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.