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 If, however, 1 mg/kg MK-801 is withdrawn after 2 weeks post-axotomy in the RN and 3 weeks postaxotomy in CN, all axotomized neurons survive.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.

Neurotrophin-3 prevents death of axotomized Clarke's nucleus neurons in adult rat

“…Another possibility is that at longer survival periods NT-3 no longer has access to the injured axons, perhaps because of scar formation. Permanent rescue of a significant percentage of axotomized neurons by limited exposure to active agents has been previously reported in several different experimental systems (Eagleson et al, 1992;Diener and Bregman, 1994;Sanner et al, 1994;Winkler et al, 1996). One implication of these results is that the processes involved in axotomy-induced cell death are triggered in the first few weeks after injury and that, if axotomized neurons can be sustained during this critical period, then survival may be permanent.…”

Passive or Active Immunization with Myelin Basic Protein Promotes Recovery from Spinal Cord Contusion

“…The number of labeled neurons in each rat is given by the average number of cells counted in its two red nuclei. In the statistical analysis, we used a corrective factor to allow for the thickness of the sections and the size of a single nucleus so as to correct for possible recounting of the same cell (Smolen et al, 1983;Sanner et al, 1994).…”

“…Attempts to promote CNS recovery have focused on two goals: (1) the stimulation of regeneration (Caroni and Schwab, 1988;Reier et al, 1992;Cheng et al, 1996;Davies et al, 1997;Li et al, 1997;Miya et al, 1997;Rapalino et al, 1998;Wang et al, 1998;Chong et al, 1999;Neumann and Woolf, 1999), and (2) neuroprotection, or the arrest of secondary degeneration (Behrmann et al, 1994;Constantini and Young, 1994;Sanner et al, 1994;Basso et al, 1996;Gruner et al, 1996;Beattie et al, 1997;Crowe et al, 1997;Bethea et al, 1998;Yong et al, 1998;Bavetta et al, 1999;Moalem et al, 1999;Schwartz et al, 1999). Attempts have also been made to improve the functional outcome of surviving neurons (Blight, 1989).…”

Identification of a Survival-Promoting Peptide in Medium Conditioned by Oxidatively Stressed Cell Lines of Nervous System Origin

“…Glutamate toxicity and associated oxidative stress have long been recognized as destructive in a variety of neural degenerative disorders, including trauma (Choi, 1988;Simonian and Coyle, 1996). NMDA receptor blockade in such situations may be protective (Sanner et al, 1994), and it is now clear that phosphatases (calcineurin in particular) are involved in depression NMDA receptor activity (Tong et al, 1995;Torii et al, 1995;Oliet et al, 1997;Raman et al, 1996). Inhibition of calcineurin reverses the protective effects of NMDA receptor Figure 9.…”