Work

A dose-finding study shows terazosin enhanced energy metabolism in neurologically healthy adults

Year: 2025

Type: article

Abstract: Background Parkinson's disease (PD) is a common neurodegenerative disease lacking treatments that modify progressive neuron loss. Terazosin (TZ) increases activity of the glycolytic enzyme phosphoglycerate kinase 1 and could potentially benefit impaired brain bioenergetics in PD. Preclinical data are encouraging, but we lack human data on relationships between TZ dose and measures of TZ target engagement in women and men. Objective This study evaluated the dose-dependent effects of TZ on brain and systemic bioenergetics and safety and tolerability in neurologically healthy older adults. Methods We administered TZ (1, 5, and 10 mg/day) to 18 neurologically healthy 60–85-year-old people. We measured plasma and cerebrospinal fluid TZ concentrations and changes in levels of whole blood ATP, brain ATP with 31 P magnetic resonance spectroscopy, cerebral metabolic activity with 18 F-FDG PET imaging, and plasma metabolomics. We also assayed tolerability and safety. Results TZ crossed the blood-brain barrier, and 5 mg/day increased whole blood ATP and decreased brain 18 F-FDG uptake. TZ 1 mg/day lacked significant effects, and 10 mg/day did not produce additional metabolic benefit compared to 5 mg/day. These effects were similar for both sexes. Mild dizziness occurred in 3 females and 1 male. Conclusions These findings in humans align with results from preclinical cell, animal, and epidemiological studies. Our data show that TZ increases markers of energy metabolism with a biphasic dose-response and suggest that 5 mg/day TZ may provide maximal benefit while minimizing adverse consequences of higher doses. These results lay groundwork for clinical trials in people with PD.

Source: Journal of Parkinson s Disease

DOI: 10.1177/1877718x251356503