Excitotoxicity in a chronic model of multiple sclerosis: Neuroprotective effects of cannabinoids through CB1 and CB2 receptor activation Fabian Docagne, a, ⁎ Vilma Muñetón, b Diego Clemente, a Carine Ali, c Frida Loría, a Fernando Correa, a Míriam Hernangómez, a Leyre Mestre, a Denis Vivien, c and Carmen Guaza a a Grupo de Neuroinmunología - Instituto Ramón y Cajal, CSIC -Avda Dr Arce, 37 - 28002 Madrid, Spain b Neural Plasticity Group, Instituto Ramón y Cajal, Consejo Superior de Investigaciones Científicas, Madrid, Spain c INSERM Avenir “t-PA in the working brain”, Centre Cyceron, BP 5229, 14074 Caen, France Received 2 August 2006; revised 22 November 2006; accepted 10 December 2006 Available online 16 January 2007 Inflammation, autoimmune response, demyelination and axonal damage are thought to participate in the pathogenesis of multiple sclerosis (MS). Understanding whether axonal damage causes or originates from demyelination is a crucial issue. Excitotoxic processes may be responsible for white matter and axonal damage. Experimental and clinical studies indicate that cannabinoids could prove efficient in the treatment of MS. Using a chronic model of MS in mice, we show here that clinical signs and axonal damage in the spinal cord were reduced by the AMPA antagonist, NBQX. Amelioration of sympto- matology by the synthetic cannabinoid HU210 was also accompanied by a reduction of axonal damage in this model. Moreover, HU210 reduced AMPA-induced excitotoxicity both in vivo and in vitro through the obligatory activation of both CB1 and CB2 cannabinoid receptors. Together, these data underline the implication of excitotoxic processes in demyelinating pathologies such as MS and the potential therapeutic properties of cannabinoids. © 2006 Elsevier Inc. All rights reserved. Keywords: Multiple sclerosis; TMEV; Axonal damage; Excitotoxicity; Cannabinoids Introduction Multiple sclerosis (MS) is the most common chronic demye- linating disease of the central nervous system (CNS) in humans and leads to motor and sensory deficits, tremor and ataxia. While demyelination is considered as the main element in the pathology of MS, the deleterious processes leading to neurological decline include chronic inflammation, infiltration of T cells and macro- phages, axonal damage, and autoimmune response against myelin. However, the way these different processes articulate with each other remains controversial. As demyelination does not necessarily correlate with the severity of neurological decline, an important issue to understand is the timing of axonal damage in this pathology, to characterize it as a cause or as a consequence of demyelination. In the Theiler ’ s murine encephalomyelitis virus- induced demyelinating disease (TMEV-IDD)-model of MS, Tsunoda et al. (2003) suggested that demyelination could be secondary to axonal damage. Moreover, pioneer studies using experimental allergic encephalomyelitis (EAE) as a model of MS suggested that excitotoxic processes could induce axonal damage and may represent a key element in the pathogenesis of MS (Smith et al., 2000; Pitt et al., 2000). Finally, antagonising α-amino-3- hydroxy-5-methyl-4-isoxazolepropionate (AMPA) glutamatergic receptors led to lesser axonal damage and to better neurological score in EAE (Smith et al., 2000; Pitt et al., 2000). Cannabinoids form a class of molecules that include active components of marijuana, endogenous ligands (endocannabi- noids), and a variety of synthetic compounds. They induce their effects through activation of two G-protein-coupled receptors termed CB1 and CB2, and several yet-to-be-cloned receptors (Howlett et al., 2002) which might mediate some of the effects of cannabinoids. Therapeutic properties have been attributed to cannabinoids in various SNC pathologies including Parkinson’ s disease (Lastres-Becker et al., 2005), Alzheimer’ s disease (Ramirez et al., 2005), head trauma (Panikashvili et al., 2001) and MS. (Pryce et al., 2003) Arévalo-Martín and collaborators showed in 2003 that cannabinoids could exert therapeutic actions in the TMEV-IDD model of MS, reducing motor impairment and inflammation, and eventually promoting remyelination. However, the precise mechanisms promoting these beneficial effects of cannabinoids remain to be more clearly elucidated. Several studies described neuroprotective actions of cannabi- noids in different in vitro and in vivo models (Sarne and www.elsevier.com/locate/ymcne Mol. Cell. Neurosci. 34 (2007) 551 – 561 ⁎ Corresponding author. Fax: +34 91 585 47 54. E-mail address: docagne@cajal.csic.es (F. Docagne). Available online on ScienceDirect (www.sciencedirect.com). 1044-7431/$ - see front matter © 2006 Elsevier Inc. All rights reserved. doi:10.1016/j.mcn.2006.12.005