NMDA and non-NMDA receptor antagonists protect against excitotoxic injury in the rat spinal cord.

The neuroprotective properties of the N-methyl-D-aspartate (NMDA) antagonist dizocilpine (MK-801) and the non-NMDA antagonists 2,3-dihydroxy-6-nitro-7-sulfamoylbenzo[f]quinoxaline (NBQX) and alpha-methyl-4-carboxyphenylglycine (MCPG) were evaluated against neuronal injury produced by the intraspinal injection of NMDA and alpha-amino-3-hydroxy-5-methylisoxazole-4-propionic acid (AMPA). Forty-nine animals were divided into eight groups in order to evaluate the effects of different drug combinations: (a) NMDA; (b) NMDA + MCPG; (c) NMDA + NBQX; (d) NMDA + MK-801; (e) AMPA; (f) AMPA + MCPG; (g) AMPA + MK-801; and (h) AMPA + NBQX. Drugs were microinjected into spinal segments T12-L3 through a micropipette attached to a Hamilton microliter syringe. Spinal cords were evaluated after a survival period of 48 h at which time NMDA and AMPA were found to produce morphological changes over the concentration ranges of 125-500 mM and 75-500 microM, respectively. Neuronal loss following injections of NMDA + MK-801 or AMPA + NBQX was significantly less than that following injections of NMDA or AMPA alone. By contrast, neuronal loss following co-injections of NMDA or AMPA with inappropriate antagonists, i.e., NMDA + NBQX/MCPG or AMPA + MCPG/MK-801, was not significantly different from that produced by NMDA or AMPA. The results suggest that elevations in spinal levels of glutamate followed by prolonged activation of NMDA and AMPA receptor subtypes initiate an excitotoxic cascade resulting in neuronal injury. Blockade of NMDA and AMPA effects by MK-801 and NBQX respectively confirms the well documented neuroprotective effects of these drugs and lends support to the potential importance of NMDA and especially AMPA receptor antagonists as therapeutic agents in the treatment of acute spinal cord injury.

Neuronal damage following intraspinal injection of a nitric oxide synthase inhibitor in the rat.

Intraspinal microinjection of the nonspecific nitric oxide synthase (NOS) inhibitor N-nitro-L-arginine methyl ester (L-NAME) was used to determine if inhibition of NOS results in morphological changes in the rat spinal cord. Following spinal injections of 100-750 mM L-NAME (pH 7.0), 1.0-500 mM L-NAME (pH 2.5-5.4), or L-NAME + L-arginine, quantitative analysis of morphological changes revealed a positive dose-response relationship between L-NAME and neuronal loss. This effect was blocked by L-arginine and was inversely related to spinal levels of NOS enzyme activity. Results of this study have shown the importance of basal NOS activity in maintaining the structural integrity of spinal neurons. It is proposed that the effects of L-NAME on nitric oxide (NO) production leads to decreased blood flow, secondary to vasoconstriction, and a hypoxic-ischemic reaction in spinal tissue. The results suggest that a potential contributing factor to neuronal damage in pathological conditions such as spinal cord injury may be the decreased production of nitric oxide.