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Cannabinoid control of neuroinflammation related to multiple sclerosis

By December 17, 2013No Comments
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Br J Pharmacol. 2007 November; 152(5): 649–654.
Published online 2007 September 24. doi:  10.1038/sj.bjp.0707458
PMCID: PMC2190016

Cannabinoid control of neuroinflammation related to multiple sclerosis

This article has been cited by other articles in PMC.

Abstract

The cannabis plant (Cannabis sativa) has been known by many names but the question remains ‘Can we call it medicine?’ There has been renewed interest in the value of cannabis for the control of neuroinflammatory conditions such as multiple sclerosis, where it has been shown to have some effect on spasticity and pain both experimentally and in clinical trials in humans. However, in addition to symptom control potential, the question remains whether cannabinoids can modify the neuroinflammatory element which drives relapsing neurological attacks and the accumulation of progressive disability. In experimental studies it has been recently shown that synthetic cannabinoids can affect the immune response both indirectly via CB1 receptor-mediated signalling nerve centres controlling the systemic release of immunosuppressive molecules and directly by CB2 receptor-mediated inhibition of lymphocyte and macrophage/microglial cell function. However, these immunosuppressive possibilities that would limit the frequency of relapsing attacks will probably not be realized clinically, following use of medical cannabis, due to dose constraints. However, cannabinoids may still affect the glial response within the damaged central nervous system, which facilitate the slow, neurodegenerative processes that account for progressive neurodegeneration, and therefore may have utility in addition to value of cannabis-related drugs for symptom control.

Keywords: cannabinoid, CB1 receptor, CB2 receptor, immunosuppression, multiple sclerosis, neuroinflammation, neuroimmunology, neurodegeneration

Introduction

The cannabis plant (Cannabis sativa) has been used for millennia. In addition to the well-known, euphoric ‘high’, appetite stimulation (the munchies) and other psychoactive effects associated with the use of this recreational drug (Howlett et al., 2002), there has been recent, renewed interest in its medicinal potential (Schnelle et al., 1999; Howlett et al., 2002). This potential will be based on the biology of the drug and the disease, and this is slowly being uncovered (Howlett et al., 2002). It has already been recognized that cannabis acts because it activates cannabinoid receptors (Howlett et al., 2002; Baker et al., 2006). The cannabinoid type I receptor (CB1) is the most abundant G-protein-coupled receptor within the adult nervous system and functions as a regulator of synaptic neurotransmission (Howlett et al., 2002; Wilson and Nicoll, 2002). This would be consistent with the capacity of cannabinoids to control a number of neurological symptoms, such as pain and spasticity, as can be shown experimentally in rodents (Buxbaum, 1972; Baker et al., 2000) and more recently in humans (Consroe et al., 1997; Zajicek et al., 2003, 2005;Collin et al., 2007; Iskedjian et al., 2007). The cannabinoid type II receptor (CB2) is mostly restricted to the cells of the immune system, notably on B cells and macrophages, where its function is less well-characterized (Howlett et al., 2002). However, these distributions of receptors on immune cells and nerves may lead one to suspect that cannabinoids may control neuroinflammatory conditions.

Neuroinflammation

Inflammation involves complex biological processes that act as a protective mechanism to remove the injurious stimuli as well as initiating the healing process for the affected tissue, which in the case of neuroinflammation relates to inflammation of the nervous systems. However, the nature of inflammation depends on the perspective of the individual studying the pathology. This could include acute inflammation involving polymorphonuclear cells and pharmacological mediators or chronic inflammation involving the actions of mononuclear cells as immunological mediators. Currently, there is a marked paucity of information relating to acute inflammatory effects of cannabinoids within the central nervous system (CNS) and much of the available literature relates to the peripheral nervous system and the generation of pain (Hohmann and Suplita, 2006; Agarwal et al., 2007; Lever and Rice, 2007). Most studies are geared towards the understanding of cannabinoid effects in chronic inflammation. These studies are typically within the context of understanding events occurring in multiple sclerosis (MS), where patients have long perceived benefit from taking cannabis (Consroe et al., 1997; Pertwee, 2002; Chong et al., 2006).

