Neuroprotective effects of nitric oxide synthase inhibitors in spinal cord injury-induced pathophysiology and motor functions: an experimental study in the rat.
The role of nitric oxide (NO) in spinal cord injury (SCI)-induced motor dysfunction, breakdown of the blood-spinal cord barrier (BSCB), edema formation, and cell injury was examined using a pharmacological approach. We used three types of nitric oxide synthase (NOS) inhibitors: a nonselective blocker, L-NAME; an irreversible inhibitor of all isoforms of NOS, L-NMMA; and a long-term competitive inhibitor of neuronal NOS with equal potency to inhibit endothelial NOS, L-NNA. The compounds were administered once daily in separate groups of rats for 7 days. On the 8th day, SCI was performed by making a longitudinal incision into the right dorsal horn of the T10-11 segments, and the rats were allowed to survive 5 h after injury. Long-term treatment with L-NNA attenuated SCI-induced NOS upregulation, BSCB breakdown, edema formation, and cell injury, whereas comparatively less neuroprotection is offered by L-NMMA. The magnitude of neuroprotection is much less evident in injured animals that received L-NAME. Interestingly, SCI-induced motor dysfunction measured according to the Tarlov scale showed close correlation with the magnitude of neuroprotection. Thus, an improvement in motor function was seen in animals pretreated with L-NNA, whereas rats treated with L-NAME or L-NMMA did not show any influence on motor dysfunction after SCI. This observation suggests that inhibition of neuronal NOS is important for neuroprotection, and the disturbances in motor function following SCI are associated with the state of spinal cord pathology.
Sharma
Hari Shanker
HS
Department of Surgical Sciences, Anesthesiology, and Intensive Care Medicine, University Hospital, Uppsala University, SE-75185 Uppsala, Sweden. sharma@surgsci.uu.se
Badgaiyan
Rajendra D
RD
Alm
Per
P
Mohanty
S
S
Wiklund
Lars
L
D000818:Animals; D002463:Cell Membrane Permeability; D004487:Edema / Q000473:pathology / Q000517:prevention & control; D004791:Enzyme Inhibitors / Q000627:therapeutic use*; D008297:Male; D009068:Movement / Q000187:drug effects*; D019331:NG-Nitroarginine Methyl Ester / Q000627:therapeutic use; D018696:Neuroprotective Agents; D052248:Nitric Oxide Synthase Type I / Q000037:antagonists & inhibitors* / Q000378:metabolism; D010243:Paralysis / Q000209:etiology / Q000517:prevention & control; D051381:Rats; D017207:Rats, Sprague-Dawley; D013116:Spinal Cord / Q000473:pathology; D013119:Spinal Cord Injuries / Q000188:drug therapy* / Q000201:enzymology / Q000503:physiopathology; D019323:omega-N-Methylarginine / Q000627:therapeutic use
D004791:Enzyme Inhibitors; D018696:Neuroprotective Agents; D019323:omega-N-Methylarginine; D052248:Nitric Oxide Synthase Type I; D019331:NG-Nitroarginine Methyl Ester