Chaperone Sigma1R mediates the neuroprotective action of afobazole in the 6-OHDA model of Parkinson's disease.

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.

SUBMITTER: Voronin MV 

PROVIDER: S-EPMC6863824 | biostudies-literature | 2019 Nov

REPOSITORIES: biostudies-literature