Differential pattern of neuroprotection in lumbar, cervical and thoracic spinal cord segments in an organotypic rat model of glutamate-induced excitotoxicity

Glutamate-induced excitotoxicity is a major contributor to motor neuron (MN) degeneration in disorders such as amyotrophic lateral sclerosis (ALS), stroke and spinal cord injury. Numerous in vitro and in vivo models have been developed to evaluate the efficacy and mode of action of neuroprotective agents. However, the dominance of glutamate receptor-subtype in the different regions of the spinal cord in these models has generally been overlooked. This study first compared the neuroprotective effect of administering glutamate receptor antagonists, (+)-5-methyl-10,11-dihydro-5H-dibenzo[a,d]cyclo-hepten-5,10-imine (MK-801) and 6-cyano-7-nitroquinoxaline-2,3-dione (CNQX), into a serum-free excitotoxic organotypic in vitro system, on the survival of MNs located in the lumbar area of spinal cord. The poor neuroprotection provided by MK-801 (NMDA (N-methyl-D-aspartate) antagonist) in comparison to CNQX (AMPA/KA (a-amino-3-hydroxy-5-methyl-4-isoxazole propionate/kainate) antagonist), raised the hypothesis that the extent of engagement by glutamate receptor sub-types in the mechanism of excitotoxicity may differ within different populations of MNs, The consequent examination of MN susceptibility to glutamate-induced excitotoxicity in relation to the rostro-caudal level from which MN originated revealed a differential glutamate receptor sub-type dominance at different spinal cord regions (i.e. cervical, thoracic and lumbar). In the cervical and lumbar regions, the AMPA receptor was the main contributor to MN excitotoxicity, whereas in thoracic regions, the NMDA receptor was the main contributor. This study provides a new way of looking at mechanisms leading to glutamate-induced excitotoxicity in MN and may therefore be important for the development of treatment strategies in protection of spinal MNs in neurodegenerative disease and traumatic injury.