Influence of dizocilpine (MK-801) on neurotoxic effect of dexamethasone: behavioral and histological studies.
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.
Danilczuk
Zofia
Z
Department of Pharmacology and Clinical Pharmacology, Medical University of Lublin, Jaczewskiego 8, 20-090 Lublin, Poland. Zofia.Danilczuk@am.lublin.pl.
Sekita-Krzak
Joanna
J
Lupina
Tomasz
T
Danilczuk
Marcin
M
Czerny
Krystyna
K
D000704:Analysis of Variance; D000818:Animals; D001362:Avoidance Learning / Q000187:drug effects; D001522:Behavior, Animal / Q000187:drug effects*; D001835:Body Weight / Q000187:drug effects; D003907:Dexamethasone / Q000494:pharmacology*; D016291:Dizocilpine Maleate / Q000494:pharmacology*; D004334:Drug Administration Schedule; D004347:Drug Interactions; D018691:Excitatory Amino Acid Antagonists / Q000494:pharmacology*; D006624:Hippocampus / Q000648:ultrastructure; D008297:Male; D046529:Microscopy, Electron, Transmission / Q000379:methods; D009498:Neurotoxins / Q000494:pharmacology*; D051381:Rats; D012153:Retention, Psychology / Q000187:drug effects; D018709:Statistics, Nonparametric
D018691:Excitatory Amino Acid Antagonists; D009498:Neurotoxins; D016291:Dizocilpine Maleate; D003907:Dexamethasone