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Annexin A1 and its N-terminal peptide Ac2-26 regulate dopaminergic degeneration and neuroinflammation in a 6-OHDA model of Parkinson's disease

Year: 2026

Type: article

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 Ac 2-26 have shown neuroprotective potential, but the mechanisms underlying their effects in PD remain unclear. Here, we investigated the effects of AnxA1 and Ac 2-26 in 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 Ac 2-26 or saline. Motor behavior, dopaminergic neuron survival, cytokine levels, and glial changes were analyzed. Ac 2-26 improved motor performance and protected against 6-OHDA-induced dopaminergic degeneration in the striatum and substantia nigra (SN) of AnxA1 +/+ mice, preventing the loss of tyrosine hydroxylase (TH) + neurons. These protective effects were reduced in AnxA1 -/- mice. Ac 2-26 also modulated neuroinflammation in a genotype-dependent manner, increasing anti-inflammatory cytokines and limiting pro-inflammatory mediators in the SN of AnxA1 +/+ animals. In females, genetic deletion of AnxA1 led to reduced TH expression, impaired behavioral recovery, and disruption of the estrous cycle. Overall, Ac 2-26 confers neuroprotection through AnxA1-dependent regulation of neuroinflammation, dopaminergic integrity, and hormonal balance, supporting its potential as a therapeutic target in PD. • Ac 2-26 preserves dopaminergic neurons in a Parkinson's disease mouse model • Neuroprotection by Ac 2-26 depends on endogenous Annexin A1 signaling • Ac 2-26 differentially modulates neuroinflammatory cytokine responses • Annexin A1 deficiency disrupts hormone cycles and sex-based neuroprotection

Source: Neuropharmacology

DOI: 10.1016/j.neuropharm.2026.110942