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REL‐1017 (esmethadone) did not produce initial or cumulative neurotoxic effects or other evidence of damage to cortical neurons
Author(s) -
Pappagallo Marco,
Bifari Francesco,
Bleavins Michael,
Folli Franco,
Manfredi Paolo
Publication year - 2021
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.2021.35.s1.02195
Subject(s) - medicine , dextromethorphan , lesion , anesthesia , vacuolization , nmda receptor , endocrinology , pharmacology , receptor , surgery
Objective The objective of this study was to determine if Olney's lesions are induced by REL‐1017 administered once daily via oral gavage for 1‐4 days to Sprague‐Dawley (SD) rats. Background Olney's lesion is a characteristic vacuolization which can be seen by light microscopy in H&E stained brain sections, in neurons of rats. These lesions are mainly observed in the posterior cingulate and retro‐splenial cortices, after administration of NMDAR antagonists, including MK‐801, ketamine and dextromethorphan at 1 mg/kg, 40 mg/kg and 75 mg/kg, respectively. While there is no evidence for a cumulative neurotoxic effect and progression to irreversible damage with repeated doses, novel NMDAR antagonists are generally characterized for their potential to induce Olney's lesions. REL‐1017 (esmethadone) is an uncompetitive NMDAR channel blocker undergoing Phase 3 clinical trials for the treatment of major depressive disorder (MDD). Methods Ninety male SD rats were randomized in groups of 15 to vehicle, REL‐1017 at 31.25, 62.5, or 110 kg/mg/day, racemic methadone at 31.25 mg/kg/day by oral gavage, or subcutaneous (SC) MK‐801 at 5 mg/kg/day. Ninety female SD rats were randomized in groups of 15 to vehicle, REL‐1017 at 20, 40, or 80 mg/kg/day, racemic methadone at 20 mg/kg/day by oral gavage, or SC MK‐801 at 2 mg/kg/day. Animals were treated once daily for up to 4 days. An evaluation for the presence of neuronal vacuoles (Olney's effect) was performed by light microscopy in H&E stained brain 2mm thick sections, with emphasis on the cingulate gyrus (including the retro‐splenial region). Neuronal necrosis was confirmed with Fluoro Jade B staining. Results and conclusions The brains of animals treated either with REL‐1017 or with racemic methadone did not show the microscopic features of Olney's lesions. The animals administered MK‐801 (positive control), however, showed, as expected, neuronal vacuolation and necrosis (hallmarks of Olney's lesions) (Fix, 1996). In particular, daily administration via oral gavage of REL‐1017 for up to 4 days at all doses to both male and female SD rats did not produce Olney's lesions, similar to saline, and had a significantly different effect on brain cortex as compared to MK‐801 (p<0.01). Furthermore, the oral administration of methadone racemate to both male and female SD rats did not produce Olney's lesions. In conclusion, our data indicated that administration of the uncompetitive NMDAR channel blocker REL‐1017 did not produce either initial nor cumulative neurotoxic effects or other evidence of damage to cortical neurons. These results encourage the continued development of REL‐1017 (esmethadone) for the treatment of MDD and other neuropsychiatric disorders.