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.

Deferred Administration of Afobazole Induces Sigma1R-Dependent Restoration of Striatal Dopamine Content in a Mouse Model of Parkinson’s Disease

“…6-OHDA lesions were made according to [ 22 ]. In detail, 30 min prior to surgery, the animals were anesthetized with chloral hydrate (400 mg/kg intraperitoneally) [ 67 , 86 ].…”

“…Motor behavior was studied in male ICR mice utilizing a Rota-rod/RS LE 8500 apparatus (Panlab/Harvard apparatus, Barcelona, Spain). The rotarod test was performed as described previously [ 22 , 87 ]. Two training sessions spaced 24 h apart were performed to acclimate the experimental animals to the apparatus and to exclude hypodynamic animals from the study.…”

“…One of the promising targets for PD treatment is chaperone Sigma1R [ 20 , 21 , 22 ]. Sigma1Rs are widely spread in the brain and nigrostriatal pathway in particular [ 23 , 24 ].…”

“…Different in vivo models of PD have demonstrated the possibility of neuroprotective activity due to Sigma1R ligand activation [ 20 , 22 , 72 ]. The selective Sigma1R agonist PRE-084, administered to mice with unilateral intrastriatal 6-OHDA lesions, restored DA content in the striatum, increased the number of TH+ cells in SNc, and facilitated motor behavior in various tests [ 20 , 22 ]. The Sigma1R agonist with antidepressant activity, SA4503, improved both motor deficits and cognitive impairments in 1-methyl-4-phenyl-3,6-dihydro-2H-pyridine (MPTP)-treated mice [ 72 ].…”

“…Afobazole restored DA content in the striatum of mice with unilateral intrastriatal 6-OHDA lesions [ 83 ]. Previously, in a 6-OHDA-induced model of PD using selective Sigma1R ligands, we demonstrated the contribution of chaperone Sigma1R to the neuroprotective effect of a 14-day afobazole course started on the day of 6-OHDA lesion [ 22 ]. The aim of the present investigation became the study of Sigma1R’s contribution to the action of afobazole upon deferred administration to mice with intrastriatal 6-OHDA lesions.…”