Safinamide

Abstract

Ideal treatment in Parkinson's disease (PD) aims at relieving symptoms and slowing disease progression. Of all remedies, levodopa remains the most effective for symptomatic relief, but the medical need for neuroprotectant drugs is still unfulfilled. Safinamide, currently in phase III clinical trials for the treatment of PD, is a unique molecule with multiple mechanisms of action and a very high therapeutic index. It combines potent, selective, and reversible inhibition of MAO-B with blockade of voltage-dependent Na+ and Ca2+ channels and inhibition of glutamate release. Safinamide has neuroprotective and neurorescuing effects in MPTP-treated mice, in the rat kainic acid, and in the gerbil ischemia model. Safinamide potentiates levodopa-mediated increase of DA levels in DA-depleted mice and reverses the waning motor response after prolonged levodopa treatment in 6-OHDA-lesioned rats. Safinamide has excellent bioavailability, linear kinetics, and is suitable for once-a-day administration. Therefore, safinamide may be used in PD to reduce l-dopa dosage and also represents a valuable therapeutic drug to test disease-modifying potential.

Safinamide for the treatment of Parkinson’s disease

“…Morsali et al in their rat model showed that safinamide acted directly on cultured microglial cells to reduce superoxide formation by NADPH oxidase inhibition and to increase glutathione levels [28]. In 1-methyl 4-phenyl 1,2,3,6 tetrahydropyridine (MPTP) treated mice, safinamide administered 4 hours after the toxin attenuates nigral cell body degeneration [27], which is in agreement with with Morsali's findings. A rat study using toxins such as veratridine to induce neuronal death demonstrated that safinamide reduced glutamate and gamma-aminobutyric acid (GABA) release, thereby attenuating excitotoxic neuronal death [27].…”

“…Animal studies (mouse, rat and primate) have shown that safinamide concentrations are 9-16 times higher in the brain than in the plasma and that safinamide, in dopamine deficient mice, potentiates levodopa induced dopamine release [27]. Safinamide has no Catechol-O-methyltransferase (COMT) activity [21] and as mentioned its MAOB activity is saturated at doses below those that produce clinical motor improvements.…”

Safinamide

“…However, tyrosine hydroxylase (TH) staining of the SN showed a significant dose-dependent sparing of dopaminergic neurons in the SAF-treated animals compared with the 80% depletion observed in the control batch. 15 Transient forebrain ischemia caused by 5-min bilateral carotid occlusion (BCO) in mongolian gerbils results in behavioral deficits and neuronal loss in selected hippocampal sectors. 15 Days after, animals tested with the passive avoidance retention test showed poor performance, reflecting cognitive impairment.…”

“…15 Transient forebrain ischemia caused by 5-min bilateral carotid occlusion (BCO) in mongolian gerbils results in behavioral deficits and neuronal loss in selected hippocampal sectors. 15 Days after, animals tested with the passive avoidance retention test showed poor performance, reflecting cognitive impairment. In an initial series of experiments, SAF was administered intraperitoneally; 100 mg/kg both 30 min prior to and after BCO.…”

Current Status of Symptomatic Medical Therapy in Parkinson’s Disease

“…Safinamide is a highly selective and reversible MAO B inhibitor that also appears to have the capability of blocking voltage-dependent sodium and calcium channels and therefore inhibiting glutamate release. [137][138][139] Pilot studies have demonstrated improvement in nonfluctuating and fluctuating PD. 138 Finally, changes in technology may allow the development of an easier and safer way to provide continuous infusions.…”