Category Archives: Amyotrophic lateral sclerosis (ALS) -Lou Gehrig’s disease

Cannabinol Regulates the Expression of Cell Cycle-Associated Genes in Motor Neuron-like NSC-34: A Transcriptomic Analysis

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“Cannabinoids are reported to have neuroprotective properties and play a role in neurogenesis and neuroplasticity in in vitro and in vivo models. Cannabinol (CBN) is a minor cannabinoid produced by the degradation of Δ9-tetrahydrocannabinol in Cannabis sativa L. and exhibits anti-oxidant, analgesic, anti-bacterial, and anti-inflammatory effects.

In this study, we explored the biological effects of 20 µM CBN (6.20 µg/mL) on differentiated NSC-34 cells by MTT assay and next-generation sequencing analysis on the transcriptome. KEGG and Gene Ontology enrichment analyses have been performed to evaluate potential CBN-associated processes.

Our results highlighted the absence of any cytotoxic effect of CBN. The comparative transcriptomic analysis pointed out the downregulation of Cdkn2a, Cdkn2c and Cdkn2d genes, which are known to suppress the cell cycle. Ccne2, Cdk2, Cdk7, Anapc11, Anapc10, Cdc23, Cdc16, Anapc4, Cdc27, Stag1, Smc3, Smc1a, Nipbl, Pds5a, Pds5b, and Wapl genes, renowned for their role as cell cycle progression activators, were instead upregulated. Our work suggests that CBN regulates the expression of many genes related to the cell cycle, which are required for axonal maturation, migration, and synaptic plasticity, while not affecting the expression of genes involved in cell death or tumorigenesis.”

https://pubmed.ncbi.nlm.nih.gov/38927547/

“The results obtained could be a starting point for testing CBN on models of motor neuron diseases characterized by synaptic dysfunctions and aberrant reactivation of the cell cycle leading to cell death.”

https://www.mdpi.com/2227-9059/12/6/1340

Medicinal cannabis in neurodegenerative disorders: an open label, dose finding, safety and efficacy study

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“Aim: Currently, there exist no curative treatments for neurodegenerative disorders. Recently, there has been a resurgence of interest in the use of medicinal cannabis to improve neurological conditions. 

Methods: A 12-month, open label, dose-finding, safety and efficacy study was conducted including 48 subjects with a variety of neurodegenerative disorders. 

Results: In our participants, we observed a reduction in pain, improved sleep, enhanced well-being and less agitation. 

Conclusion: Our findings suggest that medicinal cannabis might be useful in patients with neurodegenerative disorders in controlling pain, enhancing sleep, reducing difficult behaviors, controlling unusual and complex symptoms when other treatments have failed – this offers medicinal cannabis a role in palliation.”

https://pubmed.ncbi.nlm.nih.gov/38639578/

The Therapeutic Potential and Molecular Mechanisms Underlying the Neuroprotective Effects of Sativex® – A Cannabis-derived Spray

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“Sativex is a cannabis-based medicine that comes in the form of an oromucosal spray. It contains equal amounts of Δ9-tetrahydrocannabinol and cannabidiol, two compounds derived from cannabis plants.

Sativex has been shown to have positive effects on symptoms of amyotrophic lateral sclerosis (ALS), multiple sclerosis (MS), and sleep disorders. It also has analgesic, antiinflammatory, antitumoral, and neuroprotective properties, which make it a potential treatment option for other neurological disorders.

The article reviews the results of recent preclinical and clinical studies that support the therapeutic potential of Sativex and the molecular mechanisms behind its neuroprotective benefits in various neurological disorders. The article also discusses the possible advantages and disadvantages of using Sativex as a neurotherapeutic agent, such as its safety, efficacy, availability, and legal status.”

https://pubmed.ncbi.nlm.nih.gov/38318827/

https://www.eurekaselect.com/article/138318

Cannabis for the treatment of amyotrophic lateral sclerosis: What is the patients’ view?

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“Cannabis may have therapeutic benefits to relieve symptoms of amyotrophic lateral sclerosis (ALS) thanks to its pleiotropic pharmacological activity. This study is the first to present a large questionnaire-based survey about the “real-life” situation regarding cannabis use in the medical context in ALS patients in France. There were 129 respondents and 28 reported the use of cannabis (21.7%) to relieve symptoms of ALS. Participants mostly reported the use of cannabidiol (CBD) oil and cannabis weed and declared benefits both on motor (rigidity, cramps, fasciculations) and non-motor (sleep quality, pain, emotional state, quality of life, depression) symptoms and only eight reported minor adverse reactions (drowsiness, euphoria and dry mouth). Even if cannabis is mostly used outside medical pathways and could expose patients to complications (street and uncontrolled drugs, drug-drug interactions, adverse effects…), most of the participants reported “rational” consumption (legal cannabinoids, with only few combustion and adverse reactions). Despite some limitations, this study highlights the need for further research on the potential benefits of cannabis use for the management of ALS motor and non-motor symptoms. Indeed, there is an urgent need and call for and from patients to know more about cannabis and secure its use in a medical context.”