Cannabinoids in neuroimmunological disease

Multiple sclerosis is thought to be an autoimmune, demyelinating disease of the CNS, which is triggered by the action of a viral or other environmental stimulus on a susceptible genotype of the affected individual (Compston and Coles, 2002). Immune attack of the CNS not only induces damage to the oligodendrocytes that form myelin, but also to the nerves themselves (Compston and Coles, 2002). This creates a microenvironment containing many demyelinated axons and neuroinflammatory effectors. These sustain the autoimmune-independent neurodegeneration that underlies the development of progressive disability, which is unresponsive to treatments with anti-immunological agents such as cladribine (2-chlorodeoxyadenosine), CD52-leukocyte-depleting antibodies and bone marrow transplantation (Rice et al., 2000; Coles et al., 2006; Confavreux and Vukusic, 2006; Samijn et al., 2006). Symptoms are due to uncontrolled or inappropriate neural transmission that accumulates as the compensatory potential of the CNS decreases, countercurrent to the progression of neurodegeneration (Compston and Coles, 2002). It is important to realize that cannabinoids may have clinical activity because they can act on distinct disease processes, which can be dissociated in human disease as well as in the animal models (Baker et al., 2000; Pryce et al., 2003; Maresz et al., 2007). In MS, cannabis is largely used for symptom control (Consroe et al., 1997; Chong et al., 2006), where signs can be shown experimentally to be inhibited due to CB1 receptor-mediated control of neurotransmission (Baker et al., 2000; Pryce and Baker, 2007). More recently, there are indications that cannabinoids may slow progressive neurodegeneration (Pryce et al., 2003; Zajicek et al., 2005; Witting et al., 2006; Docagne et al., 2007). However, in relation to MS, cannabinoids were first assessed experimentally for their capacity to inhibit the immune response (Lyman et al., 1989; Wirguin et al., 1994). These effects have recently been shown to be mediated by both CB1 and CB2 receptors in viral and autoimmune models of MS (Figure 1; Arevalo-Martin et al., 2003; Maresz et al., 2007).

Figure 1

Immune regulation by cannabinoids. Exogenously administered cannabinoids (a, b) or endocannabinoids (c) may inhibit the action of the immune response in either the periphery (a, b) or the central nervous system (CNS; c) via either a direct (a, c) or indirect …

