Therapeutic use of the endocannabinoid system in demyelinating diseases

Demyelinating diseases are medical conditions in which the principal pathogenic process targets the myelin sheath covering the axons of the neurons. This sheath enables proper conduction of nerve impulses. The most common demyelinating disease is multiple sclerosis (MS). MS is characterised by a reduction in the number of oligodendrocytes producing myelin in the central nervous system (CNS) and by a process of progressive axonal degeneration, which lies at the heart of the symptoms of the disease.

MS is a chronic early-onset disease. Although clinical manifestations vary, they include loss of strength and/or sensitivity in the limbs, blurred vision, pain, spasticity, ataxia and bladder dysfunction. According to the Spanish Society of Neurology (SEN), MS is the second most common cause of disability among 20–40 year-olds in Spain (after traffic accidents) making it the leading disease-related cause in this age group. Over the last fifteen years, the prevalence and incidence of MS have both doubled, and it now affects 2.3 million people globally. In Spain 47,000 people now suffer MS and around 1800 new cases are diagnosed each year. Because of its epidemiology and the chronic disability it causes, MS has a high socio-economic cost and puts a significant burden on the national health and social security systems.

First described by Jean-Martin Charcot in 1868, the aetiology of MS has yet to be determined. Pathological features of MS include the presence of inflammatory demyelinating foci in the CNS, with the presence of T cells, microglia and reactive astrocytes which release different pro- and anti-inflammatory cytokines. There are also trophic factors involved in the disease. MS generally takes the form of attacks or episodes of neurological deficit. Such episodes are of varying duration and are associated with the appearance of a new demyelinating lesion in the CNS or the reactivation of an existing lesion. During the course of the disease the patient also accumulates a sustained neurological disability as a consequence of the neurodegenerative process. The therapeutic approach to MS is multidisciplinary. It includes anti-inflammatories to treat the attacks, specific drugs to relieve symptoms affecting quality of life, and disease-modifying medications, whose purpose is to limit the advance of the long-term neurological damage.

Importantly, destruction of the myelin sheath in MS triggers repair or regeneration mechanisms, in a process known as remyelination. Most mature myelin-producing oligodendrocytes in the CNS are generated during postnatal development from immature cells, called oligodendrocyte progenitor cells (OPCs). OPCs remain in the adult brain, and are capable of generating new mature oligodendrocytes when the myelin becomes damaged. In MS, therefore, regeneration of the myelin sheath requires the presence and proper maturation of OPCs in demyelinating lesions. In animal models of MS, the remyelination process has been shown to promote survival of the demyelinated axons, thus mitigating the neurological deficits. In consequence, the search for new MS therapies is now primarily centred on identifying the factors that promote repair of the myelin sheath.

Over the last twenty years, the therapeutic potential of the endocannabinoid system for treating MS has been comprehensively studied. It is well-established that cannabinoid compounds improve the neurological deficits associated with neuron damage and attenuate the inflammatory process in MS animal models. At a clinical level, medical treatment with cannabinoid derivatives has also proved beneficial in managing certain MS-associated symptoms. In mechanistic terms, the beneficial effects of cannabinoid compounds in experimental models of demyelination entail activation of CB₁ and/or CB₂ cannabinoid receptors located in a wide variety of cell substrata. CB₁ and CB₂ receptors are the principal signalling proteins in the endocannabinoid system and mediate most of the biological effects of the cannabinoid compounds contained in cannabis derivatives. CB₁ receptors are expressed at high levels in neurons. They are considered to be responsible for the neuroprotective effects associated with treatment of MS patients using cannabinoid compounds. In pioneering studies carried out over a decade ago, mutant mice lacking CB₁ receptors showed exacerbated neurological symptoms in experimental models of MS and were more sensitive to the excitotoxic insults that promote axon degeneration in this disease. Cannabinoid compounds have also been shown to have anti-inflammatory effects in experimental models of MS through activation of CB₂ receptors. The CB₂ receptors are essentially expressed in T cells and microglia, which are fundamentally implicated in the inflammatory reaction that accompanies and contributes to myelin destruction. Activation of the CB2 receptors by natural or synthetic cannabinoid pharmaceuticals inhibits the pro-inflammatory function of these cells, and aids management of the inflammatory process in animal models of MS. Finally, oligodendrocytes and their progenitors also express CB₁ and CB₂ receptors, which are implicated in the beneficial effects of cannabinoid compounds in MS. Recent studies have shown that cannabinoid compounds protect mature oligodendrocytes against excitotoxic damage through the CB₁ receptors expressed in these cells. Studies in experimental models of MS have also found that cannabinoid drugs facilitate repair of the myelin sheath by acting through the cannabinoid receptors expressed in oligodendrocyte progenitor cells. In view of these findings, it is reasonable to expect that cannabinoid therapy will have anti-inflammatory effects in MS patients. This would contribute to controlling the acute deterioration associated with attacks. Moreover, such therapy can be expected to protect neurons and oligodendrocytes and regenerate the myelin sheath, thus slowing the advance of the disease.

