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Influence of dizocilpine (MK-801) on neurotoxic effect of dexamethasone: behavioral and histological studies
Zofia Danilczuk1, Joanna Sekita-Krzak, Tomasz Lupina
1Department of Pharmacology and Clinical Pharmacology, Medical University of Lublin, Jaczewskiego 8, 20-090 Lublin, Poland. Zofia.Danilczuk@am.lublin.pl.
Abstract:
Elevated levels of endogenous glucocorticoids (GCs) or prolonged treatment with high doses of dexamethasone (DEX) or other GCs preparations are frequently associated with psychosis as well as cognitive deficits, such as the impairment of memory and learning. GCs potentiate stress or ischemia-induced accumulation of excitatory amino acids in the extracellular space of hippocampus. The antagonism of glutamate receptors may potentially improve safety profile of therapy with GCs. The purpose of the present study was to investigate the effect of dizocilpine maleate (MK-801), non-competitive NMDA glutamate receptor antagonist, on neurotoxic effect of the prolonged treatment with the high dose of DEX. The results showed that DEX (120 mg/kg/day for 7 days) impaired the long-term memory and the motor coordination, reduced the body weight and induced the lethality of mice. The morphological and ultrastructural study have confirmed damage to hippocampal neurons especially in the CA3 region after the prolonged treatment with DEX alone. Damaged pyramidal neurons showed robust changes in the shape of the nucleus and cytoplasm condensation. MK-801 alone (at non-toxic dose of 0.3 mg/kg/day), changed neither the behavior of mice nor morphology of the hippocampal neurons. However, it did not prevent the neurotoxic effects of DEX. On the contrary, it intensified DEX-induced neurotoxicity.
Insights
Glucocorticoids (GCs) like dexamethasone (DEX) can harm memory and brain cells. Blocking NMDA glutamate receptors with MK-801 did not protect against DEX neurotoxicity and worsened it in mice.
Area of Science:
- Neuroscience
- Pharmacology
- Toxicology
Background:
- Glucocorticoids (GCs) and high-dose dexamethasone (DEX) are linked to psychosis and cognitive deficits.
- GCs can increase excitatory amino acids in the hippocampus, potentially contributing to neurotoxicity.
Purpose of the Study:
- To investigate if the NMDA glutamate receptor antagonist dizocilpine maleate (MK-801) can protect against DEX-induced neurotoxicity.
- To assess the impact of MK-801 on DEX-related behavioral and morphological changes in mice.
Main Methods:
- Mice received high-dose DEX (120 mg/kg/day for 7 days) with or without MK-801 (0.3 mg/kg/day).
- Behavioral tests assessed memory and motor coordination.
- Morphological and ultrastructural analyses examined hippocampal neuron damage.
Main Results:
- DEX alone impaired long-term memory, motor coordination, reduced body weight, and caused lethality.
- DEX induced significant damage to hippocampal neurons, particularly in the CA3 region.
- MK-801 alone had no adverse effects but failed to prevent DEX neurotoxicity and intensified it.
Conclusions:
- MK-801 does not protect against DEX-induced neurotoxicity.
- Co-administration of MK-801 exacerbates DEX-induced neurotoxic effects in the hippocampus.
- NMDA receptor antagonism may not be a viable strategy to mitigate GC-induced neurotoxicity.
