Category Archives: Muscular Dystrophy

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


Genetic and pharmacological regulation of the endocannabinoid CB1 receptor in Duchenne muscular dystrophy.

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 Nature Communications

“The endocannabinoid system refers to a widespread signaling system and its alteration is implicated in a growing number of human diseases.

However, the potential role of endocannabinoids in skeletal muscle disorders remains unknown. Here we report the role of the endocannabinoid CB1 receptors in Duchenne’s muscular dystrophy.

In murine and human models, CB1 transcripts show the highest degree of expression at disease onset, and then decline overtime. Similar changes are observed for PAX7, a key regulator of muscle stem cells. Bioinformatics and biochemical analysis reveal that PAX7 binds and upregulates the CB1 gene in dystrophic more than in healthy muscles.

Rimonabant, an antagonist of CB1, promotes human satellite cell differentiation in vitro, increases the number of regenerated myofibers, and prevents locomotor impairment in dystrophic mice.

In conclusion, our study uncovers a PAX7-CB1 cross talk potentially exacerbating DMD and highlights the role of CB1 receptors as target for potential therapies.”

https://www.ncbi.nlm.nih.gov/pubmed/30262909

“We propose that the endocannabinoid system participates in the development of degenerative muscle disease, through effects on muscle differentiation, regeneration, and repair processes, and suggest that CB1 receptor may represent a potential target for the adjuvant therapy of muscle dystrophies.”

https://www.nature.com/articles/s41467-018-06267-1

Effects of non-euphoric plant cannabinoids on muscle quality and performance of dystrophic mdx mice.

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“Duchenne muscular dystrophy (DMD), caused by dystrophin deficiency, results in chronic inflammation and irreversible skeletal muscle degeneration. Moreover, the associated impairment of autophagy leads to the accumulation of damaged intracellular organelles that greatly contribute to the aggravation of muscle damage.

We explored the possibility of using non-euphoric compounds present in Cannabis sativa, including cannabidiol (CBD), cannabidivarin (CBDV) and tetrahydrocannabidivarin (THCV) to reduce inflammation, restore functional autophagy and positively enhance muscle function in vivo.

We found that CBD and CBDV promote the differentiation of murine C2C12 myoblast cells into myotubes by increasing [Ca2+ ]i mostly via TRPV1 activation, an effect that undergoes rapid desensitization. CBD and CBDV also promoted the differentiation of myoblasts from DMD donors. In primary cultures prepared from satellite cells isolated from healthy donors, not only CBD and CBDV but also THCV promoted myotube formation, in this case mostly via TRPA1 activation. In mdx mice, CBD (60 mg Kg-1), CBDV (60 mg Kg-1 ) prevented the loss of locomotor activity at two distinct ages (from 5 to 7 and 32 to 34 weeks of age). This effect was associated with a reduction in tissue and plasma pro-inflammatory markers, together with the restoration of autophagy.

CONCLUSION AND IMPLICATIONS:

We provide new insights into plant cannabinoid interactions with TRP channels in skeletal muscle, highlighting a potential opportunity for novel co-adjuvant therapies to prevent muscle degeneration in DMD patients.”

https://www.ncbi.nlm.nih.gov/pubmed/30074247

ENDOCANNABINOID SYSTEM: A multi-facet therapeutic target.

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“Cannabis sativa is also popularly known as marijuana. It is being cultivated and used by man for recreational and medicinal purposes from many centuries.

Study of cannabinoids was at bay for very long time and its therapeutic value could not be adequately harnessed due to its legal status as proscribed drug in most of the countries.

The research of drugs acting on endocannabinoid system has seen many ups and down in recent past. Presently, it is known that endocannabinoids has role in pathology of many disorders and they also serve “protective role” in many medical conditions.

Several diseases like emesis, pain, inflammation, multiple sclerosis, anorexia, epilepsy, glaucoma, schizophrenia, cardiovascular disorders, cancer, obesity, metabolic syndrome related diseases, Parkinson’s disease, Huntington’s disease, Alzheimer’s disease and Tourette’s syndrome could possibly be treated by drugs modulating endocannabinoid system.

Presently, cannabinoid receptor agonists like nabilone and dronabinol are used for reducing the chemotherapy induced vomiting. Sativex (cannabidiol and THC combination) is approved in the UK, Spain and New Zealand to treat spasticity due to multiple sclerosis. In US it is under investigation for cancer pain, another drug Epidiolex (cannabidiol) is also under investigation in US for childhood seizures. Rimonabant, CB1 receptor antagonist appeared as a promising anti-obesity drug during clinical trials but it also exhibited remarkable psychiatric side effect profile. Due to which the US Food and Drug Administration did not approve Rimonabant in US. It sale was also suspended across the EU in 2008.

Recent discontinuation of clinical trial related to FAAH inhibitor due to occurrence of serious adverse events in the participating subjects could be discouraging for the research fraternity. Despite of some mishaps in clinical trials related to drugs acting on endocannabinoid system, still lot of research is being carried out to explore and establish the therapeutic targets for both cannabinoid receptor agonists and antagonists.

