{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,2,27]],"date-time":"2026-02-27T15:13:22Z","timestamp":1772205202491,"version":"3.50.1"},"reference-count":33,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2022,4,25]],"date-time":"2022-04-25T00:00:00Z","timestamp":1650844800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":["frontiersin.org"],"crossmark-restriction":true},"short-container-title":["Front. Pharmacol."],"abstract":"<jats:p>REL-1017 (esmethadone; dextromethadone; (S)-methadone) is the opioid-inactive dextro-isomer of the racemic mixture, (R, S)-methadone. REL-1017 acts as a low affinity, low potency N-methyl-D-aspartate receptor (NMDAR) channel blocker with rapid, robust, and sustained therapeutic effects in patients with major depressive disorder (MDD). Systemic administration of NMDAR blockers may cause transient and reversible pathomorphological alterations in brain cortical neurons characterized by cytoplasmic vacuolization, which are called Olney\u2019s lesions, and may also lead to irreversible neuronal necrosis. We determined whether REL-1017 administration via oral gavage for 1\u20134\u00a0days to Sprague-Dawley rats could produce Olney\u2019s lesions and cortical neuronal death and microgliosis as compared with MK-801, a known neurotoxic potent NMDAR blocker. As previously reported, MK-801 produced Olney\u2019s lesions, neuronal necrosis and cortical microgliosis, and impaired behavior and activity. In contrast, administration of REL-1017 at low (20\u201331.25 mg\/kg in females and males), medium (40\u201362.5 mg\/kg) or high (80\u2013110\u00a0mg\/kg) doses did not cause pathomorphological changes in brain neurons and did not cause impaired behavior and activity. In conclusion, REL-1017 did not produce initial or cumulative neurotoxic effects or other evidence of damage to cortical neurons, further encouraging the development of REL-1017 as a potentially safe novel candidate for rapid treatment of MDD.<\/jats:p>","DOI":"10.3389\/fphar.2022.863959","type":"journal-article","created":{"date-parts":[[2022,4,25]],"date-time":"2022-04-25T05:10:30Z","timestamp":1650863430000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":10,"title":["REL-1017 (Esmethadone), A Novel NMDAR Blocker for the Treatment of MDD is Not Neurotoxic in Sprague-Dawley Rats"],"prefix":"10.3389","volume":"13","author":[{"given":"Francesco","family":"Bifari","sequence":"first","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Marco","family":"Pappagallo","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Michael","family":"Bleavins","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Sergio","family":"Traversa","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Franco","family":"Folli","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Paolo L.","family":"Manfredi","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1965","published-online":{"date-parts":[[2022,4,25]]},"reference":[{"key":"B1","doi-asserted-by":"publisher","first-page":"689","DOI":"10.1002\/da.22501","article-title":"Ketamine's Mechanism of Action: A Path to Rapid-Acting Antidepressants","volume":"33","author":"Abdallah","year":"2016","journal-title":"Depress. Anxiety"},{"key":"B2","doi-asserted-by":"publisher","first-page":"743","DOI":"10.1161\/01.str.27.4.743","article-title":"Effect of Age and Sex on N-Methyl-D-Aspartate Antagonist-Induced Neuronal Necrosis in Rats","volume":"27","author":"Auer","year":"1996","journal-title":"Stroke"},{"key":"B3","doi-asserted-by":"publisher","first-page":"226","DOI":"10.1097\/JCP.0000000000001035","article-title":"Characterization of the Safety and Pharmacokinetic Profile of D-Methadone, a Novel N-Methyl-D-Aspartate Receptor Antagonist in Healthy, Opioid-Naive Subjects: Results of Two Phase 1 Studies","volume":"39","author":"Bernstein","year":"2019","journal-title":"J. Clin. Psychopharmacol."