Background: Parkinson's disease (PD) is a prevalent neurodegenerative disorder where progressive neuron loss is driven by impaired brain bioenergetics, particularly mitochondrial dysfunction and disrupted cellular respiration. Terazosin (TZ), an alpha1 adrenergic receptor antagonist with a known efficacy in treating benign prostatic hypertrophy and hypertension, has shown potential in addressing energy metabolism deficits associated with PD due to its action on phosphoglycerate kinase 1 (PGK1). This study aimed to investigate the safety, tolerability, bioenergetic target engagement, and optimal dose of TZ in neurologically healthy subjects. Methods: Eighteen healthy men and women (60 to 85 years old) were stratified into two cohorts based on maximum TZ dosages (5 mg and 10 mg daily). Methods included plasma and cerebrospinal fluid TZ concentration measurements, whole blood ATP levels, 31Phosphorous magnetic resonance spectroscopy for brain ATP levels, 18F FDG PET imaging for cerebral metabolic activity, and plasma metabolomics. Results: Our results indicated that a 5 mg/day dose of TZ significantly increased whole blood ATP levels and reduced global cerebral 18F FDG PET uptake without significant side effects or orthostatic hypotension. These effects were consistent across sexes. Higher doses did not result in additional benefits and showed a potential biphasic dose-response. Conclusions: TZ at a dosage of 5 mg/day engages its metabolic targets effectively in both sexes without inducing significant adverse effects and provides a promising therapeutic avenue for mitigating energetic deficiencies. Further investigation via clinical trials to validate TZ's efficacy and safety in neurodegenerative (i.e., PD) contexts is warranted.

The University of Iowa Research Foundation has filed patents for intellectual property related to use of TZ and related compounds for neurodegeneration. MJW is a co-founder of Shandong Bangentai Biomedical Technology Group Co., Ltd in Jinan, China. This company is working to develop treatments for people with PD. The authors declare no other competing interests.

NCT04551040

This study was funded by the Michael J. Fox Foundation for Parkinsons Research (to JLS and NSN), NIH Grant 5UL1TR002537 04 through the University of Iowa Institute for Clinical and Translational Science and was conducted using equipment supported by NIH Grant S10RR028821, and NIH Grant K23NS117736 (to JLS). MJW is an investigator of the Howard Hughes Medical Institute. The study sponsors had no role in the conduct, analysis, or reporting of these results.

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