Annexin A1 and its N-terminal peptide Ac(2-26) regulate dopaminergic degeneration and neuroinflammation in a 6-OHDA model of Parkinson's disease.

“Annexin A1 and its N-terminal peptide Ac(2-26) regulate dopaminergic degeneration and neuroinflammation in a 6-OHDA model of Parkinson's disease. de Souza Ferreira LP(1), da Silva RA(2), Janisset NRLL(3), da Silva Alves A(4), Almeida JS(5), Vieira RR(6), Santos DD(6), de Oliva SU(6), Oliani SM(7), Cruz FC(3), Dati LMM(8), Gil CD(9). Author information: (1)Structural and Functional Biology Graduate Program, Department of Morphology and Genetics, Escola Paulista de Medicina, Universidade Federal de São Paulo (EPM/UNIFESP), São Paulo, Brasil. Electronic address: luiz.philipe@unifesp.br. (2)Biosciences Graduate Program, Instituto de Biociências, Letras e Ciências Exatas, Universidade Estadual Paulista (UNESP), São José do Rio Preto, Brasil. (3)Department of Pharmacology, EPM/UNIFESP, São Paulo, SP, Brasil. (4)Department of Physiology, Laboratory of Cellular Neurobiology, Instituto de Ciências Biomédicas, Universidade de São Paulo (ICB-USP), São Paulo, SP, Brasil. (5)Department of Pathology, EPM/UNIFESP, São Paulo, Brazil. (6)Structural and Functional Biology Graduate Program, Department of Morphology and Genetics, Escola Paulista de Medicina, Universidade Federal de São Paulo (EPM/UNIFESP), São Paulo, Brasil. (7)Structural and Functional Biology Graduate Program, Department of Morphology and Genetics, Escola Paulista de Medicina, Universidade Federal de São Paulo (EPM/UNIFESP), São Paulo, Brasil; Biosciences Graduate Program, Instituto de Biociências, Letras e Ciências Exatas, Universidade Estadual Paulista (UNESP), São José do Rio Preto, Brasil. (8)Instituto Butantan, São Paulo, SP, Brasil. (9)Structural and Functional Biology Graduate Program, Department of Morphology and Genetics, Escola Paulista de Medicina, Universidade Federal de São Paulo (EPM/UNIFESP), São Paulo, Brasil; Biosciences Graduate Program, Instituto de Biociências, Letras e Ciências Exatas, Universidade Estadual Paulista (UNESP), São José do Rio Preto, Brasil. Electronic address: cristiane.gil@unifesp.br. 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 Ac2-26 have shown neuroprotective potential, but the mechanisms underlying their effects in PD remain unclear. Here, we investigated the effects of AnxA1 and Ac2-26 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 Ac2-26 or saline. Motor behavior, dopaminergic neuron survival, cytokine levels, and glial changes were analyzed. Ac2-26 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. Ac2-26 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, Ac2-26 confers neuroprotection through AnxA1-dependent regulation of neuroinflammation, dopaminergic integrity, and hormonal balance, supporting its potential as a therapeutic target in PD. Copyright © 2026. Published by Elsevier Ltd. Conflict of interest statement: Declaration of Competing Interest ☒ The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: CRISTIANE DAMAS GIL reports financial support was provided by National Council for Scientific and Technological Development (CNPq; Grant No. 308524/2022-5). CRISTIANE DAMAS GIL reports financial support was provided by State of Sao Paulo Research Foundation (FAPESP; Grant No. 2022/02327-6). Luiz Philipe de Souza Ferreira reports financial support was provided by State of Sao Paulo Research Foundation (Grant No. 2021/00270-4). If there are other authors, they declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.”