Increasing cannabinoid levels by pharmacological and genetic manipulation delay disease progression in SOD1 mice.

“Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disorder characterized by the selective loss of motoneurons in the spinal cord, brain stem, and motor cortex. However, despite intensive research, an effective treatment for this disease remains elusive. In this study we show that treatment of postsymptomatic, 90-day-old SOD1G93A mice with a synthetic cannabinoid, WIN55,212-2, significantly delays disease progression…

Increasing evidence suggests that cannabinoids might have therapeutic potential in neurodegenerative conditions. In a variety of in vivo and in vitro models, cannabinoids exert neuroprotective effects under excitotoxic, ischemic, and inflammatory conditions. This combination of neuroprotective actions might be particularly relevant to ALS and suggests that cannabinoids might have a greater impact on disease progression than the established therapy that targets excitotoxicity alone.

… the neuroprotective effects observed following pharmacological and genetic augmentation of cannabinoid levels are not necessarily mediated by the CB1 receptor, and indeed inhibition of the CB1 receptor might actually be neuroprotective. Therefore, in contrast to previous studies that have suggested that cannabinoids exert neuroprotection via the CB1 receptor, the present results suggest that activation of CB2 receptors might underlie the beneficial effects of cannabinoids at least in SOD1G93A mice .”

Together these results show that cannabinoids have significant neuroprotective effects in this model of ALS and suggest that these beneficial effects may be mediated by non-CB1 receptor mechanisms.”

http://www.fasebj.org/content/20/7/1003.long

Endocannabinoids accumulate in spinal cord of SOD1 G93A transgenic mice.

Abstract

“Approximately 2% of amyotrophic lateral sclerosis (ALS) cases are caused by mutations in the super oxide dismutase 1 (SOD1) gene and transgenic mice for these mutations recapitulate many features of this devastating neurodegenerative disease. Here we show that the amount of anandamide (AEA) and 2-arachidonoylglycerol (2-AG), two endocannabinoids that have neuroprotective properties, increase in spinal cord of SOD1(G93A) transgenic mice. This increase occurs in the lumbar section of spinal cords, the first section to undergo neurodegeneration, and is significant before overt motor impairment. Our results show that chronic neurodegeneration induced by a genetic mutation increases endocannabinoid production possibly as part of an endogenous defense mechanism.”

http://www.ncbi.nlm.nih.gov/pubmed/15189359

The CB2 cannabinoid agonist AM-1241 prolongs survival in a transgenic mouse model of amyotrophic lateral sclerosis when initiated at symptom onset.

“Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disease characterized by progressive motor neuron loss, paralysis and death within 2-5 years of diagnosis. Currently, no effective pharmacological agents exist for the treatment of this devastating disease. Neuroinflammation may accelerate the progression of ALS. Cannabinoids produce anti-inflammatory actions via cannabinoid receptor 1 (CB1) and cannabinoid receptor 2 (CB2), and delay the progression of neuroinflammatory diseases…

 …treatment with non-selective cannabinoid partial agonists prior to, or upon, symptom appearance minimally delays disease onset and prolongs survival through undefined mechanisms…

…Δ9-Tetrahydrocannabinol (Δ9-THC) is the main psychoactive constituent in the plant Cannabis sativa (marijuana) and produces its effects by activation of cannabinoid receptor 1 (CB1) and cannabinoid receptor 2 (CB2) cannabinoid receptors. CB1 receptors are expressed throughout the CNS, while CB2 receptors are expressed predominantly in immune cells and non-neuronal tissues. Therapeutic agents which modulate the cann-abinoid system are effective in treating a wide variety of disorders characterized by inflammation. More specifically, drugs which activate CB2 receptors successfully improve the symptoms of several inflammatory diseases…

More importantly, daily injections of the selective CB2 agonist AM-1241, initiated at symptom onset, increase the survival interval after disease onset by 56%. Therefore, CB2 agonists may slow motor neuron degeneration and preserve motor function, and represent a novel therapeutic modality for treatment of ALS.”

http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2819701/

 

AM1241, a cannabinoid CB2 receptor selective compound, delays disease progression in a mouse model of amyotrophic lateral sclerosis.

