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Pathological effects of MK-801 in the rat posterior cingulate/retrosplenial cortex
1Eli Lilly and Company, Greenfield, IN, USA.
Abstract:
Many N-methyl-D-aspartate (NMDA) antagonists cause vacuolization and necrosis in the posterior cingulate/retrosplenial (PC/RS) cortex of rats after single-dose administration. This article reviews a series of investigational studies that have characterized this effect. All the studies have used single doses of MK-801 in rats. Techniques employed were light microscopy, transmission electron microscopy, quantitative enzyme-linked immunosorbent assay (ELISA), and cell counting. Our studies demonstrated: (1) formation of vacuoles within 30 minutes of treatment, (2) dose-dependent necrosis of susceptible PC/RS neurons, (3) increased glial fibrillary acidic protein in response to neuronal necrosis, (4) significantly greater necrosis in female than in male rats, and (5) increases in necrosis along a rostrocaudal gradient within the PC/RS cortex. In addition, these studies illustrate a number of variables that impact the expression and detection of neuronal vacuolization and necrosis in rats after treatment with MK-801.
Insights
N-methyl-D-aspartate (NMDA) antagonists like MK-801 cause vacuolization and necrosis in rat brains. This effect is dose-dependent, more severe in females, and varies along the brain's rostrocaudal axis.
Area of Science:
- Neuroscience
- Toxicology
- Pharmacology
Background:
- N-methyl-D-aspartate (NMDA) receptor antagonists are known to induce neuropathological changes.
- Vacuolization and neuronal necrosis in the posterior cingulate/retrosplenial (PC/RS) cortex are significant side effects observed after administration of certain NMDA antagonists.
Purpose of the Study:
- To review and characterize the neuropathological effects, specifically vacuolization and necrosis, in the PC/RS cortex of rats following single-dose administration of MK-801.
- To investigate the dose-dependency, temporal profile, and influencing factors of these neurotoxic effects.
Main Methods:
- Utilized light microscopy and transmission electron microscopy for ultrastructural analysis.
- Employed quantitative enzyme-linked immunosorbent assay (ELISA) to measure specific protein markers.
- Conducted cell counting to quantify neuronal damage.
- Administered single doses of MK-801 to Sprague-Dawley rats.
Main Results:
- Vacuole formation was observed within 30 minutes post-treatment.
- A dose-dependent pattern of necrosis in susceptible PC/RS neurons was established.
- Increased glial fibrillary acidic protein (GFAP) levels indicated a reactive astrogliosis in response to neuronal necrosis.
- Significantly higher levels of necrosis were found in female rats compared to male rats.
- Necrosis exhibited a rostrocaudal gradient within the PC/RS cortex.
Conclusions:
- Single-dose administration of MK-801 induces significant vacuolization and dose-dependent necrosis in the rat PC/RS cortex.
- Sex and anatomical location within the PC/RS cortex are critical variables influencing the severity of MK-801-induced neurotoxicity.
- These findings highlight the importance of considering these factors when evaluating NMDA antagonist neurotoxicity.