Evidence from multiple sclerosis (MS) tissue pathology and in vivo functional studies in EAE suggests that neuronal/axonal ion channels and neurotransmitter receptors represent potential therapeutic targets in MS [Nat. Med. (2000) 6:62-66; Arch Neurol. (2002) 59:1377-80]. Voltage-dependent calcium channels (VDCCs), which mediate Ca2+ entry into cells, are implicated in gray and white matter damage in the CNS. In both MS and EAE, VDCCs are incorporated into the axoplasmic membrane, this ectopic distribution perhaps contributing to the axonal degeneration seen in these disease states [Brain (2001) 124:1114-24]. Here, we describe the effect two N-type calcium channel antagonists on the course of EAE, an animal model of MS [see also Tokuhara et al SFN 2003]. E2050 [profiled in Soc. Neurosci. Abstr. Vol 27 Prog No 332.15, 2001] and an additional compound, ER-129002-02, administered just prior to disease onset (30 and 100 mg/kg; p.o.), dose dependently reduced disease severity. Improved neurological outcome coul...