A comparison of the pharmacokinetics and NMDAR antagonism-associated neurotoxicity of ketamine, (2R,6R)-hydroxynorketamine and MK-801

Abstract

With the increasing use of ketamine as an off-label treatment for depression and the recent FDA approval of (S)-ketamine for treatment-resistant depression, there is an increased need to understand the long-term safety profile of chronic ketamine administration. Of particular concern is the neurotoxicity previously observed in rat models following acute exposure to high doses of ketamine, broadly referred to as 'Olney's lesions'. This type of toxicity presents as abnormal neuronal cellular vacuolization, followed by neuronal death and has been associated with ketamine's inhibition of the N-methyl-d-aspartate receptor (NMDAR). In this study, a pharmacological and neuropathological analysis of ketamine, the potent NMDAR antagonist MK-801, and the ketamine metabolite (2R,6R)-hydroxynorketamine [(2R,6R)-HNK)] in rats is described following both single dose and repeat dose drug exposures. Ketamine dosing was studied up to 20 mg/kg intravenously for the single-dose neuropathology study and up to 60 mg/kg intraperitoneally for the multiple-dose neuropathology study. MK-801 dosing was studied up to 0.8 mg/kg subcutaneously for both the single and multiple-dose neuropathology studies, while (2R,6R)-HNK dosing was studied up to 160 mg/kg intravenously in both studies. These studies confirm dose-dependent induction of 'Olney's lesions' following both single dose and repeat dosing of MK-801. Ketamine exposure, while showing common behavioral effects, did not induce wide-spread Olney's lesions. Treatment with (2R,6R)-HNK did not produce behavioral effects, toxicity or any evidence of Olney's lesion formation. Based on these results, future NMDAR-antagonist neurotoxicity studies should strongly consider taking pharmacokinetics more thoroughly into account.

Keywords: Ketamine; MK-801; NMDAR antagonists; Neuropathology; Neurotoxicology; Olney lesions; Pharmacokinetics.

Conflict of interest statement

Declaration of interests

The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.

Published by Elsevier Inc.

Figures

Figure 1:

Sex differences in the drug exposure of (2R,6R)-HNK (10 mg/kg), ketamine (10 mg/kg), or MK-801 (0.5 mg/kg), when administeredvia various routes. IV: Intravenous; IP: intraperitoneal; SC: subcutaneous. Data are mean +/- standard deviation (N=3).

Figure 2:

Representative neuropathology images after single dosing of saline or MK-801 in the retrosplenial cortex A) H&E staining, saline dose, 3 hour time point. B) H&E staining, 0.5 mg/kg MK-801, 3 hour time point. The small arrow designates vacuolization in the cells. C) H&E staining, 0.8 mg/kg MK-801, 3 hour time point. Note the more pronounced vacuolization. D) H&E staining, saline dose, terminal euthanization. E) H&E staining, 0.5 mg/kg MK-801, terminal euthanization. F) H&E staining, 0.8 mg/kg MK-801, terminal euthanization. Note the necrosis pointed by the arrows. G) Fluorojade staining, saline dose, terminal euthanization. H) Fluorojade staining, 0.5 mg/kg MK-801, terminal euthanization. I) Fluorojade staining, 0.8 mg/kg MK-801, terminal euthanization. Note the necrotic neurons observed by fluorojade staining J) Iba-1 staining, saline dose, terminal euthanization. K) IBA1 staining, 0.5 mg/kg MK-801, terminal euthanization. L) Iba-1 staining, 0.8 mg/kg MK-801, terminal euthanization. Note the increase in Iba-1 staining. Bar length is 0.06 mm