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

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“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

Neuroprotection of Cannabidiol, Its Synthetic Derivatives and Combination Preparations against Microglia-Mediated Neuroinflammation in Neurological Disorders

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“The lack of effective treatment for neurological disorders has encouraged the search for novel therapeutic strategies. Remarkably, neuroinflammation provoked by the activated microglia is emerging as an important therapeutic target for neurological dysfunction in the central nervous system. In the pathological context, the hyperactivation of microglia leads to neuroinflammation through the release of neurotoxic molecules, such as reactive oxygen species, proteinases, proinflammatory cytokines and chemokines.

Cannabidiol (CBD) is a major pharmacologically active phytocannabinoids derived from Cannabis sativa L. CBD has promising therapeutic effects based on mounting clinical and preclinical studies of neurological disorders, such as epilepsy, multiple sclerosis, ischemic brain injuries, neuropathic pain, schizophrenia and Alzheimer’s disease.

A number of preclinical studies suggested that CBD exhibited potent inhibitory effects of neurotoxic molecules and inflammatory modulators, highlighting its remarkable therapeutic potential for the treatment of numerous neurological disorders. However, the molecular mechanisms of action underpinning CBD’s effects on neuroinflammation appear to be complex and are poorly understood.

This review summarises the anti-neuroinflammatory activities of CBD against various neurological disorders with a particular focus on their main molecular mechanisms of action, which were related to the downregulation of NADPH oxidase-mediated ROS, TLR4-NFκB and IFN-β-JAK-STAT pathways. We also illustrate the pharmacological action of CBD’s derivatives focusing on their anti-neuroinflammatory and neuroprotective effects for neurological disorders. We included the studies that demonstrated synergistic enhanced anti-neuroinflammatory activity using CBD and other biomolecules.

The studies that are summarised in the review shed light on the development of CBD, including its derivatives and combination preparations as novel therapeutic options for the prevention and/or treatment of neurological disorders where neuroinflammation plays an important role in the pathological components.”

https://pubmed.ncbi.nlm.nih.gov/35956911/

“Cannabinoids are a group of terpenophenolic compounds derived from the Cannabis sativa L. plant. The preclinical studies summarised in this review supported the therapeutic use of CBD in treating neurological disorders from its action in addressing microglia-mediated neuroinflammation. The findings of this review shed light on the development of CBD and relevant compounds as novel and more advantageous therapeutics to prevent or treat neurological disorders by targeting microglia-mediated neuroinflammation.”

https://www.mdpi.com/1420-3049/27/15/4961/htm


Endocannabinoid Modulation in Neurodegenerative Diseases: In Pursuit of Certainty

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“Neurodegenerative diseases are an increasing cause of global morbidity and mortality. They occur in the central nervous system (CNS) and lead to functional and mental impairment due to loss of neurons. Recent evidence highlights the link between neurodegenerative and inflammatory diseases of the CNS. These are typically associated with several neurological disorders. These diseases have fundamental differences regarding their underlying physiology and clinical manifestations, although there are aspects that overlap.

The endocannabinoid system (ECS) is comprised of receptors (type-1 (CB1R) and type-2 (CB2R) cannabinoid-receptors, as well as transient receptor potential vanilloid 1 (TRPV1)), endogenous ligands and enzymes that synthesize and degrade endocannabinoids (ECBs). Recent studies revealed the involvement of the ECS in different pathological aspects of these neurodegenerative disorders.

The present review will explore the roles of cannabinoid receptors (CBRs) and pharmacological agents that modulate CBRs or ECS activity with reference to Alzheimer’s Disease (AD), Parkinson’s Disease (PD), Huntington’s Disease (HD) and multiple sclerosis (MS).”

https://pubmed.ncbi.nlm.nih.gov/35336814/

“Neurodegenerative diseases represent an important cause of morbidity and mortality worldwide. Existing therapeutic options are limited and focus mostly on improving symptoms and reducing exacerbations. The endocannabinoid system is involved in the pathophysiology of such disorders, an idea which has been highlighted by recent scientific work. The current work focusses its attention on the importance and implications of this system and its synthetic and natural ligands in disorders such as Alzheimer’s, Parkinson’s, Huntington’s and multiple sclerosis.”

https://www.mdpi.com/2079-7737/11/3/440/htm


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

Archive of "Frontiers in Cellular Neuroscience". - PMC

“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


The Efficacy of Cannabis on Multiple Sclerosis-Related Symptoms

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“Multiple sclerosis (MS) is known as an autoimmune disease that damages the neurons in the central nervous system. MS is characterized by its most common symptoms of spasticity, muscle spasms, neuropathic pain, tremors, bladder dysfunction, dysarthria, and some intellectual problems, including memory disturbances. Several clinical studies have been conducted to investigate the effects of cannabis on the relief of these symptoms in MS patients. The efficacy of Cannabis sativa (C. Sativa) in the management of MS outcomes such as spasticity, pain, tremors, ataxia, bladder functions, sleep, quality of life, and adverse effects were assessed in this review.

