Sex differences in the effect of MK-801 on normal and spinal cord injured rats

The induction of functional paraplegia in female rats by contusive spinal cord injury was not prevented by compound MK-801. However, the treatment reduced cavitation around the lesion epicenter to 14 mm³ compared to 17 mm³ in untreated controls t-test, P < 0.28) and conserved more neurons in defined regions outside the lesion epicenter (drug-treated animals vs untreated controls: 299 vs 73 neurons/mm²; t-test, P < 0.009). Thus, although MK-801 was only partially effective in preventing neuronal death secondary to contusion injury it appeared to have a definite neuroprotective effect. In view of the variety of side effects of MK-801 and the controversy on the mechanism of neuroprotection, we examined the action of the drug on non-injured animals. The effects of the drug were strongly sex-dependent. One hour after subcutaneous injection (0.5 mg/kg), female rats were hypothermic (36.8 °C treated vs 38.3 °C control) whereas male rats were hyperthermic (39.6 °C treated vs 38.4 °C control). In females, MK-801 caused cessation of cycling and appearance of numerous polymorphonuclear (PMN) phagocytes in vaginal frotis. Also, beginning 24 h after MK-801 injection, the proportion of PMN increased 400% in female blood, whereas males maintained control values. Arthritis-like joint inflammation was prominent in the toes of female rats, but males were unaffected. After continued treatment with the drug for 15 days, PMN count in female rats decreased and the animals resumed cycling. However, during this period female rats lost 20% of their weight, whereas males gained 26%. One hour after MK-801 injection large increases in blood pressure occurred in both sexes, returning to normal values 2 h later. Hypothermia does not appear to be a factor in the neuroprotective effect of MK-801, but the drug has a number of potentially dangerous side effects, particularly in female rats. Because polymorphonuclear cells are known sources of oxygen free radicals, neuroprotection by MK-801 treatment ought to be much more efficient in males than in females and the drug should be used in combination with a free-radical scavenger.