NMDA receptor blockade rescues Clarke's and red nucleus neurons after spinal hemisection

Abstract

Hemisection of the adult rat spinal cord at T9 transects the ascending ipsilateral axons of Clarke's nucleus (CN) neurons and the descending contralateral axons of red nucleus (RN) neurons. Eight weeks following axotomy, 30% of CN neurons and 22% of RN neurons die. Since both nuclei receive glutamatergic input, we wished to examine the possibility that glutamatergic excitotoxicity contributes to axotomy-induced neuronal death in these nuclei. To test this we studied the effects of administration of the NMDA receptor antagonist MK-801 on cell survival after axotomy. When 1 mg/kg body weight MK-801 is administered subcutaneously every day for 1-8 weeks to hemisected rats, cell death is prevented. Treatment with 0.5 mg/kg body weight MK-801 over the same time periods results in only partial rescue of axotomized neurons. Paradoxically, when 1 mg/kg MK-801 administration is restricted to the first week of an 8 week survival period, cell death in both the RN and CN is greatly exaggerated over the cell loss found in saline-treated animals. Withdrawal of 1 mg/kg MK-801 after 1 week of administration induces the loss of 92% of CN neurons, which is 63% greater than that occurring after axotomy alone. If, however, 1 mg/kg MK-801 is withdrawn after 2 weeks post-axotomy in the RN and 3 weeks postaxotomy in CN, all axotomized neurons survive. This rescue is found at 6 months postsurgery, the longest survival period studied, and therefore appears to be permanent. These results suggest that glutamatergic afferent input contributes significantly to the death of axotomized red nucleus and Clarke's nucleus neurons via NMDA receptors located on these neurons.