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Intracerebroventricular delivery of an ODN peptide analog protects dopaminergic neurons and modulates miRNA expression in a mouse model of Parkinson’s disease

Year: 2026

Type: article

Abstract: Introduction Parkinson’s disease (PD) is characterized by progressive dopaminergic neuron degeneration, accompanied by oxidative stress, neuroinflammation and apoptosis. Octadecaneuropeptide, ODN, is an astroglia-derived neuropeptide known to exert potent antioxidant and anti‐apoptotic effects, protecting neuronal cells against oxidative damage and inflammation both in vivo and in vitro . In the present study, we investigated the neuroprotective potential of OP, an iso-active ODN analog, in an acute MPTP‐induced mouse model of PD. Methods Mice were assigned to four groups i.e., control, MPTP, OP, and MPTP plus OP. MPTP was administered intraperitoneally (3 × 20 mg/kg, 2‐h intervals), followed 1 h later by an intracerebroventricular injection of the OP (10 ng/10 μL). Brains were collected on day 7 for real-time PCR, Western blotting, immunohistochemistry, and Biochemical analyses. Results and Discussion Intracerebroventricular administration of OP significantly prevented the loss of tyrosine hydroxylase expression and mediating neuroprotective effect with stimulation of antiapoptotic gene Bcl‐2 in the substantia nigra and ventral tegmental area in MPTP‐treated mice. Moreover, OP markedly reduced MPTP‐induced oxidative damage by reducing ROS overproduction and lipid peroxidation and enhancing antioxidant catalase activity. OP also stimulated ERK1/2 phosphorylation and reduced the expression of pro‐inflammatory genes such as TNF‐α and increased IL‐10 mRNA levels. In addition, OP prevented MPTP‐induced down regulation of tight junction proteins i.e. occludin, ZO‐1 preserving blood–brain barrier (BBB) integrity. Furthermore, OP abolished MPTP‐induced dysregulation of PD‐related microRNAs including miR‐21‐3p, miR‐29a‐5p and markedly increased miR‐34b‐5p expression in nigrostriatal DA neurons. Taken together, these findings indicate that OP exerts potent neuroprotective effects by reducing oxidative stress, preserving BBB integrity, and limiting neuroinflammation and apoptosis. OP may therefore represent a promising therapeutic candidate for preventing dopaminergic neurodegeneration through modulation of key molecular pathways, including microRNAs involved in oxidative neurodegeneration.

Source: Frontiers in Pharmacology

DOI: 10.3389/fphar.2026.1933852