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

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

Could the Combination of Two Non-Psychotropic Cannabinoids Counteract Neuroinflammation? Effectiveness of Cannabidiol Associated with Cannabigerol.

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medicina-logo“Neuroinflammation is associated with many neurodegenerative diseases, including amyotrophic lateral sclerosis (ALS). In this study, we investigate the anti-inflammatory, anti-oxidant, and anti-apoptotic properties of two non-psychoactive phytocannabinoids, cannabigerol (CBG) and cannabidiol (CBD).

Results: Pre-treatment with CBG (at 2.5 and 5 µM doses) alone and in combination with CBD (at 2.5 and 5 µM doses) was able to reduce neuroinflammation induced by a culture medium of LPS-stimulated macrophages. In particular, the pre-treatment with CBD at a 5 µM dose decreased TNF-α levels and increased IL10 and IL-37 expression. CBG-CBD association at a 5 µM dose also reduced NF-kB nuclear factor activation with low degradation of the inhibitor of kappaB alpha (IkBα). CBG and CBD co-administered at a 5 µM dose decreased iNOS expression and increased Nrf2 levels. Furthermore, the pre-treatment with the association of two non-psychoactive cannabinoids downregulated Bax protein expression and upregulated Bcl-2 expression. Our data show the anti-inflammatory, anti-oxidant, and anti-apoptotic effects PPARγ-mediated.

Conclusions: Our results provide preliminary support on the potential therapeutic application of a CBG-CBD combination for further preclinical studies.”

https://www.ncbi.nlm.nih.gov/pubmed/31752240

https://www.mdpi.com/1010-660X/55/11/747

Study protocol for a randomised, double-blind, placebo-controlled study evaluating the Efficacy of cannabis-based Medicine Extract in slowing the disease pRogression of Amyotrophic Lateral sclerosis or motor neurone Disease: the EMERALD trial.

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Image result for bmj open“Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disorder with no known cure and with an average life expectancy of 3-5 years post diagnosis.

The use of complementary medicine such as medicinal cannabis in search for a potential treatment or cure is common in ALS.

Preclinical studies have demonstrated the efficacy of cannabinoids in extending the survival and slowing of disease progression in animal models with ALS.

There are anecdotal reports of cannabis slowing disease progression in persons with ALS (pALS) and that cannabis alleviated the symptoms of spasticity and pain.”

https://www.ncbi.nlm.nih.gov/pubmed/31719072

https://bmjopen.bmj.com/content/9/11/e029449

Real world experience of patients with amyotrophic lateral sclerosis (ALS) in the treatment of spasticity using tetrahydrocannabinol:cannabidiol (THC:CBD).

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Image result for bmc neurology“Treatment of spasticity poses a major challenge in amyotrophic lateral sclerosis (ALS) patient management.

Delta-9-tetrahydrocannabinol (THC):cannabidiol (CBD) oromucosal spray (THC:CBD), approved for the treatment of spasticity in multiple sclerosis, serves as a complementary off-label treatment option in ALS-related spasticity.

The mean dose THC:CBD were 5.5 daily actuations (range < 1 to 20). Three subgroups of patients were identified: 1) high-dose daily use (≥ 7 daily actuations, 34%, n = 11), 2) low-dose daily use (< 7 daily actuations, 50%, n = 16), 3) infrequent use (< 1 daily actuation, 16%, n = 5). Overall NPS was + 4.9 (values above 0 express a positive recommendation to fellow patients). Remarkably, patients with moderate to severe spasticity (NRS ≥ 4) reported a high recommendation rate (NPS: + 29) in contrast to patients with mild spasticity (NRS < 4; NPS: - 44). For the three main domains of TSQM-9 high mean satisfaction levels were found (maximum value 100): effectiveness 70.5 (±22.3), convenience 76.6 (±23.3) and global satisfaction 75.0 (±24.7).

CONCLUSION:

THC:CBD is used in a wide dose range suggesting that the drug was applied on the basis of individual patients’ needs and preferences. Contributing to this notion, moderate to severe spasticity was associated with an elevated number of daily THC:CBD actuations and stronger recommendation rate (NPS) as compared to patients with mild spasticity. Overall, treatment satisfaction (TSQM-9) was high. The results suggest that THC:CBD may serve as a valuable addition in the spectrum of symptomatic therapy in ALS. However, prospective studies and head-to-head comparisons to other spasticity medications are of interest to further explore the effectiveness of THC:CBD in the management of spasticity, and other ALS-related symptoms.”

 https://www.ncbi.nlm.nih.gov/pubmed/31493784
“Overall, patients reported outcomes as assessed by TSQM-9 revealed a high treatment satisfaction with THC:CBD. The results of our study suggest that THC:CBD may serve as an important addition to the spectrum of treatment options of spasticity in ALS.”
https://bmcneurol.biomedcentral.com/articles/10.1186/s12883-019-1443-y

The Endocannabinoid System, Our Universal Regulator

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Image result for journal of young investigators

“The endocannabinoid system (ECS) plays a very important role in the human body for our survival. This is due to its ability to play a critical role in maintaining the homeostasis of the human body, which encompasses the brain, endocrine, and immune system, to name a few. ECS is a unique system in multiple dimensions.

To begin with, it is a retrograde system functioning post- to pre-synapse, allowing it to be a “master regulator” in the body. Secondly, it has a very wide scope of influence due to an abundance of cannabinoid receptors located anywhere from immune cells to neurons. Finally, cannabinoids are rapidly synthesized and degraded, so they do not stay in the body for very long in high amounts, possibly enabling cannabinoid therapy to be a safer alternative to opioids or benzodiazepines. This paper will discuss how ECS functions through the regulation of neurotransmitter function, apoptosis, mitochondrial function, and ion-gated channels. The practical applications of the ECS, as well as the avenues for diseases such as epilepsy, cancer, amyotrophic lateral sclerosis (ALS), and autism, which have no known cure as of now, will be explored.

