{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,8,5]],"date-time":"2026-08-05T09:46:34Z","timestamp":1785923194995,"version":"3.56.0"},"reference-count":102,"publisher":"MDPI AG","issue":"8","license":[{"start":{"date-parts":[[2026,7,29]],"date-time":"2026-07-29T00:00:00Z","timestamp":1785283200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Neurol. Int.","Neurology International"],"abstract":"<jats:p>Neurodegenerative diseases are targets for pridopidine therapy, which aims to improve quality of life through neuroprotective mechanisms that involve sigma-1 receptor (S1R) activation. Neurodegenerative motor and cognitive diseases are influenced by dopamine imbalance, where disruptions in pathways contribute to states that are hyperkinetic or hypokinetic, while current dopaminergic treatments are symptomatic rather than disease-modifying, especially for Huntington\u2019s disease and Amyotrophic lateral sclerosis. This review summarizes the mechanisms underlying pridopidine-mediated neuroprotection and examines the current evidence supporting its therapeutic potential. The S1R is an endoplasmic reticulum-mitochondria-associated chaperone involved in homeostasis of calcium, stress regulation, and mitochondrial function. Pridopidine is a small lipophilic molecule that crosses the blood\u2013brain barrier and acts as an S1R agonist, with minimal dopamine D2 receptor occupancy. Activation of S1R by pridopidine modulates calcium signaling and enhances anti-apoptotic activity. Collectively, available evidence suggests that pridopidine may improve motor outcomes and slow disease progression in Huntington\u2019s disease and amyotrophic lateral sclerosis, supporting its promise as a disease-modifying therapeutic strategy.<\/jats:p>","DOI":"10.3390\/neurolint18080144","type":"journal-article","created":{"date-parts":[[2026,7,29]],"date-time":"2026-07-29T08:16:52Z","timestamp":1785313012000},"page":"144","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Pridopidine Mediated Sigma-1 Receptor Activation and Therapeutic Implications in Neurodegenerative Diseases"],"prefix":"10.3390","volume":"18","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-3140-357X","authenticated-orcid":false,"given":"Ahmed I.","family":"Anwar","sequence":"first","affiliation":[{"name":"School of Medicine, Louisiana State University Health Shreveport, Shreveport, LA 71103, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Abdul-rahman A.","family":"Hegazi","sequence":"additional","affiliation":[{"name":"Department of Anesthesiology, Louisiana State University Health Shreveport, Shreveport, LA 71103, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0772-5015","authenticated-orcid":false,"given":"Hamsa Priya","family":"Bhuchakra","sequence":"additional","affiliation":[{"name":"Department of Anesthesiology, Louisiana State University Health Shreveport, Shreveport, LA 71103, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0008-2568-2964","authenticated-orcid":false,"given":"Joshua R.","family":"Nelson","sequence":"additional","affiliation":[{"name":"School of Medicine, Louisiana State University Health Shreveport, Shreveport, LA 71103, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ty L.","family":"Birdsong","sequence":"additional","affiliation":[{"name":"School of Medicine, Louisiana State University Health Shreveport, Shreveport, LA 71103, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Cy J.","family":"Fontenot","sequence":"additional","affiliation":[{"name":"School of Medicine, Louisiana State University Health Shreveport, Shreveport, LA 71103, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Majed","family":"Zeibo","sequence":"additional","affiliation":[{"name":"School of Medicine, Louisiana State University Health Shreveport, Shreveport, LA 71103, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Moiz M.","family":"Fazal-ur-Rehman","sequence":"additional","affiliation":[{"name":"School of Medicine, Louisiana State University Health Shreveport, Shreveport, LA 71103, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0003-4061-7865","authenticated-orcid":false,"given":"Harrison P.","family":"Bieber","sequence":"additional","affiliation":[{"name":"School of Medicine, Louisiana State University Health Shreveport, Shreveport, LA 71103, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Claudia J.","family":"Spring","sequence":"additional","affiliation":[{"name":"School of Medicine, Louisiana State University Health Shreveport, Shreveport, LA 71103, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Joshua L.","family":"Smith","sequence":"additional","affiliation":[{"name":"School of Medicine, Louisiana State University Health Shreveport, Shreveport, LA 71103, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0001-6746-4008","authenticated-orcid":false,"given":"Ibraheem A.","family":"Hachem","sequence":"additional","affiliation":[{"name":"School of Medicine, Louisiana State University Health Shreveport, Shreveport, LA 71103, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Taranjit","family":"Singh","sequence":"additional","affiliation":[{"name":"School of Medicine, Louisiana State University Health Shreveport, Shreveport, LA 71103, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"M. Farris","family":"Sawaya","sequence":"additional","affiliation":[{"name":"Department of Pharmacology, Toxicology & Neuroscience, School of Graduate Studies, Louisiana State University Health Shreveport, Shreveport, LA 71103, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8143-0541","authenticated-orcid":false,"given":"Kevin S.","family":"Murnane","sequence":"additional","affiliation":[{"name":"Department of Pharmacology, Toxicology & Neuroscience, School of Graduate Studies, Louisiana State University Health Shreveport, Shreveport, LA 71103, USA"},{"name":"Louisiana Addiction Research Center, Louisiana State University Health Shreveport, Shreveport, LA 71103, USA"},{"name":"Department of Psychiatry and Behavioral Medicine, School of Medicine, Louisiana State University Health Shreveport, Shreveport, LA 71103, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2464-0187","authenticated-orcid":false,"given":"Alan D.","family":"Kaye","sequence":"additional","affiliation":[{"name":"Department of Anesthesiology, Louisiana State University Health Shreveport, Shreveport, LA 71103, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2026,7,29]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","unstructured":"Gershoni Emek, N., Tan, A.M., Geva, M., Fekete, A., Abate, C., and Hayden, M.R. 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