{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"institution":[{"name":"medRxiv"}],"indexed":{"date-parts":[[2026,10,7]],"date-time":"2026-10-07T15:33:38Z","timestamp":1791387218668,"version":"4.3.3"},"posted":{"date-parts":[[2024,5,22]]},"group-title":"Neurology","reference-count":55,"publisher":"openRxiv","content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"accepted":{"date-parts":[[2024,5,22]]},"abstract":"<jats:title>ABSTRACT<\/jats:title>\n                <jats:sec>\n                  <jats:title>Background<\/jats:title>\n                  <jats:p>Parkinson\u2019s 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 \u03b1-1 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.<\/jats:p>\n                <\/jats:sec>\n                <jats:sec>\n                  <jats:title>Methods<\/jats:title>\n                  <jats:p>\n                    Eighteen healthy men and women (60 \u2013 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,\n                    <jats:sup>31<\/jats:sup>\n                    Phosphorous magnetic resonance spectroscopy for brain ATP levels,\n                    <jats:sup>18<\/jats:sup>\n                    F-FDG PET imaging for cerebral metabolic activity, and plasma metabolomics.\n                  <\/jats:p>\n                <\/jats:sec>\n                <jats:sec>\n                  <jats:title>Results<\/jats:title>\n                  <jats:p>\n                    Our results indicated that a 5 mg\/day dose of TZ significantly increased whole blood ATP levels and reduced global cerebral\n                    <jats:sup>18<\/jats:sup>\n                    F-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.\n                  <\/jats:p>\n                <\/jats:sec>\n                <jats:sec>\n                  <jats:title>Conclusions<\/jats:title>\n                  <jats:p>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\u2019s efficacy and safety in neurodegenerative (i.e., PD) contexts is warranted.<\/jats:p>\n                <\/jats:sec>","DOI":"10.1101\/2024.05.22.24307622","type":"posted-content","created":{"date-parts":[[2024,5,22]],"date-time":"2024-05-22T23:20:14Z","timestamp":1716420014000},"source":"Crossref","is-referenced-by-count":4,"title":["A pilot dose-finding study of Terazosin in humans"],"prefix":"10.64898","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-0985-7268","authenticated-orcid":false,"given":"Jordan L.","family":"Schultz","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3945-8820","authenticated-orcid":false,"given":"Phillip E.","family":"Gander","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8360-0199","authenticated-orcid":false,"given":"Craig D.","family":"Workman","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1197-6714","authenticated-orcid":false,"given":"Laura L.","family":"Ponto","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Stephen","family":"Cross","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Christopher S.","family":"Nance","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6228-0824","authenticated-orcid":false,"given":"Christopher L.","family":"Groth","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4549-6567","authenticated-orcid":false,"given":"Eric B.","family":"Taylor","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sarah E.","family":"Ernst","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0189-5833","authenticated-orcid":false,"given":"Jia","family":"Xu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4430-6960","authenticated-orcid":false,"given":"Ergun Y.","family":"Uc","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8639-5354","authenticated-orcid":false,"given":"Vincent A.","family":"Magnotta","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1646-6206","authenticated-orcid":false,"given":"Michael J.","family":"Welsh","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0427-0003","authenticated-orcid":false,"given":"Nandakumar S.","family":"Narayanan","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"54368","reference":[{"key":"2024052506450681000_2024.05.22.24307622v1.1","doi-asserted-by":"crossref","first-page":"170","DOI":"10.1038\/s41531-022-00410-y","article-title":"Incidence of Parkinson disease in North America","volume":"8","year":"2022","journal-title":"NPJ Parkinsons Dis"},{"key":"2024052506450681000_2024.05.22.24307622v1.2","doi-asserted-by":"publisher","DOI":"10.1007\/978-94-007-5416-4_16"},{"key":"2024052506450681000_2024.05.22.24307622v1.3","doi-asserted-by":"publisher","DOI":"10.1136\/jnnp-2019-322338"},{"key":"2024052506450681000_2024.05.22.24307622v1.4","doi-asserted-by":"crossref","unstructured":"Strope TA , Birky CJ , Wilkins HM . 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