},{"key":"B4","doi-asserted-by":"publisher","first-page":"S194","DOI":"10.12531016\/j.biopsych.2021.02.732","article-title":"Esmethadone (REL-1017) Compares With NMDA Receptor 1252 Antagonists in FLIPR-Calcium Assay","volume":"89","author":"Bettini","year":"","journal-title":"Biol. Psychiatry"},{"key":"B5","doi-asserted-by":"publisher","first-page":"S198","DOI":"10.1016\/j.biopsych.2021.02.503","article-title":"Esmethadone (REL-1017) Reduces Glutamate-Induced Currents in NMDA Receptors with the GluN2D Subunit","volume":"89","author":"Bettini","year":"","journal-title":"Biol. Psychiatry"},{"key":"B6","doi-asserted-by":"publisher","first-page":"S294","DOI":"10.1016\/j.biopsych.2021.02.733","article-title":"Esmethadone (REL-1017) Shows Similar Effects to Ketamine in Manual Patch Clamp Studies.","volume":"89","author":"Bettini","year":"","journal-title":"Biol. Psychiatry"},{"key":"B7","doi-asserted-by":"publisher","first-page":"135","DOI":"10.1002\/ddr.430020204","article-title":"Central Sympathomimetic Activity of (+)-5-Methyl-10,11-Dihydro-5h-Dibenzo [a, D]cyclohepten-5,10-Imine (MK-801), a Substance with Potent Anticonvulsant, central Sympathomimetic, and Apparent Anxiolytic Properties","volume":"2","author":"Clineschmidt","year":"1982","journal-title":"Drug Dev. Res."},{"key":"B8","doi-asserted-by":"publisher","first-page":"493","DOI":"10.1152\/japplphysiol.00565.2001","article-title":"Sexually Dimorphic Effects of Morphine and MK-801: Sex Steroid-dependent and -independent Mechanisms","volume":"92","author":"D'Souza","year":"2002","journal-title":"J. Appl. Physiol. (1985)"},{"key":"B9","doi-asserted-by":"publisher","first-page":"671859","DOI":"10.3389\/fphar.2021.671859","article-title":"REL-1017 (Esmethadone) Increases Circulating BDNF Levels in Healthy Subjects of a Phase 1 Clinical Study","volume":"12","author":"De Martin","year":"2021","journal-title":"Front. Pharmacol."},{"key":"B10","first-page":"2021","article-title":"Drug Enforcement Administration Diversion Control Division: Drug & Chemical Information Section","volume":"9","year":"2019","journal-title":"Methadone"},{"key":"B11","doi-asserted-by":"publisher","first-page":"2688","DOI":"10.1097\/00001756-199412000-00070","article-title":"Competitive and Non-competitive NMDA Antagonists Induce Similar Limbic Degeneration","volume":"5","author":"Ellison","year":"1994","journal-title":"Neuroreport"},{"key":"B12","doi-asserted-by":"publisher","first-page":"347","DOI":"10.1016\/0893-133X(95)00048-I","article-title":"Alpha 2 Adrenergic Agonists Prevent MK-801 Neurotoxicity","volume":"12","author":"Farber","year":"1995","journal-title":"Neuropsychopharmacology"},{"key":"B13","doi-asserted-by":"publisher","first-page":"57","DOI":"10.1016\/S0893-133X(97)00127-9","article-title":"Serotonergic Agents that Activate 5HT2A Receptors Prevent NMDA Antagonist Neurotoxicity","volume":"18","author":"Farber","year":"1998","journal-title":"Neuropsychopharmacology"},{"key":"B14","doi-asserted-by":"publisher","first-page":"119","DOI":"10.1016\/0006-3223(93)90265-f","article-title":"Antipsychotic Drugs Block Phencyclidine Receptor-Mediated Neurotoxicity","volume":"34","author":"Farber","year":"1993","journal-title":"Biol. Psychiatry"},{"key":"B15","doi-asserted-by":"publisher","first-page":"122","DOI":"10.1176\/appi.ajp.2021.21020197","article-title":"REL-1017 (Esmethadone) as Adjunctive Treatment in Patients with Major Depressive Disorder: A Phase 2a Randomized Double-Blind Trial","volume":"179","author":"Fava","year":"2022","journal-title":"Am. J. Psychiatry"},{"key":"B16","doi-asserted-by":"publisher","first-page":"204","DOI":"10.1006\/exnr.1993.1153","article-title":"Neuronal Vacuolization and Necrosis Induced by the Noncompetitive N-Methyl-D-Aspartate (NMDA) Antagonist MK(+)801 (Dizocilpine Maleate): a Light and Electron Microscopic Evaluation of the Rat Retrosplenial Cortex","volume":"123","author":"Fix","year":"1993","journal-title":"Exp. Neurol."},{"key":"B17","doi-asserted-by":"publisher","first-page":"2230","DOI":"10.1038\/s41386-019-0501-x","article-title":"N-Methyl-D-aspartate Receptor Antagonist D-Methadone Produces Rapid, mTORC1-dependent Antidepressant Effects","volume":"44","author":"Foga\u00e7a","year":"2019","journal-title":"Neuropsychopharmacology"},{"key":"B18","doi-asserted-by":"publisher","first-page":"743","DOI":"10.1016\/S0140-6736(15)60692-4","article-title":"Global, Regional, and National Incidence, Prevalence, and Years Lived with Disability for 301 Acute and Chronic Diseases and Injuries in 188 Countries, 1990-2013: a Systematic Analysis for the Global Burden of Disease Study 2013","volume":"386","year":"2015","journal-title":"Lancet"},{"key":"B19","doi-asserted-by":"publisher","first-page":"5","DOI":"10.1016\/s0304-3940(97)13391-2","article-title":"The D- and L-Isomers of Methadone Bind to the Non-competitive Site on the N-Methyl-D-Aspartate (NMDA) Receptor in Rat Forebrain and Spinal Cord","volume":"223","author":"Gorman","year":"1997","journal-title":"Neurosci. Lett."