One challenge is to develop drugs that target only cannabinoid receptors in a particular tissue and another is to invent drugs that acts selectively on cannabinoid receptors located outside the blood brain barrier. Besides this, development of the suitable dosage forms with maximum efficacy and minimum adverse effects is also warranted.

Another angle to be introspected for therapeutic abilities of this group of drugs is non-CB1 and non-CB2 receptor targets for cannabinoids.

In order to successfully exploit the therapeutic potential of endocannabinoid system, it is imperative to further characterize the endocannabinoid system in terms of identification of the exact cellular location of cannabinoid receptors and their role as “protective” and “disease inducing substance”, time-dependent changes in the expression of cannabinoid receptors.”

http://www.ncbi.nlm.nih.gov/pubmed/27086601

Therapeutic potential of cannabinoid medicines.

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Drug Testing and Analysis

“Cannabis was extensively used as a medicine throughout the developed world in the nineteenth century but went into decline early in the twentieth century ahead of its emergence as the most widely used illicit recreational drug later that century. Recent advances in cannabinoid pharmacology alongside the discovery of the endocannabinoid system (ECS) have re-ignited interest in cannabis-based medicines.

The ECS has emerged as an important physiological system and plausible target for new medicines. Its receptors and endogenous ligands play a vital modulatory role in diverse functions including immune response, food intake, cognition, emotion, perception, behavioural reinforcement, motor co-ordination, body temperature, wake/sleep cycle, bone formation and resorption, and various aspects of hormonal control. In disease it may act as part of the physiological response or as a component of the underlying pathology.

In the forefront of clinical research are the cannabinoids delta-9-tetrahydrocannabinol and cannabidiol, and their contrasting pharmacology will be briefly outlined. The therapeutic potential and possible risks of drugs that inhibit the ECS will also be considered. This paper will then go on to review clinical research exploring the potential of cannabinoid medicines in the following indications: symptomatic relief in multiple sclerosis, chronic neuropathic pain, intractable nausea and vomiting, loss of appetite and weight in the context of cancer or AIDS, psychosis, epilepsy, addiction, and metabolic disorders.”

http://www.ncbi.nlm.nih.gov/pubmed/24006213

http://onlinelibrary.wiley.com/doi/10.1002/dta.1529/abstract

Muscular Dystrophy-Cannabinoids-Symptom Relief

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“Cannabinoids Help Muscular Dystrophy Symptoms: Cannabinoids are now known to have the capacity for neuromodulation, via direct, receptor-based mechanisms, at numerous levels within the nervous system. 

These provide therapeutic properties that may be applicable to the treatment of neurological disorders, including anti-oxidative, neuroprotective effects, analgesia, anti-inflammatory actions, immunomodulation, modulation of glial cells and tumor growth regulation. 

Beyond that, the cannabinoids have also been shown to be “remarkably safe with no potential for overdose.”

(vaporizing) Marijuana:

“miraculously improved his quality of life so much so that he left his family and friends in New Jersey to live in California, where he can readily get his medication.”

Sublingual (under the tongue)-tincture (alcohol based) or infused oil (olive or food grade glycerin or coconut)

Topicals (salves, ointments, balms) for muscle pain and spasms.

Cannabinoids:  increase appetite, analgesic (rid pain), muscle relaxant, saliva reduction, bronchodialation,  and sleep induction.

 

CBD-rich strains are best choice.  Sativa dominant x Indica.”

More: http://medicalmarijuana.com/medical-marijuana-treatments/MD

Medical Marijuana use for Muscular Dystrophy

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“Since he can’t use his arms Michael Oliveri’s mother Christiane assists him when drinking his green tea. Michael Oliveri, 25, is in a wheel chair due to muscular dystrophy.”

Medical Marijuana use for Muscular Dystrophy 

“After trying numerous medications in search for relief from tremendous pain, he tried medical marijuana, which he says miraculously improved his quality of life so much so that he left his family and friends in New Jersey to live in California, where his meds is legal and accessible.”
 
 

Medical Marijuana Patient Clayton Holton Tells His Story.

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“Clayton Holton uses marijuana to help fight Muscular Dystrophy. Help convince the New Hampshire legislature protect patients like Clayton!”

 

Video: http://www.youtube.com/watch?v=EQS3KEGtdBI

“Clayton Holton, 27, suffers from Duchenne Muscular Dystrophy (DMD), a genetic disorder characterized by degeneration of muscle tissue. This illness manifested itself in early childhood and robbed him of his ability to walk at age 10.  Clayton knows DMD will eventually claim his life, so the purpose of treatment is to keep him alive and help him enjoy a decent quality of life for as long as possible.

Clayton first experienced serious painkillers at age 16 when his wheelchair was struck by a car. The doctors gave him Vicodin. “I blacked out for a day and a half, and I don’t remember any of it,” he explained.

Soon after the wheelchair accident, Clayton tried marijuana as a substitute for Vicodin. The effects were entirely positive. Clayton was able to dramatically reduce his intake of painkillers, and as an added bonus, he found that marijuana took the edge off his anxiety and depression, stimulated his appetite, and helped him maintain a healthier weight.