Cannabis for control of neuroimmunological disease

There have been studies using cannabis plant extracts to assess the immunomodulatory effects of cannabinoids, but these have been restricted to tetrahydrocannabinol (THC) and cannabidiol (CBD), the major psychoactive and non-psychoactive cannabinoids within the plant, respectively. THC is a partial CB1 receptor agonist that can induce immunosuppression (Lyman et al., 1989; Wirguin et al., 1994; Maresz et al., 2007). This has been found to be largely a CB1 receptor-mediated effect (Fujiwara and Egashira, 2004; Mareszet al., 2007). Furthermore, this appears to occur secondary to activation of CB1 receptors expressed on nerves rather than by directly targeting the leukocytes (Maresz et al., 2007). This indicates that cannabinoid receptor activation can drive the production of molecules that are immunosuppressive (Figure 1). Cannabinoids control neurotransmitter release that can influence a number of hormonal systems, such as gonad hormones, leptin and notably glucocorticosteroids, which are well-known to inhibit lymphocyte activation and cytokine production, blood–brain barrier dysfunction and antigen-presenting cell function (Wirguin et al., 1994; Maccarrone and Wenger, 2005). Cannabinoids can induce the inhibition of stimulatory molecules and cytokine production involved in antigen-presenting cell function, inhibit T-cell autoimmunity, inhibit proinflammatory cytokine (for example, interleukin-1, tumour-necrosis factor-α) production and can control apoptosis of autoreactive cells (Arevalo-Martin et al., 2003; Croxford and Miller, 2003;Newton et al., 2004; Klein, 2005; Maresz et al., 2007). Cannabidiol has recently been reported to exhibit some CB2 receptor antagonist potential (Thomas et al., 2007), but it is unknown whether this is of any functional relevance to the in vivo immunoregulatory effects of CBD. There are some claims that CBD can be immunosuppressive in experimental, peripheral autoimmunity, within a narrow bell-shaped dose–response (Malfait et al., 2000; Weiss et al., 2006). This action has been attributed to an effect on the inhibition of tumour-necrosis factor, which is a pathogenic mediator in rheumatoid arthritis (Malfait et al., 2000; Roberts and McColl, 2004), but also appears detrimental in MS (The Lenercept Multiple Sclerosis Study Group, 1999; Roberts and McColl, 2004). Cannabidiol has not been shown to be immunosuppressive in CNS, T-cell-mediated autoimmunity (Maresz et al., 2007). However, it has been reported to inhibit antibody production and B-cell function (Jan et al., 2007) and appears to exhibit anti-inflammatory properties such as being antioxidant, and inhibiting cytokine production and may mediate neuroprotective effects (El-Remessy et al., 2003, 2006; Raman et al., 2004; Hayakawa et al., 2007). Furthermore, within the context of experimental models of MS, inhibition of T-cell function may also be mediated within the periphery (Figure 1). There is evidence that CB2 receptors may control the process of leukocyte extravasation and inhibit T-cell function, including inhibition of proinflammatory cytokine release (Ni et al., 2004;Maresz et al., 2007; Xu et al., 2007). Furthermore, if T cells enter the CNS, the level of endocannabinoids (2-arachidonoyl glycerol) within the CNS compared to the circulation may be sufficiently high to inhibit T-cell function via a CB2receptor-dependent mechanism (Figure 1; Maresz et al., 2007). However, in non-CNS immunity there is some confusion currently, concerning whether CB2 receptor agonists, antagonists or receptor-independent effects limit the immune response, and this requires further clarification (Cabranes et al., 2005; Lunn et al., 2006; Oka et al., 2006; Sanchez et al., 2006; Maresz et al., 2007; Xu et al., 2007).

Neuroinflammatory effects of cannabis within the clinic

Currently, THC (Marinol) is licensed for the treatment of chemotherapy-induced nausea and wasting associated with acquired immunodeficiency syndrome. Indeed, many believe that cannabis has value in coping with disease symptoms in people with acquired immunodeficiency syndrome (Woolridge et al., 2005; Abrams et al., 2007). Therefore, if cannabis really induced a marked immunosuppression, it would be unlikely that this would be considered to be useful or desirable in people infected with the HIV. In experimental models, the immunosuppression induced with THC and other synthetic CB1 receptor agonists largely occurs only at high doses, which typically induce profound cannabimimetic effects (Lyman et al., 1989;Wirguin et al., 1994; Croxford and Miller, 2003; Maresz et al., 2007, unpublished). These are significantly higher than are currently used in humans (Zajicek et al., 2003). Cannabis smokers are not overtly immunosuppressed (Rachelefsky et al., 1976; Kraft and Kress, 2004) and evidence for marked immunomodulation was not detected in recent cannabis trials (Killestein et al., 2003; Katona et al., 2005). In addition, cannabis did not inhibit the relapse rate in trials in MS, which would be indicative of significant immunosuppression (Zajicek et al., 2003, 2005). Thus, although cannabinoids may have some limited potential for modulating neuroimmune responses, this immunosuppressive mode of action of cannabinoids is probably irrelevant to human use of cannabis. However, cannabinoids may shape the inflammatory response such that it affects neurodegenerative components of neurological disease.

