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High-dose dextromethorphan produces myelinoid bodies in the hippocampus of rats
Hai-Quyen Tran1, Yoon Hee Chung2, Eun-Joo Shin1
1Neuropsychopharmacology and Toxicology Program, College of Pharmacy, Kangwon National University, Chunchon 24341, Republic of Korea.
Abstract:
Dextromethorphan (DM) administered at supra-antitussive doses produce psychotoxic and neurotoxic effects in humans. We administered DM (80 mg/kg) to rats intraperitoneally to determine the ultrastructural change induced by DM, because intraperitoneal route is sensitive for the behavioral responses. Treatment with DM resulted in mitochondrial dysfunction and formation of myelinoid bodies in the hippocampus. MK-801 [(+)-5-methyl-10,11-dihydro-5H-dibenzo[a,d]cyclohepten-5,10-imine maleate] attenuated DM-induced cytosolic oxidative burdens. However, neither MK-801 nor naloxone affected DM-induced mitochondrial dysfunction and formation of myelinoid bodies, indicating that the neurotoxic mechanism needs to be further elucidated. Therefore, the spectrum of toxicological effects associated with DM need to be reassessed.
Insights
High doses of Dextromethorphan (DM) cause neurotoxic effects. In rats, DM induced mitochondrial dysfunction and myelinoid bodies, suggesting a need to reassess its toxicological profile.
Area of Science:
- Neuroscience
- Toxicology
- Pharmacology
Background:
- Supra-antitussive doses of Dextromethorphan (DM) are known to cause psychotoxic and neurotoxic effects in humans.
- The intraperitoneal route in rats is sensitive for behavioral responses to DM.
Purpose of the Study:
- To investigate the ultrastructural changes induced by Dextromethorphan (DM) administration in rats.
- To elucidate the neurotoxic mechanisms of DM at supra-antitussive doses.
Main Methods:
- Rats were administered Dextromethorphan (DM) at 80 mg/kg intraperitoneally.
- Ultrastructural changes in the hippocampus were examined.
- The effects of MK-801 and naloxone on DM-induced changes were assessed.
Main Results:
- Dextromethorphan (DM) administration led to mitochondrial dysfunction and the formation of myelinoid bodies in the hippocampus.
- MK-801 attenuated DM-induced cytosolic oxidative burdens.
- Neither MK-801 nor naloxone reversed DM-induced mitochondrial dysfunction or myelinoid body formation.
Conclusions:
- Dextromethorphan (DM) induces specific ultrastructural changes in the rat hippocampus, including mitochondrial dysfunction and myelinoid bodies.
- The neurotoxic mechanism of DM involves pathways not fully mitigated by MK-801 or naloxone.
- The full spectrum of toxicological effects of Dextromethorphan (DM) requires reassessment.