Isoprenol-Induced Neuroprotection in Experimental Multiple Sclerosis

Abstract

Abstract Farnesol is a 15-carbon organic acyclic sesquiterpene alcohol (isoprenol) produced by plants and animals. It is a potent blocker of neuronal voltage-gated Ca2+ found in the human brain. It has potent anti-oxidant and antiinflammatory effects in vitro, and neuroprotection based on the regulation of free radicals production by glial cells was demonstrated in a murine model of neurotoxicity. Because inflammation, oxidative stress and intraneuronal Ca2+ overload are associated with central nervous system (CNS) demyelinating diseases, we sought to determine if farnesol treatment would result in protection against experimental autoimmune encephalomyelitis (EAE), a model of multiple sclerosis (MS). We compared the progression of EAE in C57BL/6 mice treated orally with farnesol (100 mg/kg/daily by gavage in olive oil) versus EAE progression in untreated mice (control) (n = 10/group). Treatment started at EAE induction and continued for 25 days. EAE clinical severity was monitored daily. Factorial repeated measures ANOVA of the scores showed: 1) a significant Day effect (disease onset 9 days after induction), 2) a significant Group effect (approx. 80% reduction in scores in the Farnesol group), and 3) a significant Day * Group interaction with scores being significantly lower in the Farnesol group every day starting one day after disease onset. At day 25, 50% of control mice had been euthanized due to scores ≥ 3.5 vs. none in the Farnesol group. Our results indicate that Farnesol significantly reduces disease onset in EAE. Studies to elucidate the mechanism of action of farnesol, screening of structural analogues of farnesol for anti-EAE activity, and assessment of farnesol therapeutic efficacy in other animal models of MS are being conducted.