Annexin A1 and its N-terminal peptide Acregulate dopaminergic degeneration and neuroinflammation in a 6-OHDA model of Parkinson's disease.

Abstract

Parkinson's disease (PD) is a neurodegenerative disorder characterized by dopaminergic neuron loss, and growing evidence highlights neuroinflammation as a key contributor to disease progression. Annexin A1 (AnxA1), a glucocorticoid-regulated protein with anti-inflammatory and pro-resolving functions, and its N-terminal peptide Achave shown neuroprotective potential, but the mechanisms underlying their effects in PD remain unclear. Here, we investigated the effects of AnxA1 and Acin a 6-hydroxydopamine (6-OHDA) mouse model of PD using C57BL/6 wild-type (AnxA1) and AnxA1 knockout (AnxA1) mice. Animals received a unilateral 6-OHDA injection into the striatum, followed by intraperitoneal injection of Acor saline. Motor behavior, dopaminergic neuron survival, cytokine levels, and glial changes were analyzed. Acimproved motor performance and protected against 6-OHDA-induced dopaminergic degeneration in the striatum and substantia nigra (SN) of AnxA1mice, preventing the loss of tyrosine hydroxylase (TH)neurons. These protective effects were reduced in AnxA1mice. Acalso modulated neuroinflammation in a genotype-dependent manner, increasing anti-inflammatory cytokines and limiting pro-inflammatory mediators in the SN of AnxA1animals. In females, genetic deletion of AnxA1 led to reduced TH expression, impaired behavioral recovery, and disruption of the estrous cycle. Overall, Acconfers neuroprotection through AnxA1-dependent regulation of neuroinflammation, dopaminergic integrity, and hormonal balance, supporting its potential as a therapeutic target in PD.