Neuroprotection of locomotor networks after experimental injury to the neonatal rat spinal cord in vitro.
Treatment to block the pathophysiological processes triggered by acute spinal injury remains unsatisfactory as the underlying mechanisms are incompletely understood. Using as a model the in vitro spinal cord of the neonatal rat, we investigated the feasibility of neuroprotection of lumbar locomotor networks by the glutamate antagonists 6-cyano-7-nitroquinoxaline-2, 3-dione (CNQX) and aminophosphonovalerate (APV) against acute lesions induced by either a toxic solution (pathological medium (PM) to mimic the spinal injury hypoxic-dysmetabolic perturbation) or excitotoxicity with kainate. The study outcome was presence of fictive locomotion 24 h after the insult and its correlation with network histology. Inhibition of fictive locomotion by PM was contrasted by simultaneous and even delayed (1 h later) co-application of CNQX and APV with increased survival of ventral horn premotoneurons and lateral column white matter. Neither CNQX nor APV alone provided neuroprotection. Kainate-mediated excitotoxicity always led to loss of fictive locomotion and extensive neuronal damage. CNQX and APV co-applied with kainate protected one-third of preparations with improved motoneuron and dorsal horn neuronal counts, although they failed with delayed application. Our data suggest that locomotor network neuroprotection was possible when introduced very early during the pathological process of spinal injury, but also showed how the borderline between presence or loss of locomotor activity was a very narrow one that depended on the survival of a certain number of neurons or white matter elements. The present report provides a model not only for preclinical testing of novel neuroprotective agents, but also for estimating the minimal network membership compatible with functional locomotor output.
Margaryan
G
G
Neurobiology Sector, International School for Advanced Studies, 34151 Trieste, Italy.
Mattioli
C
C
Mladinic
M
M
Nistri
A
A
D015763:2-Amino-5-phosphonovalerate / Q000008:administration & dosage / Q000494:pharmacology*; D018750:6-Cyano-7-nitroquinoxaline-2,3-dione / Q000008:administration & dosage / Q000494:pharmacology*; D000818:Animals; D000831:Animals, Newborn; D002470:Cell Survival / Q000187:drug effects; D004195:Disease Models, Animal; D004359:Drug Therapy, Combination; D004525:Efferent Pathways / Q000187:drug effects / Q000503:physiopathology; D018691:Excitatory Amino Acid Antagonists / Q000008:administration & dosage / Q000494:pharmacology; D066298:In Vitro Techniques; D007608:Kainic Acid; D008124:Locomotion / Q000187:drug effects* / Q000502:physiology; D009046:Motor Neurons / Q000187:drug effects / Q000502:physiology; D009413:Nerve Fibers, Myelinated / Q000187:drug effects / Q000502:physiology; D009474:Neurons / Q000187:drug effects / Q000502:physiology; D018696:Neuroprotective Agents / Q000008:administration & dosage / Q000494:pharmacology*; D020671:Posterior Horn Cells / Q000187:drug effects / Q000502:physiology; D051381:Rats; D017208:Rats, Wistar; D013119:Spinal Cord Injuries / Q000139:chemically induced / Q000188:drug therapy* / Q000503:physiopathology; D013997:Time Factors
D018691:Excitatory Amino Acid Antagonists; D018696:Neuroprotective Agents; D018750:6-Cyano-7-nitroquinoxaline-2,3-dione; D015763:2-Amino-5-phosphonovalerate; D007608:Kainic Acid