“Effective treatment for amyotrophic lateral sclerosis (ALS) remains elusive. Motor neuron degeneration is the primary pathology in ALS; however non-neuronal cells contribute to the disease process. In particular, inflammatory processes have been shown to play an important role. AM1241 is a cannabinoid CB2 receptor selective agonist that has been shown to be effective in models of inflammation and hyperalgesia. Here we report that treatment with AM1241 was effective at slowing signs of disease progression when administered after onset of signs in an ALS mouse model (hSOD1(G93A) transgenic mice)…. As AM1241 was well tolerated by the animals, cannabinoid CB2 receptor-selective compounds may be the basis for developing new drugs for the treatment of ALS and other chronic neurodegenerative diseases.”

http://www.ncbi.nlm.nih.gov/pubmed/16781706

Abnormal sensitivity of cannabinoid CB1 receptors in the striatum of mice with experimental amyotrophic lateral sclerosis.

“Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease that primarily affects motor neurons.

The sensitivity of cannabinoid CB1 receptors controlling both glutamate and GABA transmission was remarkably potentiated in ALS mice, indicating that adaptations of the endocannabinoid system might be involved in the pathophysiology of ALS. In conclusion, our data identify possible physiological correlates of striatal dysfunction in ALS mice, and suggest that cannabinoid CB1 receptors might be potential therapeutic targets for this dramatic disease.”

http://www.ncbi.nlm.nih.gov/pubmed/19452308

Identification of receptors and enzymes for endocannabinoids in NSC-34 cells: relevance for in vitro studies with cannabinoids in motor neuron diseases.

“NSC-34 cells, a hybridoma cell line derived from the fusion of neuroblastoma cells with mice spinal cord cells, have been widely used as an in vitro model for the study of motor neuron diseases [i.e. amyotrophic lateral sclerosis (ALS)]. In the present study, they were used to characterize different elements of the cannabinoid signaling system, which have been reported to serve as targets for the neuroprotective action of different natural and synthetic cannabinoid compounds…

Assuming that glutamate toxicity is one of the major causes of neuronal damage in ALS and other motor neurons diseases, the differentiated NSC-34 cells might serve as a useful model for studying neuroprotection with cannabinoids in conditions of excitotoxic injury, mitochondrial malfunctioning and oxidative stress.”

http://www.ncbi.nlm.nih.gov/pubmed/22206832

The endocannabinoid system in the inflammatory and neurodegenerative processes of multiple sclerosis and of amyotrophic lateral sclerosis.

Abstract

“Multiple sclerosis (MS) and amyotrophic lateral sclerosis (ALS) are chronic diseases of the central nervous system (CNS), featured by a complex interplay between inflammation and neurodegeneration. Increasing evidence supports the involvement of the endocannabinoid system (ECS) in both inflammatory and neurodegenerative processes typical of these pathological conditions. Exogenous or endogenous cannabinoids regulate the function of immune system by limiting immune response. On the other hand, by preventing excitotoxic damage, cannabinoids protect neuronal integrity and function. Of note, the ECS not only plays a role as modulator of disease processes, but it can also be disrupted by the same diseases. Agents modulating cannabinoid receptors or endocannabinoid tone provide promising therapeutic opportunities in the treatment of inflammatory neurodegenerative disorders of the CNS.”

http://www.ncbi.nlm.nih.gov/pubmed/20353778

The (endo)cannabinoid system in multiple sclerosis and amyotrophic lateral sclerosis.

“Alterations of the endocannabinoid system (ECS) have been recently implicated in a number of neuroinflammatory and neurodegenerative conditions so that the pharmacological modulation of cannabinoid (CB) receptors and/or of the enzymes controlling synthesis, transport, and degradation of these substances has emerged as a valuable option to treat neurological diseases.

