Isoprenol‐Induced Neuroprotection in Experimental Multiple Sclerosis

Abstract

Study ObjectivesFarnesol is a 15‐carbon organic acyclic sesquiterpene alcohol (isoprenol) produced by plants and animals. It is a potent blocker of neuronal voltage‐gated Ca2+ channels (L‐ and N‐type) and it is found in the human brain (Roullet, J. Biol. Chem., 1999). Other studies have shown farnesol has potent anti‐oxidant and anti‐inflammatory effects in vitro. Neuroprotection by farnesol was demonstrated in a murine model of neurotoxicity in a mechanism based on the regulation of the production of free radicals by glial cells, and the production of proinflammatory cytokines within the central nervous system. Because inflammation, oxidative stress and intraneuronal Ca2+ overload are associated with CNS demyelinating diseases, we sought to determine if farnesol treatment would result in protection against experimental autoimmune encephalomyelitis (EAE), a well‐established model of multiple sclerosis (MS).MethodsWe compared the progression of EAE in myelin‐oligodendrocyte‐glycoprotein (MOG35–55) immunized C57BL/6 mice (male, approx. 20 g body weight) treated orally with farnesol (100 mg/kg administered daily by gavage in olive oil) versus EAE progression in untreated mice (control) (n = 10/group). Farnesol treatment was started at the time of EAE induction and continued for 25 days at which time animals were euthanized. EAE clinical severity (CS) was monitored daily using a 0 to 5 neurological (paralysis) scoring system (0, normal, 5 most severe or death).ResultsFactorial repeated measures ANOVA of the CS scores showed: 1) a significant (p<0.001) Day effect (disease onset 9 days after induction), 2) a significant (p<0.002) Group effect (approx. 80% reduction in CS scores in the Farnesol group on average), and 3) a significant (p<0.001) [Day * Group] interaction with CS scores being significantly lower in the Farnesol group at all time points every day starting one day after disease onset until day 25). At day 25, 5 out of 10 mice had died or had been euthanized due to scores ≥ 3.5 in controls vs. none in the Farnesol group. Mice treated with farnesol maintained a constant body weight (BW, in g) throughout the study (BW = 19.1, 19.2, 18.6 and 19.6 on average at days 0, 7, 14 and 21 respectively), and displayed normal locomotor activity (video not shown). In contrast, control mice lost weight: 18.1, 18.8, 16.1 and 17.5 on average at days 0, 7, 14 and 21 (ANOVA: p<0.012 [Group], p < 0.001 [Day], and p<0.012 [Group * Day] interaction).Discussion/ConclusionFarnesol significantly reduces disease onset in experimental MS, suggesting that farnesol may have therapeutic efficacy in MS patients. The molecular and cellular mechanisms underlying disease protection by farnesol remain to be determined but could involve protection against either intracellular Ca2+ overload, oxidative stress, or inflammation. Studies to elucidate the mechanism of action of farnesol, screening of structural analogues of farnesol for anti‐MS activity, and assessment of farnesol therapeutic efficacy in other animal models of MS are being conducted.