https://pubmed.ncbi.nlm.nih.gov/37460332/

https://www.sciencedirect.com/science/article/abs/pii/S0035378723009712?via%3Dihub

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


Effects of Cannabidiol in a Caenorhabditis Elegans Amyotrophic Lateral Sclerosis Model

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“Amyotrophic Lateral Sclerosis (ALS) is a fatal neurodegenerative disease caused by the progressive death of motor neurons. Cannabidiol, the second most prevalent cannabinoid in the Cannabis sativa plant, is a potential therapeutic tool for ALS due to its antioxidant, anti-inflammatory, and anti-spasticity effects, as well as its complementary role in treating other neurodegenerative diseases. In SOD1-G93A murine ALS models, cannabinoids have been shown to slow disease progression, extending lifespan and increasing motor function. However, the effects of specific cannabinoids-including cannabidiol-are yet undefined and their functions slowing disease progression are unknown. To advance this understanding we aim to study the effects of cannabidiol treatment in a Caenorhabditis elegans ALS model: a SOD-1 mutant transgenic strain with SOD-1 aggregation in muscular cells. We will use a death assay to measure the lifespan of SOD-1 mutant C. elegans and cannabidiol-treated SOD-1 mutant C. elegans to investigate whether treatment with cannabidiol impacts the lifespan of SOD-1 mutants. To assess mechanosensation, we will touch C. elegans with sutures of various sizes, based on the Von Frey filaments touch response assay in humans. We will develop a novel computational analysis system to measure C. elegans movement in response to touch. We will then compare the motor response of the SOD-1 mutant transgenic strain to wild type and study if cannabidiol modulates a possible change in motor response. This study will evaluate the functions of cannabidiol as a potential therapeutic tool in ALS using a SOD-1 mutant C. elegans model.”

https://pubmed.ncbi.nlm.nih.gov/35555765/

https://faseb.onlinelibrary.wiley.com/doi/10.1096/fasebj.2022.36.S1.0R317

Cannabinoids for the treatment of refractory neuropathic pruritus in amyotrophic lateral sclerosis: A case report

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Journals | SAGE Publications Inc“Background: Neuropathic symptoms have a wide variety of manifestations, ranging from pain to pruritus. Neuropathic pruritus is a type of chronic pruritus related to damaged small fibers. Cannabinoids have evidence to manage neuropathic symptoms. We present a case of refractory neuropathic pruritus that was successfully managed with the use of oral cannabinoids.

Case presentation: A 60-year-old male with amyotrophic lateral sclerosis with ongoing pruritus despite the use of standard neuropathic therapies.

Formulation of a plan: A balanced oral cannabinoid from a licensed producer was preferred as it has evidence for neuropathic symptoms and is generally well tolerated.

Outcome: The patient showed improvement to his pruritus score from 7/10 to 3/10. There was initial increased sedation but tolerance developed quickly.

Lessons learned from case: Cannabinoids are possibly safe and effective in management of neuropathic pruritus.”

https://pubmed.ncbi.nlm.nih.gov/34510973/

“Neuropathic pruritus is a chronic form of pruritus that causes significant symptom burden and can be difficult to treat. Cannabinoids have evidence to manage chronic neuropathic pain. This case demonstrates the safe and effective use of cannabinoids to manage neuropathic pruritus.”

https://journals.sagepub.com/doi/10.1177/02692163211045314

The Endocannabinoid System: A Potential Target for the Treatment of Various Diseases

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ijms-logo“The Endocannabinoid System (ECS) is primarily responsible for maintaining homeostasis, a balance in internal environment (temperature, mood, and immune system) and energy input and output in living, biological systems.

In addition to regulating physiological processes, the ECS directly influences anxiety, feeding behaviour/appetite, emotional behaviour, depression, nervous functions, neurogenesis, neuroprotection, reward, cognition, learning, memory, pain sensation, fertility, pregnancy, and pre-and post-natal development.

The ECS is also involved in several pathophysiological diseases such as cancer, cardiovascular diseases, and neurodegenerative diseases. In recent years, genetic and pharmacological manipulation of the ECS has gained significant interest in medicine, research, and drug discovery and development.