Research into the potential of the endocannabinoid system in MS treatment has led to commercialisation of the first cannabis-based pharmaceutical preparation approved for clinical use, Sativex. The drug is composed of Δ⁹-THC (a natural agonist of the CB₁/CB₂ receptors) and cannabidiol, which lacks affinity for both cannabinoid receptors but has neuroprotective properties in preclinical models. In Spain, the drug has been used for the last seven years to improve the symptoms of adult patients with moderate-to-serious MS-induced spasticity who have failed to respond adequately to other antispastic drugs. However, the clinical usefulness in MS of cannabinoid compounds in general and Sativex in particular is a hot topic in the scientific community. To gain therapeutic benefits from cannabinoid pharmaceuticals in patients with MS, it is necessary to use high doses. This tends to have adverse psychiatric reactions, among other side effects, often associated with non-selective activation of all CB₁ receptors in neuron populations. Studies to date also suggest that prolonged use of high doses of cannabinoid compounds causes pharmacological tolerance to their neuroprotective effects which are dependent on activation of the CB₁ receptors, and limits their usefulness in clinical practice.

In recent years, the scientific community’s interest in the endocannabinoid system as a pharmacological target in MS has shifted from the CB₁ and CB₂ receptors to the enzymes responsible for the hydrolysis of their endogenous ligands, the endocannabinoids. Like the cannabinoid compounds found in the cannabis plant, endocannabinoids prevent neurological damage in MS by acting through their targets, the cannabinoid receptors. For this reason, genetically-modified mice with no CB₁ receptors evolve less well when subjected to demyelinating insults. Endocannabinoid ligands are degraded naturally in the CNS by the activity of specific enzymes. This process of degradation or hydrolysis of endocannabinoids limits the protective activity of cannabinoid receptors. In particular, the enzyme known as monoacylglycerol lipase (MAGL) is responsible for approximately 85% of the degradation of the most abundant endocannabinoid composite in CNS, 2-arachidonoylglycerol (2-AG). MAGL-inhibiting drugs increase levels of 2-AG in the brain, and thus increase activation of CB₁ and/or CB₂ receptors by this endocannabinoid composite. Studies in MS have found that degeneration of the myelin sheath involves changes in the expression levels of the various elements that determine endocannabinoid signalling in the damaged tissue (CB₁/CB₂ receptors and enzymes of synthesis and degradation of endocannabinoid compounds). Based on these observations, it has been proposed that MAGL-inhibiting drugs would increase the availability of 2-AG preferentially in demyelinating lesions, thus optimising the relationship between the beneficial and adverse effects associated with the treatment.

The therapeutic utility of MAGL in MS has recently been validated at preclinical level. Studies by independent laboratories indicate that pharmacological inactivation of this enzyme attenuates degeneration of the myelin sheath, inflammatory reaction and neurological damage. It has also been found to promote remyelination processes in different animal models of MS. These results open new vistas for developing MS drugs that will act selectively on the MAGL enzyme. Although rational use of MAGL inhibitors in clinical practice requires detailed analysis of the mechanisms underlying the therapeutic benefits and the possible adverse effects of these compounds on MS patients, we are likely to see significant advances in this field in the coming years.