Chaperone Sigma1R mediates the neuroprotective action of afobazole in the 6-OHDA model of Parkinson\u2019s disease

Mikhail V Voronin,Ilya A Kadnikov,Dmitry N Voronkov,Sergey B Seredenin

doi:10.1038/s41598-019-53413-w

Abstract

Parkinson’s disease (PD) is a progressive neurodegenerative disease with limited treatment options. Therefore, the identification of therapeutic targets is urgently needed. Previous studies have shown that the ligand activation of the sigma-1 chaperone (Sigma1R) promotes neuroprotection. The multitarget drug afobazole (5-ethoxy-2-[2-(morpholino)-ethylthio]benzimidazole dihydrochloride) was shown to interact with Sigma1Rs and prevent decreases in striatal dopamine in the 6-hydroxydopamine (6-OHDA)-induced parkinsonism model. The aim of the present study was to elucidate the role of Sigma1Rs in afobazole pharmacological activity. Using ICR mice we found that administration of afobazole (2.5 mg/kg, i.p.) or selective agonist of Sigma1R PRE-084 (1.0 mg/kg, i.p.) over 14 days normalizes motor disfunction and prevents decreases in dopamine in the 6-OHDA-lesioned striatum. Afobazole administration also prevents the loss of TH + neurons in the substantia nigra. The pre-administration of selective Sigma1R antagonist BD-1047 (3.0 mg/kg, i.p.) abolishes the activity of either afobazole or PRE-084, as determined using the rotarod test and the analysis of striatal dopamine content. The current study demonstrates the contribution of Sigma1Rs in the neuroprotective effect of afobazole in the 6-OHDA model of Parkinson’s disease and defines the therapeutic perspective of Sigma1R agonists in the clinic.

Highlights

Parkinson’s disease is a neurodegenerative condition caused by injury in dopamine-producing regions of the brain, especially in neurons of the substantia nigra pars compacta (SNc) and their axonal projections to the striatum
We found that the DA content in the 6-OHDA lesioned striatum of vehicle-treated mice decreased two-fold compared to that in the contralateral striatum and in the damaged striatum of sham-operated mice (Fig. 1)
DA concentration increased in response to afobazole treatment, dihydroxyphenylacetic acid (DOPAC) content was in an intermediate range between concentrations observed in sham-operated and 6-OHDA-lesioned mice (Fig. 2)

Summary

Introduction

Parkinson’s disease is a neurodegenerative condition caused by injury in dopamine-producing regions of the brain, especially in neurons of the substantia nigra pars compacta (SNc) and their axonal projections to the striatum. In response to ligand activation, the Sigma1R enters a monomeric state and, as a part of the lipid domain, translocates to the region of nuclear and cytoplasmic membranes, where it regulates the activity of different receptors, ion channels and enzymes[18,25]. This activity prevents excitotoxicity and glial activation and may promote neuroprotective effects in Parkinson’s disease[26–34]. The aim of the present study was to determine the role of Sigma1Rs in the afobazole-mediated normalizing effect on dopamine content in the striatum in an in vivo mouse model of Parkinson’s disease induced by 6-OHDA lesions

Objectives

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Conclusion