Most clinical studies showed the positive effects of cannabinoids with their different routes of administration, such as oromucosal spray and oral form, in reducing most MS symptoms. The oromucosal spray Nabiximols demonstrated an improvement in reducing MS spasticity, pain, and quality of life with a tolerated adverse effect. Oral cannabinoids are significantly effective for treating MS pain and spasticity, while the other symptoms indicate slight improvement and the evidence is quite inconsistent. Oromucosal spray and oral cannabis are mainly used for treating patients with MS and have positive effects on treating the most common symptoms of MS, such as pain and spasticity, whereas the other MS symptoms indicated slight improvement, for which further studies are needed.”

https://pubmed.ncbi.nlm.nih.gov/35629350/

https://www.mdpi.com/2075-1729/12/5/682


Neurological Benefits, Clinical Challenges, and Neuropathologic Promise of Medical Marijuana: A Systematic Review of Cannabinoid Effects in Multiple Sclerosis and Experimental Models of Demyelination

“Despite current therapeutic strategies for immunomodulation and relief of symptoms in multiple sclerosis (MS), remyelination falls short due to dynamic neuropathologic deterioration and relapses, leading to accrual of disability and associated patient dissatisfaction. The potential of cannabinoids includes add-on immunosuppressive, analgesic, neuroprotective, and remyelinative effects. This study evaluates the efficacy of medical marijuana in MS and its experimental animal models. A systematic review was conducted by a literature search through PubMed, ProQuest, and EBSCO electronic databases for studies reported since 2007 on the use of cannabidiol (CBD) and delta-9-tetrahydrocannabinol (THC) in MS and in experimental autoimmune encephalomyelitis (EAE), Theiler’s murine encephalomyelitis virus-induced demyelinating disease (TMEV-IDD), and toxin-induced demyelination models. Study selection and data extraction were performed by 3 reviewers, and 28 studies were selected for inclusion. The certainty of evidence was appraised using the Cochrane GRADE approach. In clinical studies, there was low- and moderate-quality evidence that treatment with ~1:1 CBD/THC mixtures as a nabiximols (Sativex®) oromucosal spray reduced numerical rating scale (NRS) scores for spasticity, pain, and sleep disturbance, diminished bladder overactivity, and decreased proinflammatory cytokine and transcription factor expression levels. Preclinical studies demonstrated decreases in disease severity, hindlimb stiffness, motor function, neuroinflammation, and demyelination. Other experimental systems showed the capacity of cannabinoids to promote remyelination in vitro and by electron microscopy. Modest short-term benefits were realized in MS responders to adjunctive therapy with CBD/THC mixtures. Future studies are recommended to investigate the cellular and molecular mechanisms of cannabinoid effects on MS lesions and to evaluate whether medical marijuana can accelerate remyelination and retard the accrual of disability over the long term.”

https://pubmed.ncbi.nlm.nih.gov/35327341/

Δ 9 -Tetrahydrocannabinol promotes functional remyelination in the mouse brain

“Background and purpose: Research on demyelinating disorders aims to find novel molecules that are able to induce oligodendrocyte precursor cell differentiation to promote central nervous system remyelination and functional recovery. Δ9 -Tetrahydrocannabinol (THC), the most prominent active constituent of the hemp plant Cannabis sativa, confers neuroprotection in animal models of demyelination. However, the possible effect of THC on myelin repair has never been studied.

Experimental approach: By using oligodendroglia-specific reporter mouse lines in combination with two models of toxin-induced demyelination, we analysed the effect of THC on the processes of oligodendrocyte regeneration and functional remyelination.

Key results: We show that THC administration enhanced oligodendrocyte regeneration, white matter remyelination and motor function recovery. THC also promoted axonal remyelination in organotypic cerebellar cultures. THC remyelinating action relied on the induction of oligodendrocyte precursor differentiation upon cell cycle exit and via CB1 cannabinoid receptor activation.

Conclusions and implications: Overall, our study identifies THC administration as a promising pharmacological strategy aimed to promote functional CNS remyelination in demyelinating disorders.”

https://pubmed.ncbi.nlm.nih.gov/34216154/

Cannabis sativa L. as a Natural Drug Meeting the Criteria of a Multitarget Approach to Treatment

ijms-logo“Cannabis sativa L. turned out to be a valuable source of chemical compounds of various structures, showing pharmacological activity. The most important groups of compounds include phytocannabinoids and terpenes.

