Do Cannabinoids offer Neuroprotection in Multiple Sclerosis?

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Summary Points

Multiple sclerosis (MS) is a severe chronic illness affecting over 2.5 million people worldwide.

There is currently no disease modifying treatment, with any success in treating progressive MS.

Cannabinoids have been suggested to convey immunosuppression in the central nervous system, said to reduce the progression of MS. This has been shown to be irrelevant in clinical use.

Cannabinoids have been shown to cause neuroprotection in animal models of MS

Current clinical trials are investigating the neuroprotective potential of long term administration of THC in progressive MS.

Introduction

Cannabis has been used for recreation and self-medication for millennia. In recent years the active components of cannabis have been discovered and are now being researched to discover their actions. Cannabis is a term used colloquially to describe the extracts from the female plant of Cannabis Sativa. These extracts have been found to contain over 80 different active compounds known as Cannabinoids,, the most abundant of which is ∆9- tetrahydrocannabinol (THC) which produces the well known psychoactive effects. The potential medical benefits of these cannabinoids have attracted much attention in the last few years. Evidence suggests that cannabinoids have an effect in reducing the severity of some of the symptoms of multiple sclerosis, and it has more recently been suggested that they may have a protective and preventative effect on neurodegenerative diseases. This review will focus on the potential of cannabinoids in the treatment of progressive multiple sclerosis. As of now there are no treatments with a significant effect on altering the progression of multiple sclerosis in the progressive stages of the disease.

Method

For this clinical review, past literature was obtained searching several databases containing journals articles within the life sciences. Medline, Google Scholar and MetaLib were searched for journals meeting the criteria of the clinical review, using the following key words; "cannabinoids", "neuroprotection", "multiple sclerosis", "neurodegenerative", and immunosuppressant. I also searched the Cochrane database for any relevant systematic reviews. Articles with titles relevant to the aim of this review were selected, the abstracts were read and articles with most relevance were studies further and included in the review.

Cannabinoid System

The cannabinoid system is an important part of the central nervous system; it plays an important role in many neurophysiological processes; such as memory, cognition, movement, pain, and appetite. The cannabinoid system is made up of cannabinoid receptors, the group of endogenous lipids, which bind to these receptors, collectively known as endocannabinoids and the proteins and enzymes responsible for the production, reuptake and breakdown of the endocannabinoids. The main endocannabinoids are 2-Arachidonoylglycerol (2-AG) and arachidonoylethanolamine (AEA), although others have been identified. These endocannabinoids have a regulatory role in neurotransmission, and it is the same cannabinoid receptors that are activated by the cannabinoids found in cannabis sativa extracts.

Two separate types of cannabinoid receptors have been identified: CB1 receptor and CB2 receptor. These were first isolated and cloned in the early 1990s, and were found to be G protein-coupled receptors (a specific type of cell membrane receptor). The CB1 receptor is the main receptor at which cannabinoid compounds are active in the brain; it was found that this receptor is most abundant in the neurones of the central nervous system (CNS), while the CB2 receptor is mainly found in the cells of the peripheral immune system. The CB2 receptor has been observed in the CNS, but only in neurones within the brain stem and on microglia cells in animal models (a specific type of glial cell that acts as the central nervous system's macrophages) during CNS inflammation. ,

The CB1 receptors are located in the plasma membrane of neurone endings. Normal activation of the CB1 receptor by the endocannabinoids in the body causes an inhibition of excitatory neurotransmitter release from the presynaptic terminals, which is caused by the depolarisation of the presynaptic membrane and entry of Ca2+, thus decreasing the rate of neurotransmission. Additionally, CB1 receptor activation leads to the activation of a specific type of K+ channel which moves potassium ions back into the axon of the neurone, disrupting the K+ currents, leading to hyperpolarisation, delaying the release of the neurotransmitter. 4

Both these mechanisms have been shown to cause a cannabinoid induced depression of excitatory neurotransmission in cultured hippocampal neurones.

