PT  - JOURNAL ARTICLE
AU  - Jordan, William
AU  - Siegel, Richard
AU  - Kumar, Rajendra
AU  - Javitt, Jonathan
TI  - NRX-101, A RAPID-ACTING ANTI-DEPRESSANT, DOES NOT CAUSE NEUROTOXICITY FOLLOWING KETAMINE ADMINISTRATION IN PRECLINICAL MODELS
AID  - 10.1101/2022.06.18.496662
DP  - 2022 Jan 01
TA  - bioRxiv
PG  - 2022.06.18.496662
4099  - http://biorxiv.org/content/early/2022/06/20/2022.06.18.496662.short
4100  - http://biorxiv.org/content/early/2022/06/20/2022.06.18.496662.full
AB  - Background NMDA (N-Methyl-D aspartate) receptor antagonists have gained increasing attention as rapid-acting antidepressants. However, their use has been limited by potential neurotoxicity (Olney Lesions) and recent FDA guidance requires demonstration of safety on histologic parameters prior to initiation of human studies. D-cycloserine is a mixed NMDA agonist/antagonist awarded Breakthrough Therapy Designation and currently in clinical trials for the treatment of bipolar depression with suicidal ideation. The current study was designed to investigate the neurologic safety profile of D-cycloserine by itself and in combination with ketamine and lurasidone.Methods Sprague Dawley female rats (n=106) were randomly divided into 7 study groups. Ketamine was administered via tail vein infusion. D-cycloserine and lurasidone were administered via oral gavage in escalating doses to a maximum of 2000 mg/kg DCS. To ascertain toxicity, dose escalation with three different doses of D-cycloserine/lurasidone was given in combination with ketamine. MK-801, a known neurotoxic NMDA antagonist, was administered as a positive control. Brain tissue was sectioned and stained with H&E and Fluorojade stains.Results No fatalities were observed in any group. No microscopic abnormalities were found in the brain of animal subjects given ketamine, ketamine followed by DCS/lurasidone, or DCS/lurasidone alone. Neuronal necrosis, as expected, was seen in the MK-801 positive control group.Conclusion NRX-101, a fixed-dose combination of D-cycloserine/lurasidone, when administered with or without prior infusion of IV ketamine was tolerated and did not induce neurotoxicity, even at maximum-tolerated doses of D-cycloserine.HIGHLIGHTSNRX-101, a fixed dose combination of D-cycloserine and lurasidone does not exhibit histologic neurotoxicity, even at maximum-tolerated dosesCompeting Interest StatementDrs Siegel and Javitt are employees and shareholders of NRx Pharmaceuticals, Inc. All data collection and interpretation was conducted by individuals with no propriety interest in the outcome of the research.