Gender differences in depressive-like behavior in Parkinson’s disease
- 1Research Operative Unit of Neuropharmacology and Translational Neurosciences, Oasi Research Institute
- 2Department of Chemical, Biological, Pharmaceutical and Environmental Sciences, University of Messina
Abstract
Introduction: A Parkinson’s disease (PD) is a progressive neurodegenerative disorder characterized by both motor and non-motor symptoms, including depression, which markedly impairs patients’ quality of life. Although sex differences have been described in PD progression, the mechanisms underlying gender-specific susceptibility to depressive symptoms remain poorly understood.
Methods: This study investigated sex-dependent differences in depressive-like behaviors and their underlying molecular mechanisms in an in vivo model of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-induced dopaminergic degeneration, using adult male and female CD1 mice.
Results: Our results demonstrated that MPTP administration induced nigrostriatal degeneration and α-synuclein accumulation in both sexes, with more pronounced alterations in males. Male mice also exhibited greater depressive- and anxiety-like behaviors, accompanied by a marked reduction in 5-HT2C receptor expression, increased hippocampal acetylcholine levels, impaired expression of the synaptic markers PSD-95 and synaptophysin, and a stronger downregulation of the BDNF/PI3K/AKT pathway compared with females.
Discussion: These findings demonstrate that sex significantly influences vulnerability to PD-associated depressive symptoms, with males showing greater behavioral and molecular impairment. Overall, our results highlight the importance of considering sex as a biological variable in PD research and support the development of personalized therapeutic strategies targeting non-motor symptoms.
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BibTeX
@article{deborah2026gender,
title = {{Gender differences in depressive-like behavior in Parkinson’s disease}},
author = {Mannino Deborah and Cucinotta Laura and Basilotta Rossella and Labellarte Davide and Esposito Emanuela and Campolo Michela and Paterniti Irene},
journal = {Frontiers in Pharmacology},
year = {2026},
month = oct,
doi = {10.3389/fphar.2026.1961464},
url = {https://www.frontiersin.org/articles/10.3389/fphar.2026.1961464/full},
note = {CC BY 4.0},
}
RIS
TY - JOUR
TI - Gender differences in depressive-like behavior in Parkinson’s disease
AU - Mannino Deborah
AU - Cucinotta Laura
AU - Basilotta Rossella
AU - Labellarte Davide
AU - Esposito Emanuela
AU - Campolo Michela
AU - Paterniti Irene
PY - 2026
DA - 2026/10/21
JO - Frontiers in Pharmacology
DO - 10.3389/fphar.2026.1961464
UR - https://www.frontiersin.org/articles/10.3389/fphar.2026.1961464/full
AB - Introduction: A Parkinson’s disease (PD) is a progressive neurodegenerative disorder characterized by both motor and non-motor symptoms, including depression, which markedly impairs patients’ quality of life. Although sex differences have been described in PD progression, the mechanisms underlying gender-specific susceptibility to depressive symptoms remain poorly understood. Methods: This study investigated sex-dependent differences in depressive-like behaviors and their underlying molecular mechanisms in an in vivo model of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-induced dopaminergic degeneration, using adult male and female CD1 mice. Results: Our results demonstrated that MPTP administration induced nigrostriatal degeneration and α-synuclein accumulation in both sexes, with more pronounced alterations in males. Male mice also exhibited greater depressive- and anxiety-like behaviors, accompanied by a marked reduction in 5-HT2C receptor expression, increased hippocampal acetylcholine levels, impaired expression of the synaptic markers PSD-95 and synaptophysin, and a stronger downregulation of the BDNF/PI3K/AKT pathway compared with females. Discussion: These findings demonstrate that sex significantly influences vulnerability to PD-associated depressive symptoms, with males showing greater behavioral and molecular impairment. Overall, our results highlight the importance of considering sex as a biological variable in PD research and support the development of personalized therapeutic strategies targeting non-motor symptoms.
SN - 1663-9812
ER -