**Background**
Neurodegenerative disorders, such as Parkinson’s disease and ischemic stroke, are characterized by the progressive loss of neuronal function and structure. A key factor in the pathogenesis of these conditions is the imbalance of neurotransmitters and the accumulation of oxidative stress. Monoamine oxidase B (MAO-B) is an enzyme primarily located in glial cells and certain neurons, playing a critical role in the breakdown of dopamine. Inhibiting MAO-B can increase synaptic dopamine levels and provide neuroprotective effects, making it a primary therapeutic target for treating motor deficits and preventing neuronal death. In this context, we will introduce a potent and selective MAO-B inhibitor – Safinamide.
**Definition**
Safinamide is a potent, selective, and reversible monoamine oxidase B (MAO-B) inhibitor with an IC50 value of 0.098 μM, demonstrating high selectivity over MAO-A (IC50 = 580 μM).
**In Vitro and In Vivo Studies**
According to the Safinamide description, this compound not only inhibits MAO-B but also blocks sodium channels and modulates glutamate (Glu) release. Safinamide in vitro studies in rat cortical neurons revealed that it reduces the amplitude of peak sodium currents in a concentration-dependent manner (1-300 μM). The inhibitory effect is voltage-dependent, with an IC50 of 8 μM at depolarized potentials (-53 mV) compared to 262 μM at resting potentials (-110 mV). Furthermore, in BTI-TN-5B1-4 cells, Safinamide demonstrated potent inhibition of human microsomal MAO-B with IC50 values ranging from 5.18 nM to 23.07 nM depending on the substrate and assay used, while remaining inactive against MAO-A (IC50 > 25,900 nM).
Regarding Safinamide In Vivo activity, the compound has shown significant neuroprotective and neurorescuing effects. In a focal cerebral ischemia C57/BL6 male mouse model, treatment with Safinamide (90 mg/kg; i.p.; once daily for 14 days) prior to middle cerebral artery occlusion (MCAO) significantly reduced cerebral infarction volume, improved neurological deficits, and attenuated the disruption of the blood-brain barrier (BBB) and the expression of tight junction proteins occludin and ZO-1. Additionally, in rats, Safinamide (5, 15, and 30 mg/kg; i.p.) dose-dependently inhibited veratridine-induced GABA and Glu release, with full inhibition achieved at 5 and 15 mg/kg for Glu release. For researchers seeking detailed Safinamide technical information, these results highlight its multi-target mechanism. In conclusion, Safinamide is a selective MAO-B inhibitor and sodium channel blocker that holds promise for the study of Parkinson’s disease and ischemic stroke.
Keywords
Safinamide, 133865-89-1, FCE 26743, EMD 1195686, FCE26743, FCE-26743, EMD1195686, EMD-1195686, Monoamine Oxidase, MAO, Parkinson, anticonvulsant, neuroprotective, neurorescuing
References
[1] Leonetti F, et al. Solid-phase synthesis and insights into structure-activity relationships of safinamide analogues as potent and selective inhibitors of type B monoamine oxidase. J Med Chem, 2007, 50(20), 4909-4916.
[2] C Caccia, et al.Safinamide: from molecular targets to a new anti-Parkinson drug. Neurology. 2006 Oct 10;67(7 Suppl 2):S18-23.
[3] Michele Morari, et al. Safinamide Differentially Modulates In Vivo Glutamate and GABA Release in the Rat Hippocampus and Basal Ganglia.J Pharmacol Exp Ther. 2018 Feb;364(2):198-206.