The pharmacological activity of Cannabis (in epilepsy, sclerosis multiplex (SM), vomiting and nausea, pain, appetite loss, inflammatory bowel diseases (IBDs), Parkinson’s disease, Tourette’s syndrome, schizophrenia, glaucoma, and coronavirus disease 2019 (COVID-19)), which has been proven so far, results from the affinity of these compounds predominantly for the receptors of the endocannabinoid system (the cannabinoid receptor type 1 (CB1), type two (CB2), and the G protein-coupled receptor 55 (GPR55)) but, also, for peroxisome proliferator-activated receptor (PPAR), glycine receptors, serotonin receptors (5-HT), transient receptor potential channels (TRP), and GPR, opioid receptors.

The synergism of action of phytochemicals present in Cannabis sp. raw material is also expressed in their increased bioavailability and penetration through the blood-brain barrier. This review provides an overview of phytochemistry and pharmacology of compounds present in Cannabis extracts in the context of the current knowledge about their synergistic actions and the implications of clinical use in the treatment of selected diseases.”

https://pubmed.ncbi.nlm.nih.gov/33466734/

https://www.mdpi.com/1422-0067/22/2/778

Δ 9 -Tetrahydrocannabinol promotes functional remyelination in the mouse brain

British Journal of Pharmacology“Background and purpose: Research on demyelinating disorders aims to find novel molecules that are able to induce oligodendrocyte precursor cell differentiation to promote central nervous system remyelination and functional recovery.

Δ9 -Tetrahydrocannabinol (THC), the most prominent active constituent of the hemp plant Cannabis sativa, confers neuroprotection in animal models of demyelination. However, the possible effect of THC on myelin repair has never been studied.

Experimental approach: By using oligodendroglia-specific reporter mouse lines in combination with two models of toxin-induced demyelination, we analysed the effect of THC on the processes of oligodendrocyte regeneration and functional remyelination.

Key results: We show that THC administration enhanced oligodendrocyte regeneration, white matter remyelination and motor function recovery. THC also promoted axonal remyelination in organotypic cerebellar cultures. THC remyelinating action relied on the induction of oligodendrocyte precursor differentiation upon cell cycle exit and via CB1 cannabinoid receptor activation.

Conclusions and implications: Overall, our study identifies THC administration as a promising pharmacological strategy aimed to promote functional CNS remyelination in demyelinating disorders.”

https://pubmed.ncbi.nlm.nih.gov/34216154/

“Our study provides a novel therapeutic advantage of THC-based interventions in multiple sclerosis by promoting remyelination and functional recovery. New clinical trials with improved designs on cannabinoids in people with multiple sclerosis are needed now, considering these compounds as potential remyelinating/disease-modifying drugs to try to overcome previous failures. Our work also suggests that at least part of the neuroprotective action of phytocannabinoids in multiple sclerosis animal models and potentially in patients as well may be due to an enhanced CNS remyelination. Finally, this study also identifies THC as a potent inductor of oligodendrocyte progenitor cell differentiation under demyelination in mice, opening the possibility for this molecule to become a candidate drug to promote oligodendrocyte regeneration and remyelination in the treatment of demyelinating disorders.”

https://bpspubs.onlinelibrary.wiley.com/doi/10.1111/bph.15608

Therapeutic Attributes of Endocannabinoid System against Neuro-Inflammatory Autoimmune Disorders

molecules-logo“In humans, various sites like cannabinoid receptors (CBR) having a binding affinity with cannabinoids are distributed on the surface of different cell types, where endocannabinoids (ECs) and derivatives of fatty acid can bind. The binding of these substance(s) triggers the activation of specific receptors required for various physiological functions, including pain sensation, memory, and appetite.

The ECs and CBR perform multiple functions via the cannabinoid receptor 1 (CB1); cannabinoid receptor 2 (CB2), having a key effect in restraining neurotransmitters and the arrangement of cytokines. The role of cannabinoids in the immune system is illustrated because of their immunosuppressive characteristics. These characteristics include inhibition of leucocyte proliferation, T cells apoptosis, and induction of macrophages along with reduced pro-inflammatory cytokines secretion.

The review seeks to discuss the functional relationship between the endocannabinoid system (ECS) and anti-tumor characteristics of cannabinoids in various cancers.

The therapeutic potential of cannabinoids for cancer-both in vivo and in vitro clinical trials-has also been highlighted and reported to be effective in mice models in arthritis for the inflammation reduction, neuropathic pain, positive effect in multiple sclerosis and type-1 diabetes mellitus, and found beneficial for treating in various cancers.

In human models, such studies are limited; thereby, further research is indispensable in this field to get a conclusive outcome. Therefore, in autoimmune disorders, therapeutic cannabinoids can serve as promising immunosuppressive and anti-fibrotic agents.”

https://pubmed.ncbi.nlm.nih.gov/34205169/

https://www.mdpi.com/1420-3049/26/11/3389