The ECS is one of the, if not the most, important systems in our body. Its role in the homeostatic function of our body is undeniable, and its sphere of influence is incredible. Additionally, it also plays a major role in apoptotic diseases, mitochondrial function, and brain function.

Its contribution is more than maintaining homeostasis; it also has a profound ability in regulation. Working in a retrograde fashion and with a generally inhibitory nature, ECS can act as a “kill switch.” However, it has been shown to play an inhibitory or stimulatory role based on the size of the influx of cannabinoids, resulting in a bimodal regulation. Furthermore, due to the nature of the rate of degradation of cannabinoids, it does not have as many long-term side effects as most of the current drugs on the market.

The ECS may not only provide answers for diseases with no known cures, but it could change the way we approach medicine. This system would allow us to change our focus from invasive pharmacological interventions (i.e. SSRIs for depression, benzodiazepines for anxiety, chemotherapies for cancer) to uncovering the mystery of why the body is failing to maintain homeostasis. Understanding the roles of ECS in these diseases confers a new direction for medicine which may eradicate the use of some of the less tolerable therapeutics.”

https://www.jyi.org/2018-june/2018/6/1/the-endocannabinoid-system-our-universal-regulator

Safety and efficacy of nabiximols on spasticity symptoms in patients with motor neuron disease (CANALS): a multicentre, double-blind, randomised, placebo-controlled, phase 2 trial.

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The Lancet Neurology

“Spasticity is a major determinant of disability and decline in quality of life in patients with motor neuron disease.

Cannabinoids have been approved for symptomatic treatment of spasticity in multiple sclerosis. We investigated whether cannabinoids might also reduce spasticity in patients with motor neuron disease.

Nabiximols was well tolerated, and no participants withdrew from the double-blind phase of the study. No serious adverse effects occurred.

INTERPRETATION:

In this proof-of-concept trial, nabiximols had a positive effect on spasticity symptoms in patients with motor neuron disease and had an acceptable safety and tolerability profile.” https://www.ncbi.nlm.nih.gov/pubmed/30554828 https://www.thelancet.com/journals/laneur/article/PIIS1474-4422(18)30406-X/fulltext]]>

Effects of cannabinoids in Amyotrophic Lateral Sclerosis (ALS) murine models: A systematic review and meta-analysis.

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“Amyotrophic Lateral Sclerosis (ALS) is a neurodegenerative disorder that results from motor neuron damage. Cannabinoids have been proposed as treatments for ALS due to their anti-excitotoxicity, anti-oxidant, and anti-inflammatory effects. This review provides some evidence for the efficacy of cannabinoids in prolonging survival time in an ALS mouse model. A delay in disease progression is also suggested following cannabinoid treatment” https://www.ncbi.nlm.nih.gov/pubmed/30520038 https://onlinelibrary.wiley.com/doi/abs/10.1111/jnc.14639 “The endocannabinoid system in amyotrophic lateral sclerosis. There is increasing evidence that cannabinoids and manipulation of the endocannabinoid system may have therapeutic value in ALS, in addition to other neurodegenerative conditions. Cannabinoids exert anti-glutamatergic and anti-inflammatory actions through activation of the CB(1) and CB(2) receptors, respectively. Cannabinoid agents may also exert anti-oxidant actions by a receptor-independent mechanism. Therefore the ability of cannabinoids to target multiple neurotoxic pathways in different cell populations may increase their therapeutic potential in the treatment of ALS.”  https://www.ncbi.nlm.nih.gov/pubmed/18781981 http://www.thctotalhealthcare.com/category/amyotrophic-lateral-sclerosis-als-lou-gehrigs-disease/]]>

Antiapoptotic effects of cannabidiol in an experimental model of cognitive decline induced by brain iron overload.

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Image result for translational psychiatry “Iron accumulation in the brain has been recognized as a common feature of both normal aging and neurodegenerative diseases. Cognitive dysfunction has been associated to iron excess in brain regions in humans. We have previously described that iron overload leads to severe memory deficits, including spatial, recognition, and emotional memory impairments in adult rats. In the present study we investigated the effects of neonatal iron overload on proteins involved in apoptotic pathways, such as Caspase 8, Caspase 9, Caspase 3, Cytochrome c, APAF1, and PARP in the hippocampus of adult rats, in an attempt to establish a causative role of iron excess on cell death in the nervous system, leading to memory dysfunction. Cannabidiol (CBD), the main non-psychotropic component of Cannabis sativa, was examined as a potential drug to reverse iron-induced effects on the parameters analyzed. These results suggest that iron can trigger cell death pathways by inducing intrinsic apoptotic proteins. The reversal of iron-induced effects by CBD indicates that it has neuroprotective potential through its anti-apoptotic action.”
 https://www.ncbi.nlm.nih.gov/pubmed/30177808
“In summary, we have shown that iron treatment in the neonatal period disrupts the apoptotic intrinsic pathway. This finding may place iron excess as a central component in neurodegenerative processes since many neurodegenerative disorders are accompanied by iron accumulation in brain regions. Moreover, indiscriminate iron supplementation to toddlers and infants, modeled here by iron overload in the neonatal period, has been considered a potential environmental risk factor for the development of neurodegenerative disorders later in life. Our findings also strongly suggest that CBD has neuroprotective effects, at least in part by blocking iron-induced apoptosis even at later stages, following iron overload, which puts CBD as a potential therapeutic agent in the treatment of neurodegenerative diseases.”
https://www.nature.com/articles/s41398-018-0232-5
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