Testosterone modulates respiratory control but does not exert neuroprotective effects in a Parkinson's disease model

Parkinson's disease (PD) is a neurodegenerative disorder characterized by the loss of dopaminergic neurons in the substantia nigra (SN). Patients with PD exhibit classic motor symptoms such as tremors and bradykinesia, as well as non-classical symptoms, including respiratory dysfunctions, which significantly contribute to increased mortality. Epidemiological studies suggest that men are more frequently affected by PD, although the role of testosterone remains unclear. Therefore, this study aimed to investigate the role of testosterone in modulating respiratory activity and respiratory nuclei under basal conditions and in an experimental PD model. Testosterone was directly administered into the fourth brain ventricle (4 V) of C57BL/6 mice, while a separate group underwent orchiectomy (ORX) followed by induction of the experimental PD model. Both functional and neuroanatomical aspects of respiratory activity were evaluated. Testosterone injection into the 4 V reduced basal respiratory frequency, both acutely and subchronically. ORX animals showed a modest (∼12 %) reduction in TH⁺ neurons in the SN under basal conditions. However, both PD groups (Sham and ORX) exhibited a similar and extensive neuronal loss (∼76 %). Changes in basal respiratory activity, as well as in the density of neurokinin-1 receptors and phox2b⁺ neurons in the medullary respiratory nuclei, were detected exclusively in the PD model, with no significant differences in the control or ORX groups. These findings suggest that while testosterone modulates basal respiratory activity and may have a modest effect on dopaminergic neurons maintenance under physiological conditions its reduction through ORX does not influence neurodegeneration or respiratory dysfunction observed in the PD model.