice.

In this study, 2.5-month-old female wildtype-like (WT) and APPxPS1 mice were fed 20 mg/kg CBD or a vehicle via gel pellets daily for 8 months and tested at 10.5 months in behavioural paradigms relevant to cognition (fear conditioning, FC; cheeseboard, CB; and novel object recognition test, NORT) and anxiety-like behaviours (elevated plus maze, EPM).

In the CB, CBD reduced latencies to find a food reward in APPxPS1 mice, compared to vehicle-treated APPxPS1 controls, and this treatment effect was not evident in WT mice. In addition, CBD also increased speed early in the acquisition of the CB task in APPxPS1 mice. In the EPM, CBD increased locomotion in APPxPS1 mice but not in WT mice, with no effects of CBD on anxiety-like behaviour. CBD had limited effects on the expression of fear memory.

These results indicate preventive CBD treatment can have a moderate spatial learning-enhancing effect in a female amyloid-β-based AD mouse model. This suggests CBD may have some preventive therapeutic potential in female familial AD patients.”

https://pubmed.ncbi.nlm.nih.gov/36238565/

“In conclusion, we found moderate effects of long-term oral CBD treatment on the acquisition of spatial learning by CBD in a female mouse model of familial AD. This suggests that preventive CBD may help limit some cognitive impairment in women with AD.”

https://www.frontiersin.org/articles/10.3389/fphar.2022.931384/full

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Category Archives: Alzheimer’s Disease (AD)