Cannabinoids in neurodegenerative disease

During remission from immune attack during chronic neuroimmunological disease, there may be an elevation in the endocannabinoid levels of affected tissues, which can limit symptoms such as spasticity and pain (Baker et al., 2001). These endocannabinoids control nerve hyperexcitability that may trigger neuronal loss, due to glutamate excitotoxicity and toxic accumulation of ions such as Ca2+ (Baker et al., 2001; Howlett et al., 2002; Pryce et al., 2003). However, during neuroimmunological attack, endocannabinoid levels can be decreased (Cabranes et al., 2005; Witting et al., 2006) possibly due to release of cytokines such as γ interferon by infiltrating T cells, which disrupts the functionality of the purinergic P2X7 receptor that controls endocannabinoid responses by microglia (Witting et al., 2006). This loss of endocannabinoid neuroprotection may contribute to nerve damage as a direct effect of neuroimmune attack; however, it may also stimulate a glial response, which may be central to the ‘slow-burning’ neurodegenerative response that occurs in many neurological diseases, such as Alzheimer’s and motor neuron diseases (Compston and Coles, 2002). In contrast, others have indicated that endocannabinoids are increased during immune attack, in both EAE and MS (Eljaschewitsch et al., 2006; Centonze et al., 2007), but again endocannabinoids were implicated further in a neuroprotective effect (Eljaschewitsch et al., 2006; Centonze et al., 2007). Thus, the role of endogenous tone of endocannabinoids in experimental MS is conflicting. These differences may be reconciled by different timings of analysis or model systems. The studies examining endocannabinoids during neuroimmunological attack have solely examined brain regions (Cabranes et al., 2005; Witting et al., 2006; Centonze et al., 2007). In most rodent models of MS, the brain has limited involvement and it is principally the spinal cord that is targeted by the immune system and can show marked differences in endocannabinoid levels compared to the brain (Baker et al., 2001). Therefore, it is also possible that such differences in endocannabinoid levels in the brain during paralytic attack (Cabranes et al., 2005; Witting et al., 2006; Centonzeet al., 2007) may be more related to reflect alterations of brain function due to conduction block associated with loss of movement rather than to neurodegeneration.

Irrespective of this, there is evidence that cannabinoids can inhibit activation, cytokine release and migration of astroglia and microglial, which could limit nerve destruction during immune attack (Molina-Holgado et al., 1997;Arevalo-Martin et al., 2003; Franklin and Stella, 2003; Maresz et al., 2005;Aguado et al., 2006). This can occur following CB2 receptor activation (Maresz et al., 2005) and this can promote neuroprotection in some experimental neurodegenerative diseases (Kim et al., 2006; Shoemaker et al., 2007). In addition, it has been demonstrated that neuroprotective effects can be mediated by CB1-receptor activation (Pryce et al., 2003; Jackson et al., 2005; Bilsland et al., 2006). Therefore, consistent with neuroprotective effects induced by cannabinoids in neurodegenerative conditions such as: experimental ischaemia, trauma, Parkinson’s, motor neuron and Alzheimer’s diseases, which may involve inhibition of neuronal excitability and glial-induced toxicity (Biegon, 2004; Ramirez et al., 2005; Bilsland et al., 2006;Lastres-Becker and Fernandez-Ruiz, 2006; Galve-Roperh et al., 2007), by inhibiting glial neuroinflammation, cannabinoids may offer neuroprotective potential and allow initiation of repair mechanisms, including the development of synaptic plasticity to compensate for loss of neurological pathways (Galve-Roperh et al., 2007; Hashimotodani et al., 2007). Although the neuroprotective capacity of cannabinoids is yet to be definitively shown, follow-up of patients in symptom control trials in MS suggests that THC may have a neuroprotective effect (Zajicek et al., 2005). This regulation of neuroinflammatory events may offer the potential to inhibit neurodegeneration and is currently being assessed in clinical trials.

Acknowledgments

We thank support from the MS Society of Great Britain and Northern Ireland, the National Multiple Sclerosis Society and Aims2cure.

Abbreviations

CB1
cannabinoid receptor type I
CB2
cannabinoid receptor type II
CBD
cannabidiol
CNS
central nervous system
MS
multiple sclerosis
THC
tetrahydrocannabinol

Notes

Conflicts of interest

The authors state no conflict of interest.

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Articles from British Journal of Pharmacology are provided here courtesy of The British Pharmacological Society
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