Jordan L Schultz1, Alivia N Brinker2, Jia Xu3, Sarah E Ernst4, Fariba Tayyari5, Adam J Rauckhorst5, Lei Liu6, Ergun Y Uc7, Eric B Taylor8, Jacob E Simmering9, Vincent A Magnotta10, Michael J Welsh11, Nandakumar S Narayanan12. 1. Department of Psychiatry, Roy J and Lucille A Carver College of Medicine, University of Iowa, Iowa City, IA, 52242, USA; Division of Pharmacy Practice and Sciences, College of Pharmacy, University of Iowa, Iowa City, IA, 52242, USA; Department of Neurology, Roy J and Lucille A Carver College of Medicine, University of Iowa, Iowa City, IA, 52242, USA. Electronic address: jordan-schultz@uiowa.edu. 2. Department of Psychiatry, Roy J and Lucille A Carver College of Medicine, University of Iowa, Iowa City, IA, 52242, USA. 3. Department of Radiology, Roy J and Lucille A Carver College of Medicine, University of Iowa, Iowa City, IA, 52242, USA. 4. Department of Internal Medicine, Pappajohn Biomedical Institute, Roy J and Lucille A Carver College of Medicine, University of Iowa, Iowa City, IA, 52242, USA; Howard Hughes Medical Institute, University of Iowa, Iowa City, IA, 52242, USA. 5. Department of Molecular Physiology and Biophysics, Roy J and Lucille A Carver College of Medicine, University of Iowa, Iowa City, IA, 52242, USA. 6. Department of Biochemistry and Molecular Biology, Capital Medical University School of Basic Medicine, Beijing, 100069, China. 7. Department of Neurology, Roy J and Lucille A Carver College of Medicine, University of Iowa, Iowa City, IA, 52242, USA; Veteran's Affairs Medical Center, 601 US-6 W, Iowa City, IA, 52246, USA. 8. Department of Molecular Physiology and Biophysics, Roy J and Lucille A Carver College of Medicine, University of Iowa, Iowa City, IA, 52242, USA; Pappajohn Biomedical Institute, Roy J and Lucille A Carver College of Medicine, University of Iowa, Iowa City, IA, 52242, USA. 9. Department of Internal Medicine, Pappajohn Biomedical Institute, Roy J and Lucille A Carver College of Medicine, University of Iowa, Iowa City, IA, 52242, USA; Pappajohn Biomedical Institute, Roy J and Lucille A Carver College of Medicine, University of Iowa, Iowa City, IA, 52242, USA. 10. Department of Neurology, Roy J and Lucille A Carver College of Medicine, University of Iowa, Iowa City, IA, 52242, USA; Pappajohn Biomedical Institute, Roy J and Lucille A Carver College of Medicine, University of Iowa, Iowa City, IA, 52242, USA. 11. Department of Neurology, Roy J and Lucille A Carver College of Medicine, University of Iowa, Iowa City, IA, 52242, USA; Department of Internal Medicine, Pappajohn Biomedical Institute, Roy J and Lucille A Carver College of Medicine, University of Iowa, Iowa City, IA, 52242, USA; Department of Molecular Physiology and Biophysics, Roy J and Lucille A Carver College of Medicine, University of Iowa, Iowa City, IA, 52242, USA; Pappajohn Biomedical Institute, Roy J and Lucille A Carver College of Medicine, University of Iowa, Iowa City, IA, 52242, USA; Howard Hughes Medical Institute, University of Iowa, Iowa City, IA, 52242, USA. Electronic address: michael-welsh@uiowa.edu. 12. Department of Neurology, Roy J and Lucille A Carver College of Medicine, University of Iowa, Iowa City, IA, 52242, USA; Pappajohn Biomedical Institute, Roy J and Lucille A Carver College of Medicine, University of Iowa, Iowa City, IA, 52242, USA. Electronic address: nandakumar-narayanan@uiowa.edu.
Abstract
BACKGROUND: Impaired brain energy metabolism is a key feature of Parkinson's disease (PD). Terazosin (TZ) binds phosphoglycerate kinase 1 and stimulates its activity, which enhances glycolysis and increases ATP levels. Preclinical and epidemiologic data suggest that TZ may be neuroprotective in PD. We aimed to assess target engagement and safety of TZ in people with PD. METHODS: We performed a 12-week pilot study in people with PD. Participants were randomized to receive 5 mg TZ or placebo. Participants and study personnel were blinded. We assessed TZ target engagement by measuring brain ATP with 31P-magnetic resonance spectroscopy (MRS) and whole blood ATP with a luminescence assay. Robust linear regression models compared changes between groups controlling for baseline brain and blood ATP levels, respectively. We also assessed clinical measures of PD and adverse events. RESULTS: Thirteen participants were randomized. Mild dizziness/lightheadedness was more common in the TZ group, and three participants taking TZ dropped out because of dizziness and/or orthostatic hypotension. Compared to the placebo group, the TZ group had a significant increase in the ratio of βATP to inorganic phosphate in the brain. The TZ group also had a significant increase in blood ATP levels compared to the placebo group (p < 0.01). CONCLUSIONS: This pilot study suggests that TZ may engage its target and change ATP levels in the brain and blood of people with PD. Further studies may be warranted to test the disease-modifying potential of TZ.
BACKGROUND: Impaired brain energy metabolism is a key feature of Parkinson's disease (PD). Terazosin (TZ) binds phosphoglycerate kinase 1 and stimulates its activity, which enhances glycolysis and increases ATP levels. Preclinical and epidemiologic data suggest that TZ may be neuroprotective in PD. We aimed to assess target engagement and safety of TZ in people with PD. METHODS: We performed a 12-week pilot study in people with PD. Participants were randomized to receive 5 mg TZ or placebo. Participants and study personnel were blinded. We assessed TZ target engagement by measuring brain ATP with 31P-magnetic resonance spectroscopy (MRS) and whole blood ATP with a luminescence assay. Robust linear regression models compared changes between groups controlling for baseline brain and blood ATP levels, respectively. We also assessed clinical measures of PD and adverse events. RESULTS: Thirteen participants were randomized. Mild dizziness/lightheadedness was more common in the TZ group, and three participants taking TZ dropped out because of dizziness and/or orthostatic hypotension. Compared to the placebo group, the TZ group had a significant increase in the ratio of βATP to inorganic phosphate in the brain. The TZ group also had a significant increase in blood ATP levels compared to the placebo group (p < 0.01). CONCLUSIONS: This pilot study suggests that TZ may engage its target and change ATP levels in the brain and blood of people with PD. Further studies may be warranted to test the disease-modifying potential of TZ.
Authors: M T Hu; S D Taylor-Robinson; K R Chaudhuri; J D Bell; C Labbé; V J Cunningham; M J Koepp; A Hammers; R G Morris; N Turjanski; D J Brooks Journal: Brain Date: 2000-02 Impact factor: 13.501
Authors: Jacob E Simmering; Michael J Welsh; Lei Liu; Nandakumar S Narayanan; Anton Pottegård Journal: JAMA Neurol Date: 2021-04-01 Impact factor: 29.907
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