In December, 2007, Clayton weighed less than 80 pounds.  He was living in a rest home and forced to use Oxycontin rather than marijuana to treat his pain.  Fortunately, in 2008 Clayton was able to visit California for an extended period of time; while there, he had access to high quality marijuana grown for medical use.  As a result, Clayton gained 8 pounds in a few months’ time and was able to stop relying on many of his prescription drugs.

Now that Clayton is back in his home state of New Hampshire, he is forced to use whatever marijuana he is able to procure via the black market.  To make matters worse, the government of his state considers him a common criminal for trying to treat his pain and stimulate his appetite.  He must choose between risking arrest and jail or relieving his suffering. If arrested, Clayton could face up to a year in jail simply for possessing the medicine that helps him live.”

More: http://nhcompassion.org/clayton_holton

“Sign this Petition to Help Medical Cannabis Patients. Here’s the petition, and here are Clayton’s own words on why you should sign it:

Because my weight is down to 63 pounds, and there are many other patients like me who can’t afford to wait.

As a 28-year-old battling muscular dystrophy, I’ve been fighting for my life since I lost my ability to walk at age 13.

I know from personal experience that medical marijuana works for me, having spent a summer in California several years ago. In the months that I was able to use it legally, I gained more than 10 pounds and was able to stop taking prescription pain medicines altogether. There is no cure for my condition, but medical marijuana relieves my pain and stimulates my appetite, dramatically improving my quality of life when I’m able to use it.

I have been asking New Hampshire legislators to allow patients like me to use medical marijuana for nearly a decade, and it finally appears that a medical marijuana bill is going to pass this year. Unfortunately, it appears this law may not be of any benefit to patients like me who are fighting for our lives.

HB 573, which passed overwhelmingly with over 80% support in the House, allows patients to access medical marijuana from one of five state-regulated alternative treatment centers or grow up to three cannabis plants for their own use. The House version of the bill also includes an affirmative defense that patients could raise in court so that they won’t be thrown in jail during the 19 months it will take for the health department to begin issuing ID cards.

The home grow option and full affirmative defense are very important because a patient or caregiver would be able to start growing this summer rather than waiting until at least 2015 for legal protections and access. Sadly, bowing to pressure from the police chiefs’ association, Gov. Maggie Hassan has now insisted that home cultivation be removed from the bill, meaning that patients will have no choice but to buy marijuana from criminals. Her administration also requested changes gutting the affirmative defense so that patients would have no legal protections at all until ID cards are available in late 2014 or early 2015.

This means patients will continue to suffer without legal access to marijuana and with no legal protections. Frankly, I do not expect to live another two years, so for me, this may as well be a death sentence.

Patients in Maine, Vermont, and lots of other states are allowed to cultivate their own plants, and many states have provided protections for patients while regulations are being crafted. Patients like me are NOT criminals, and we should be free to grow our own medicine in the “Live Free or Die” state. Please sign our petition and tell Gov. Hassan patients can’t afford to wait!

Additionally, please call her office at 603-271-2121 and let her know how you feel about this!”

More: http://freekeene.com/2013/05/24/sign-this-petition-to-help-medical-cannabis-patients/ 

The endocannabinoid system and its therapeutic exploitation.

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“The term ‘endocannabinoid’ – originally coined in the mid-1990s after the discovery of membrane receptors for the psychoactive principle in Cannabis, Delta9-tetrahydrocannabinol and their endogenous ligands – now indicates a whole signalling system that comprises cannabinoid receptors, endogenous ligands and enzymes for ligand biosynthesis and inactivation. This system seems to be involved in an ever-increasing number of pathological conditions. With novel products already being aimed at the pharmaceutical market little more than a decade since the discovery of cannabinoid receptors, the endocannabinoid system seems to hold even more promise for the future development of therapeutic drugs. We explore the conditions under which the potential of targeting the endocannabinoid system might be realized in the years to come.”  http://www.ncbi.nlm.nih.gov/pubmed/15340387

http://www.nature.com/nrd/journal/v3/n9/full/nrd1495.html

From cannabis to the endocannabinoid system: refocussing attention on potential clinical benefits.

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“Cannabis sativa is one of the oldest herbal remedies known to man. Over the past four thousand years, it has been used for the treatment of numerous diseases but due to its psychoactive properties, its current medicinal usage is highly restricted. In this review, we seek to highlight advances made over the last forty years in the understanding of the mechanisms responsible for the effects of cannabis on the human body and how these can potentially be utilized in clinical practice. During this time, the primary active ingredients in cannabis have been isolated, specific cannabinoid receptors have been discovered and at least five endogenous cannabinoid neurotransmitters (endocannabinoids) have been identified. Together, these form the framework of a complex endocannabinoid signalling system that has widespread distribution in the body and plays a role in regulating numerous physiological processes within the body. Cannabinoid ligands are therefore thought to display considerable therapeutic potential and the drive to develop compounds that can be targeted to specific neuronal systems at low enough doses so as to eliminate cognitive side effects remains the ‘holy grail’ of endocannabinoid research.”

http://www.ncbi.nlm.nih.gov/pubmed/23155985