Here, we describe the current knowledge concerning the rearrangement of ECS in a primarily inflammatory disorder of the central nervous system such as multiple sclerosis (MS), and in a primarily degenerative condition such as amyotrophic lateral sclerosis (ALS).

 Furthermore, the data supporting a therapeutic role of agents modulating CB receptors or endocannabinoid tone in these disorders will also be reviewed. Complex changes of ECS take place in both diseases, influencing crucial aspects of their pathophysiology and clinical manifestations. Neuroinflammation, microglial activation, oxidative stress, and excitotoxicity are variably combined in MS and in ALS and can be modulated by endocannabinoids or by drugs targeting the ECS.”

http://www.ncbi.nlm.nih.gov/pubmed/17678961

Medical Marijuana For Multiple Sclerosis and Amyotrophic Lateral Sclerosis

“Marijuana has been classified as a Schedule 1 narcotic since the 1960’s, which means it is deemed by the federal government to have no medicinal value and heavy risk. However, there is an increasing body of research to show that marijuana can be helpful for certain debilitating conditions and 15 states have now legalized it for medicinal usage. One of those conditions research is showing marijuana’s medicinal value is multiple sclerosis (MS) and another is Amyotrophic Lateral Sclerosis (ALS). They are both diseases involving neurologic deterioration.

Approximately 200 individuals per week are diagnosed with MS, with the usual onset between 20 and 40 years of age. The disease has no known cure and involves a neuro-degeneration in which the brain and spinal cord nerves undergo a gradual destruction of its protective tissue called myelin.

Myelin covers these regions in what’s called a Myelin sheath, and as the sheath degenerates symptoms include painful muscle spasms, numbness, impaired vision, loss of coordination, tremors, weakness, and imbalance (ataxia). The disease is progressive and can become incapacitating and lead to death.

MS patients may find that marijuana relieves symptoms of spasticity, tremors, imbalance, depression, and fatigue. Numerous studies have looked at Sativex, which is an oral cannabis spray developed in the UK. It has been shown to relieve pain, spasticity, depression, fatigue, and incontinence.

THC appears to have some immunosuppressive or immunomodulatory effects. This may be beneficial to MS patients. Long term studies need to be completed to see if this is for real and a disease modifying effect is real.

Lou Gehrig’s disease, also called Amyotrophic Lateral Sclerosis, involves the ongoing loss of the brain’s motor neurons. It is rapidly progressive, and usually fatal. There is no known cause. The usual age of onset is 40 to 60 years, and men are more commonly affected.

The most well known person with ALS is Stephen Hawking, a physicist who has lived for over 40 years after being diagnosed. He is the exception, the unfortunate usual prognosis is grim, with about half of patients dying with 2.5 years of onset.

The cannabinoids in medical marijuana may protect against glutamate toxicity. This may be very helpful because ALS involves excessive glutamate in the brain tissue, spinal fluid, and serum of those suffering.

By lowering the chance of glutamate toxicity, there is a chance that marijuana may have a neuroprotective effect. In addition, patients describe alleviation of pain and spasms, improvement of appetite, and less drooling issues which is a common problem with ALS.”

By David L. Greene

 

Medical Marijuana Use: Miracle Medicine Good for Dozens of Diseases

“When the State of Oregon first legalized Medical Marijuana I disbelieved and was astonished at the diverse medical conditions that State DHS said were acceptable conditions for a permit to use: Cancer, Glaucoma, HIV/AIDS, Alzheimer’s, Cachexia/Anorexia, Severe pain, Severe nausea, Seizures and Muscle spasms.

I found out soon after I started seeing patients for marijuana permits that the DHS was far too modest about this surprisingly effective medicine. As I continued to see more than 4000 patients I was truly amazed at the diversity of diseases for which marijuana was helpful and more so than standard medicine.”-

Dr. Phil Leveque

Read more: http://www.salem-news.com/articles/may262009/marijuana_treatments_pl_5-26-09.php