The distribution of the components of the ECS system throughout the body, and the physiological/pathophysiological role of the ECS-signalling pathways in many diseases, all offer promising opportunities for the development of novel cannabinergic, cannabimimetic, and cannabinoid-based therapeutic drugs that genetically or pharmacologically modulate the ECS via inhibition of metabolic pathways and/or agonism or antagonism of the receptors of the ECS. This modulation results in the differential expression/activity of the components of the ECS that may be beneficial in the treatment of a number of diseases.

This manuscript in-depth review will investigate the potential of the ECS in the treatment of various diseases, and to put forth the suggestion that many of these secondary metabolites of Cannabis sativa L. (hereafter referred to as “C. sativa L.” or “medical cannabis”), may also have potential as lead compounds in the development of cannabinoid-based pharmaceuticals for a variety of diseases.”

https://pubmed.ncbi.nlm.nih.gov/34502379/

https://www.mdpi.com/1422-0067/22/17/9472

 

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

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7830475/

Emerging potential of cannabidiol in reversing proteinopathies

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Ageing Research Reviews “The aberrant accumulation of disease-specific protein aggregates accompanying cognitive decline is a pathological hallmark of age-associated neurological disorders, also termed as proteinopathies, including Alzheimer’s disease, Parkinson’s disease, Huntington’s disease, amyotrophic lateral sclerosis and multiple sclerosis.

Along with oxidative stress and neuroinflammation, disruption in protein homeostasis (proteostasis), a network that constitutes protein surveillance system, plays a pivotal role in the pathobiology of these dementia disorders.

Cannabidiol, a non-psychotropic phytocannabinoid of Cannabis sativa, is known for its pleiotropic neuropharmacological effects on the central nervous system, including the ability to abate oxidative stress, neuroinflammation, and protein misfolding. Over the past years, compelling evidence has documented disease-modifying role of cannabidiol in various preclinical and clinical models of neurological disorders, suggesting the potential therapeutic implications of cannabidiol in these disorders.

Because of its putative role in the proteostasis network in particular, cannabidiol could be a potent modulator for reversing not only age-associated neurodegeneration but also other protein misfolding disorders. However, the current understanding is insufficient to underpin this proposition. In this review, we discuss the potentiality of cannabidiol as a pharmacological modulator of the proteostasis network, highlighting its neuroprotective and aggregates clearing roles in the neurodegenerative disorders.

We anticipate that the current effort will advance our knowledge on the implication of CBD in proteostasis network, opening up a new therapeutic window for ageing proteinopathies.”

https://pubmed.ncbi.nlm.nih.gov/33181336/

“Cannabidiol reduces oxidative stress and neuroinflammation of brain.”

https://www.sciencedirect.com/science/article/pii/S1568163720303445?via%3Dihub

Cannabinoids and the expanded endocannabinoid system in neurological disorders.

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 Related image“Anecdotal evidence that cannabis preparations have medical benefits together with the discovery of the psychotropic plant cannabinoid Δ9-tetrahydrocannabinol (THC) initiated efforts to develop cannabinoid-based therapeutics.

These efforts have been marked by disappointment, especially in relation to the unwanted central effects that result from activation of cannabinoid receptor 1 (CB1), which have limited the therapeutic use of drugs that activate or inactivate this receptor.

The discovery of CB2 and of endogenous cannabinoid receptor ligands (endocannabinoids) raised new possibilities for safe targeting of this endocannabinoid system. However, clinical success has been limited, complicated by the discovery of an expanded endocannabinoid system – known as the endocannabinoidome – that includes several mediators that are biochemically related to the endocannabinoids, and their receptors and metabolic enzymes.

The approvals of nabiximols, a mixture of THC and the non-psychotropic cannabinoid cannabidiol, for the treatment of spasticity and neuropathic pain in multiple sclerosis, and of purified botanical cannabidiol for the treatment of otherwise untreatable forms of paediatric epilepsy, have brought the therapeutic use of cannabinoids and endocannabinoids in neurological diseases into the limelight.

In this Review, we provide an overview of the endocannabinoid system and the endocannabinoidome before discussing their involvement in and clinical relevance to a variety of neurological disorders, including Parkinson disease, Alzheimer disease, Huntington disease, multiple sclerosis, amyotrophic lateral sclerosis, traumatic brain injury, stroke, epilepsy and glioblastoma.”

https://www.ncbi.nlm.nih.gov/pubmed/31831863

“The existence of the endocannabinoidome explains in part why some non-euphoric cannabinoids, which affect several endocannabinoidome proteins, are useful for the treatment of neurological disorders, such as multiple sclerosis and epilepsy.”

https://www.nature.com/articles/s41582-019-0284-z