Dynorphin A-induced rat spinal cord injury: evidence for excitatory amino acid involvement in a pharmacological model of ischemic spinal cord injury.
Dynorphin A reduced lumbosacral blood flow, elevated cerebrospinal fluid lactic acid concentrations and caused flaccid hindlimb paralysis and striking neuropathological changes after its injection into the spinal subarachnoid space in rats. Coadministration of the vasodilator hydralazine substantially eliminated the paralytic, anaerobic metabolic and neuropathological responses to dynorphin A. In contrast, in concentrations up to 1 mM, dynorphin A did not alter the viability of cultured rat spinal cord neurons. Thus, it appears that this peptide lacks direct neurotoxic effects and that neuronal injuries in vivo result primarily from ischemia associated with dynorphin A-induced blood flow reductions. NMDA receptor antagonists significantly improved recovery from dynorphin A-induced hindlimb paralysis, and substantially eliminated neuropathological changes without attenuating the acute blood flow reductions or lactic acid elevations. Additionally, glutamate and aspartate concentrations were increased significantly in spinal cord cerebrospinal fluid samples removed during the time that peptide-induced spinal cord blood flow reductions were observed. In contrast, neither amino acid concentration was elevated in media removed after 1-hr exposure of spinal cord neuronal cell cultures to 100 microM concentrations of dynorphin A. These results indicate that the paralysis and spinal cord injuries produced in rats after spinal subarachnoid injection of dynorphin A result predominantly from spinal cord ischemia, and further identify excitatory amino acids and N-methyl-D-aspartate receptor mechanisms as important mediators in this injury model.
Long
J B
JB
Department of Medical Neurosciences, Walter Reed Army Institute of Research, Washington, District of Columbia.
Rigamonti
D D
DD
Oleshansky
M A
MA
Wingfield
C P
CP
Martinez-Arizala
A
A
D000596:Amino Acids / Q000502:physiology*; D000818:Animals; D002478:Cells, Cultured; D004195:Disease Models, Animal; D004399:Dynorphins / Q000633:toxicity*; D006614:Hindlimb / Q000187:drug effects / Q000502:physiology; D007511:Ischemia / Q000139:chemically induced*; D008297:Male; D009474:Neurons / Q000187:drug effects; D051381:Rats; D017207:Rats, Sprague-Dawley; D016194:Receptors, N-Methyl-D-Aspartate / Q000187:drug effects / Q000502:physiology*; D013116:Spinal Cord / Q000098:blood supply* / Q000166:cytology / Q000187:drug effects; D013119:Spinal Cord Injuries / Q000139:chemically induced*
D000596:Amino Acids; D016194:Receptors, N-Methyl-D-Aspartate; D004399:Dynorphins