Multiple Sclerosis (MS)

Multiple Sclerosis is an inflammatory autoimmune demyelinating (loss of the insulating myelin coat of the axons of neurones) disease of the central nervous system thought to be triggered viral, or environmental stimuli in people with a susceptible genotype. This leads to the formation of chronic multifocal sclerotic plaques. MS is a chronic debilitating disease, causing muscle spasticity and neuropathic pain affecting over 2.5 million people in the world today.

Cannabinoid initiated immunosuppression in MS

Cannabinoids can activate the CB1 and CB2 receptors, leading to a reduction in neurological decline in the much studied experimental autoimmune encephalomyelitis (EAE) model of MS. This is an animal model of brain inflammation, which causes demyelination of the CNS and is therefore widely used in the study of MS. It has been shown experimentally that the activation of the CB1 receptor using the synthetic cannabinoid WIN55,212 eases inflammatory events; such as reducing the production of T Lymphocytes specific to myelin and a reduction of inflammatory mediators, leading to a slowed progression of the disease. The results of this study can be applied to the progression of MS in humans, and shows that cannabinoids may be able to have the same effects on MS. In more recent studies it has been shown that both ∆9- THC and synthetic cannabinoids can produce the theoretical immunosuppressive effects, previously suggested via the CB1 receptor. However, they have also shown that these effects are only evident at doses of the cannabinoids which would produce significant side effects in humans, such sedation and hypothermia. ,

This suggests that regardless of the exact mechanism of immunosuppression, it is not relevant to medicinal or recreational use of cannabinoids. Support for this is offered by the most recent large randomised-placebo controlled trials investigating cannabinoids in symptom relief, while the study design was not for the identification of immunosuppression they did not demonstrate increased remissions (periods of the disease where the symptoms disappear or improve) in the patients, these are indicative of an immunosuppressive effect. ,

Cannabinoid Neuroprotection in MS

It is known that events such as excessive and prolonged secretion of certain excitatory neurotransmitters (e.g. glutamate) cause neuronal damage. The cannabinoid system has been found to be involved in neuroprotection. Recent studies have used neuronal material from CB1 receptor knockout (CB1R-KO) mice; these are mice where the genes for the CB1 receptors have been inactivated. These studies have shown that when neuronal material (consisting of neurons and glia) CB1R-KO are treated with a substance which causes inflammation, more readily accumulate neuronal damage with an elevated level of cell apoptosis (programmed cell death) than neuronal material from the normal mice control. The role of endocannabinoid neuroprotection is inferred from these results. These results have been confirmed, and it is now suggested by even more recent studies that activation of the cannabinoid system can decrease neuronal damage caused by autoimmune inflammation. 11, One of these in vivo studies (studies involving the whole organism) where mice bread to be CB1 receptor deficient did not tolerate the neuronal damage caused by the autoimmune inflammation in EAE and develop greater neurodegeneration than the controls. Additionally when external CB1 cannabinoids were used on normal mice significant neuroprotection was observed.17

It has, therefore, been demonstrated that cannabinoids can induce neuroprotection in CNS autoimmune inflammatory processes via long term administration of cannabinoids. The possibility of clinical application of this cannabinoid induced neuroprotection is currently being investigated in a double-blind, randomised placebo controlled trial of long-term ∆9-THC or cannabis extract administration in patients with progressive MS.

Conclusion

The cannabinoid system has been shown to play an important role in regulating neurotransmission. Through the activation of the cannabinoid receptors on the immune cells in the central nervous system, it has been shown that inflammation can be reduced. However, only at doses of the cannabinoids which would cause considerable side effects in humans, so cannabinoid mediated immunosupression is not likely to be relevant clinically in multiple sclerosis. It has been demonstrated that cannabinoids can induce neuroprotection in inflammatory processes, via long term cannabinoid administration. This evidence in animal models was sufficient to prompt the current large scale double-blind, randomised placebo controlled trial described above, which reports in spring/early summer 2012.

The results of this will provide conclusive evidence as to whether or not cannabinoids are effective in treating the progression of progressive multiple sclerosis. If the results show that cannabinoids are ineffective in conferring neuroprotection in progressive multiple sclerosis it will be more likely that cannabinoids have no role in the management of progressive MS other than in the control of the symptoms.

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