},{"key":"B20","doi-asserted-by":"publisher","first-page":"1265","DOI":"10.1517\/17425255.4.10.1265","article-title":"Neuroinflammation and Microglia: Considerations and Approaches for Neurotoxicity Assessment","volume":"4","author":"Harry","year":"2008","journal-title":"Expert Opin. Drug Metab. Toxicol."},{"key":"B21","article-title":"REL-1017 (Esmethadone) Showed No Reinforcing Properties Compared to Oxycodone in a Rat Self-Administration Study","author":"Henningfield","year":"2021"},{"key":"B22","doi-asserted-by":"publisher","first-page":"167","DOI":"10.1016\/0006-8993(93)90287-w","article-title":"Sex Differences in NMDA Receptor Mediated Responses in Rats","volume":"620","author":"H\u00f6nack","year":"1993","journal-title":"Brain Res."},{"key":"B23","doi-asserted-by":"publisher","first-page":"181","DOI":"10.1016\/s0006-8993(96)01290-5","article-title":"MK-801-induced Neuronal Damage in Rats","volume":"753","author":"Horv\u00e1th","year":"1997","journal-title":"Brain Res."},{"key":"B24","doi-asserted-by":"publisher","first-page":"1307","DOI":"10.1073\/pnas.85.4.1307","article-title":"Block of N-Methyl-D-Aspartate-Activated Current by the Anticonvulsant MK-801: Selective Binding to Open Channels","volume":"85","author":"Huettner","year":"1988","journal-title":"Proc. Natl. Acad. Sci. U S A."},{"key":"B25","doi-asserted-by":"publisher","first-page":"143","DOI":"10.1016\/s1382-6689(99)00003-4","article-title":"Sex Differences in Dizocilpine (MK-801) Neurotoxicity in Rats","volume":"7","author":"Hur","year":"1999","journal-title":"Environ. Toxicol. Pharmacol."},{"key":"B26","doi-asserted-by":"publisher","first-page":"1","DOI":"10.1056\/NEJMp1903305","article-title":"Esketamine for Treatment-Resistant Depression - First FDA-Approved Antidepressant in a New Class","volume":"381","author":"Kim","year":"2019","journal-title":"N. Engl. J. Med."},{"key":"B27","first-page":"906","article-title":"Structural Modifications to an N-Methyl-D-Aspartate Receptor Antagonist Result in Large Differences in Trapping Block","volume":"297","author":"Mealing","year":"2001","journal-title":"J. Pharmacol. Exp. Ther."},{"key":"B28","doi-asserted-by":"publisher","first-page":"106993","DOI":"10.1016\/j.ntt.2021.106993","article-title":"A Comparison of the Pharmacokinetics and NMDAR Antagonism-Associated Neurotoxicity of Ketamine, (2R,6R)-Hydroxynorketamine and MK-801","volume":"87","author":"Morris","year":"2021","journal-title":"Neurotoxicol Teratol"},{"key":"B29","doi-asserted-by":"crossref","first-page":"219","DOI":"10.31887\/DCNS.2000.2.3\/jnewcomer","article-title":"NMDA Receptor Function, Memory, and Brain Aging","volume":"2","author":"Newcomer","year":"2000","journal-title":"Dialogues Clin. Neurosci."},{"key":"B30","doi-asserted-by":"publisher","first-page":"950","DOI":"10.1176\/appi.ajp.2015.15040465","article-title":"Ketamine and Other NMDA Antagonists: Early Clinical Trials and Possible Mechanisms in Depression","volume":"172","author":"Newport","year":"2015","journal-title":"Am. J. Psychiatry"},{"key":"B31","doi-asserted-by":"publisher","first-page":"1360","DOI":"10.1126\/science.2660263","article-title":"Pathological Changes Induced in Cerebrocortical Neurons by Phencyclidine and Related Drugs","volume":"244","author":"Olney","year":"1989","journal-title":"Science"},{"key":"B32","doi-asserted-by":"publisher","first-page":"1515","DOI":"10.1126\/science.1835799","article-title":"NMDA Antagonist Neurotoxicity: Mechanism and Prevention","volume":"254","author":"Olney","year":"1991","journal-title":"Science"},{"key":"B33","doi-asserted-by":"publisher","first-page":"305","DOI":"10.1006\/nbdi.1998.0206","article-title":"Disseminated Corticolimbic Neuronal Degeneration Induced in Rat Brain by MK-801: Potential Relevance to Alzheimer's Disease","volume":"5","author":"Wozniak","year":"1998","journal-title":"Neurobiol. Dis."}],"container-title":["Frontiers in Pharmacology"],"original-title":[],"link":[{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fphar.2022.863959\/full","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2022,4,28]],"date-time":"2022-04-28T18:49:35Z","timestamp":1651171775000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fphar.2022.863959\/full"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2022,4,25]]},"references-count":33,"alternative-id":["10.3389\/fphar.2022.863959"],"URL":"https:\/\/doi.org\/10.3389\/fphar.2022.863959","relation":{},"ISSN":["1663-9812"],"issn-type":[{"value":"1663-9812","type":"electronic"}],"subject":[],"published":{"date-parts":[[2022,4,25]]},"article-number":"863959"}}