Pharmacological modulation of the endocannabinoid system in a viral model of multiple sclerosis

Abstract

Theiler's virus infection of the central nervous system (CNS) induces an immune-mediated demyelinating disease in susceptible mouse strains and serves as a relevant infection model for human multiple sclerosis (MS). Cannabinoids have been shown to exert beneficial effects on animal models of MS and evidence suggests that the endocannabinoid system plays a role in the tonic control of spasticity. In this study we, two selective inhibitors of the putative endocannabinoid transporter and hence of endocannabinoid inactivation, provide an effective therapy for Theiler murine encephalomyelitis virus-induced demyelinating disease (TMEV-IDD). Treatment of TMEV-infected mice with OMDM1 and OMDM2 enhanced anandamide levels in the spinal cord and ameliorated motor symptoms. This was associated with a down-regulation of inflammatory responses in the spinal cord. In addition we show that OMDM1 and OMDM2 down-regulate macrophage function by (i) decreasing the surface expression of major histocompatibility complex (MHC) class II molecules, (ii) inhibiting nitric oxide synthase-2 (NOS-2) expression and (iii) reducing the production of the pro-inflammatory cytokines interleukin-1beta (IL-1b) and interleukin-12 (IL-12p40). Taken together, these results point to the manipulation of the endocannabinoid system as a possible strategy to develop future MS therapeutic drugs.

Cannabinoid CB1and CB2Receptors and Fatty Acid Amide Hydrolase Are Specific Markers of Plaque Cell Subtypes in Human Multiple Sclerosis

“…Because immunohistochemical staining of MS lesions with anti-myelin antibodies to estimate lesion age is widely accepted (Bruck et al, 1995;Noseworthy et al, 2000;Chang et al, 2002;van der Goes et al, 2005), these data provide evidence that the induction of CB 2 receptor expression in plaqueassociated macrophages could be an early event in the maturation of MS plaques. Although little is known regarding the effects of the cannabinoids on myelin phagocytosis, it has been shown previously that activation of CB 1 and CB 2 receptors decreases the production of proinflammatory cytokines in macrophages, indicating that an anti-inflammatory mechanism could potentiate the neuroprotection induced by cannabinoids (Mestre et al, 2005;Ortega-Gutierrez et al, 2005a). As reviewed by Croxford and Yamamura (2005), several characteristics of macrophages, such as migration, presentation of peptide antigens, or phagocytosis of foreign particles, are significantly influenced by cannabinoids.…”

Dual Modulation of Endocannabinoid Transport and Fatty Acid Amide Hydrolase Protects against Excitotoxicity

“…The present report suggests that such compensatory signaling can be positively modulated through the inhibition of endocannabinoid transport and hydrolysis with the AM374/ AM404 drug combination. Previous reports have described various types of beneficial effects by individually inhibiting the transport activity (Lastres-Becker et al, 2002;Marsicano et al, 2003;Bifulco et al, 2004;Fernandez-Espejo et al, 2004;Mestre et al, 2005) or FAAH (Maccarrone et al, 2003;Bifulco et al, 2004). In vitro and in vivo models were used here to show that dual modulation of the endocannabinoid system protects against cellular and functional consequences ascribed to excitotoxic events, such as stroke and traumatic brain injury.…”

“…The growing list includes potential treatments for chemotherapy complications (Sharma et al, 2005), tumor growth (Bifulco et al, 2004), pain (Calignano et al, 1998), Parkinson's disease (Maccarrone et al, 2003;FernandezEspejo et al, 2004), Huntington's disease (Lastres-Becker et al, 2002), Alzheimer's disease (Ramirez et al, 2005), multiple sclerosis (Mestre et al, 2005), amyotrophic lateral sclerosis (Raman et al, 2004), glaucoma (El-Remessy et al, 2003), as well as traumatic brain injury (Panikashvili et al, 2001), cerebral ischemia (Nagayama et al, 1999), and other excitotoxic insults (Shen and Thayer, 1998;Marsicano et al, 2003). The protective effects may involve signal transduction pathways linked to cannabinoid CB 1 receptors that recognize the endocannabinoids anandamide and 2-arachidonylglycerol (Bouaboula et al, 1995;Derkinderen et al, 1998Derkinderen et al, , 2003Galve-Roperh et al, 2002;Karanian et al, 2005).…”

The therapeutic potential of drugs that target cannabinoid receptors or modulate the tissue levels or actions of endocannabinoids

“…In another model of multiple sclerosis in which mice are inoculated intracerebrally with Theiler ' s murine encephalomyelitis virus (TMEV), OMDM-1 has been found to oppose the impaired rotarod performance and reductions in spontaneous motor activity exhibited by the lesioned animals and to enhance levels of anandamide although not 2-arachidonoyl glycerol in the spinal cords of these animals. 174 There are several reasons for believing that the amelioration of spasticity induced in CREAE mice by inhibitors of FAAH or endocannabinoid cellular uptake is mediated at least in part by CB 1 and possibly also by CB 2 receptors. First, the antispastic effect of the FAAH inhibitor, AM374, has been found to be blocked by SR141716A and SR144528.…”