Safinamide and glutamate release: New insights

Abstract

s / Parkinsonism and Related Disorders 22 (2016) e149ee192 e177 Sciences, University of Ferrara, Ferrara, Italy; Consultant, Gallarate, Varese, Italy; RD Department of Medical Sciences, University of Ferrara, Ferrara, Italy; Consultant, Gallarate, Varese, Italy Objectives: Safinamide (Xadago®) is a novel drug recently approved as add-on therapy to levodopa in midto late-stage Parkinson's disease. Xadago® shows a unique dual mechanism of action: it has both dopaminergic properties (highly selective, potent and reversible inhibition of monoamine oxidase-B) and non-dopaminergic properties (state and usedependent sodium channel blockade causing inhibition of excessive glutamate release). The study aim was to evaluate the effect of safinamide on stimulated glutamate release in rat hippocampus at doses giving free brain concentrations able to block sodium channels and to provide a PK/PD approach to support its clinical relevance on overactive glutamate release inhibition. Methods: Glutamate release, stimulated by veratridine in the hippocampus of rats, was measured by in vivo microdialysis. Results: Safinamide was able to significantly inhibit the glutamate release in a dose-dependent manner and the relative measured free brain concentrations (0.3-2.2 mM) support the inhibition of sodium channels (2050% Ki. A functional blockade of sodium channels suggests that pharmacodynamically active concentrations of safinamide are available at the target sites in the brain: in rodents significant protection (50-70%) from convulsions was found when free brain concentration of 0.37-1.4 mM was reached. At the recommended clinical doses (50 and 100 mg) the estimated human free brain safinamide concentrations (0.21-1.92 mM) overlap the range of measured free brain concentrations effective in inhibiting overactive glutamate release in animals. Conclusions: These results clearly support the non-dopaminergic aspects of Xadago® mode of action in rats, likely relevant also in humans. P 6.004. 4I (N-(3-CHLORO-2-METHYLPHENYL) QUINOXALIN-2-CARBOXAMIDE), A NOVEL 5-HT3 RECEPTOR ANTAGONIST ALLEVIATES DEPRESSIVE BEHAVIOR EVOKED IN STREPTOZOTOCIN-INDUCED DIABETIC MICE: ROLE OF OXIDATIVE STRESS Deepali Gupta, Mahesh Radhakrishnan. Department of Pharmacy, Pilani,