The Endocannabinoid System Is Dysregulated in Multiple Sclerosis and in Experimental Autoimmune Encephalomyelitis

Diego Centonze; Monica Bari; Silvia Rossi; Chiara Prosperetti; Roberto Furlan; Filomena Fezza; Valentina De Chiara; Luca Battistini; Giorgio Bernardi; Sergio Bernardini; Gianvito Martino; Mauro Maccarrone

Disclosures

Brain. 2007;130(10):2543-2553. 

In This Article

Summary and Introduction

Summary

The ability of cannabinoids to modulate both inflammatory and degenerative neuronal damage prompted investigations on the potential benefits of such compounds in multiple sclerosis (MS)and in animal models of this disorder. Here we measured endocannabinoid levels, metabolism and binding, and physiological activities in 26 patients with MS (17 females, aged 19-43 years),25 healthy controls and in mice with experimental autoimmune encephalomyelitis (EAE), a preclinical model of MS. Our results show that MS and EAE are associated with significant alterations of the endocannabinoid system. We found that anandamide (AEA),but not 2-arachidonoylglycerol (2-AG), was increased in the CSF of relapsing MS patients. AEA concentrations were also higher in peripheral lymphocytes of these patients, an effect associated with increased synthesis and reduced degradation of this endocannabinoid. Increased synthesis, reduced degradation, and increased levels of AEA were also detected in the brains of EAE mice in the acute phase of the disease, possibly accounting for its anti-excitotoxicaction in this disorder. Accordingly, neurophysiological recordings from single neurons confirmed that excitatory transmission in EAE slices is inhibited by CB1 receptor activation, while inhibitory transmission is not. Our study suggests that targeting the endocannabinoid system might be useful for the treatment of MS.

Introduction

Immune-mediated attack of oligodendrocytes and myelin sheaths is a primary pathological event in multiple sclerosis (MS).Neurodegenerative damage, however, occurs early in this disorder,paralleling inflammation (Bjartmar et al., 2001; Peterson et al., 2001; De Stefano et al., 2002; Kuhlmann et al., 2002; Filippiet al., 2003; Filippi and Rocca, 2005). In recent years, the ability of cannabinoids to modulate both inflammatory (Bakeret al., 2003; Walter and Stella, 2004), and degenerative neuronal damage (Grundy et al., 2001; Iversen, 2003) prompted investigations of the potential benefits of these compounds in MS, also encouraged by early reports affirming reduced frequency of relapses (Consroeet al., 1997), and relief from spasticity, dystonia, tremor,ataxia, bladder dysfunction and pain in MS patients self-medicating with marijuana (Consroe, 1998; Fernandez-Ruiz et al., 2002;Pertwee, 2002; Zajicek et al., 2003).

In experimental animal models of MS, cannabinoid administration significantly attenuates the clinical and pathological features of the disease (Lyman et al., 1989; Wirguin et al., 1994; Arevalo-Martinet al., 2003; Croxford and Miller, 2003), an effect also achieved by pharmacological interventions aimed at enhancing the levels of the endogenous cannabinoid anandamide (AEA) (Mestre et al.,2005; Ortega-Gutierrez et al., 2005; Bari et al., 2006; Ligrestiet al., 2006). Furthermore, mice lacking the CB1 receptor develop more severe neuronal damage following experimental autoimmune encephalomyelitis (EAE) induction, supporting a role for endocannabinoids in this inflammatory neurodegeneration (Pryce et al., 2003).

Whether MS or experimental models of MS perturb the endocannabinoid system (ECS) is however controversial. Recently, increased levels of AEA, but not of the other abundant endocannabinoid 2-arachidonoylglycerol(2-AG), have been reported in tissues from inflammatory lesions of patients with MS (Eljaschewitsch et al., 2006). Another study,however, showed that the expression of the enzyme involved in AEA degradation was upregulated in MS lesions, indicating that the level of this endocannabinoid might be reduced in MS patients(Benito et al., 2007).

Furthermore, it has been reported that production of both AEA and 2-AG was normal in mice with asymptomatic to mild EAE (Shohamiand Mechoulam, 2006; Witting et al., 2006), while both endocannabinoids were elevated in the chronic relapsing mouse model of MS (Bakeret al., 2001). Finally, both AEA and 2-AG have been found to be down-regulated in the brains of rats with EAE (Cabranes etal., 2005). Decreased expression of CB1 receptors has also been reported in this rat model of MS (Berrendero et al., 2001),while the functionality of the same receptors seem to remain unchanged in mice with asymptomatic to mild EAE (Pertwee, 2002;Witting et al., 2006).

Thus, to increase our understanding of possible changes in ECS in MS, we measured endocannabinoid levels, metabolism and binding,and physiological activities in patients with MS and in mice with EAE. Our results indicate a profound rearrangement of the ECS involving AEA and the sensitivity of striatal cannabinoid CB1 receptors.

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