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

BackgroundParkinson'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.ObjectiveThis study evaluated the dose-dependent effects of TZ on brain and systemic bioenergetics and safety and tolerability in neurologically healthy older adults.MethodsWe 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 ³¹P magnetic resonance spectroscopy, cerebral metabolic activity with ¹⁸F-FDG PET imaging, and plasma metabolomics. We also assayed tolerability and safety.ResultsTZ crossed the blood-brain barrier, and 5 mg/day increased whole blood ATP and decreased brain ¹⁸F-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.ConclusionsThese 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.