Neuroprotective Effects of Intranasally Administered Octadecaneuropeptide Analog in a Mouse Model of MPTP-Induced Parkinson's Disease

Parkinson's disease (PD) is a neurodegenerative disorder for which existing therapies are primarily palliative and lack curative efficacy. Octadecaneuropeptide (ODN) is a peptide exclusively produced by astrocytes that protects neurons against oxidative cell damage and apoptosis in in vitro and in vivo models of PD. However, ODN cannot cross the blood-brain barrier (BBB) and requires intracerebroventricular injection to reach the brain, presenting a significant challenge for therapeutic application. This study investigates the neuroprotective efficacy of cyclo(1-8)OP, an ODN analog, delivered via the intranasal (IN) route to bypass the BBB in an in vivo model of PD. Male C57BL/6J mice were used for the experiments and divided into four groups: sham, MPTP- (20 mg/kg body weight, intraperitoneal), cyclo(1-8)OP- (10 ng/10 µL, IN), and MPTP + cyclo(1-8)OP-treated animals. On day 0 (D0), animals received three intraperitoneal injections of 100 µL MPTP solution at 2-h intervals (MPTP- and MPTP + cyclo(1-8)OP-treated mice) or saline solution (sham and cyclo(1-8)OP-treated mice). One hour after the final injection, 10 µL of IN instillation of cyclo(1-8)OP (cyclo(1-8)OP- and MPTP + cyclo(1-8)OP-treated mice) or IN saline solution (sham and MPTP-treated mice) was administered. On D7, a cylinder test was performed to assess motor function. Subsequently, animals were sacrificed, and the striatum was removed and analyzed by RT-qPCR to assess caspase-3 gene expression. Tissue samples were also used to measure antioxidant enzyme activities, reactive oxygen species (ROS), malondialdehyde (MDA), and carbonylated protein abundance. A single IN dose of 10 ng cyclo(1-8)OP, administered 1 h after the final MPTP dose, prevented neurotoxicity in the striatum 7 days post-treatment. Cyclo(1-8)OP-mediated neuroprotection was associated with strong inhibition of caspase-3 expression induced by MPTP in the striatum. Additionally, cyclo(1-8)OP restored the activities of antioxidant enzymes, preventing the accumulation of ROS, lipid peroxidation products, and protein carbonylation in the striatum.