The proximity of the lesion to cell bodies determines the free radical risk induced in rat rubrospinal neurons subjected to axonal injury.
To find out whether close axonal injury resulted in greater free radical risk to cord-projection central neurons than distant ones, we studied the expressions of nitric oxide synthase, calcineurin, and superoxide dismutase in rat rubrospinal neurons following brainstem, C2 and T10 axotomies using immunohistochemical methods. We found that nitric oxide synthase expression was upregulated more following brainstem than C2 lesion while T10 lesion triggered no detectable changes. This response peaked at 1 week and returned to control level by 8-week-post-injury. At the same time, calcineurin, which activated nitric oxide synthase, was increased 1 week following brainstem and C2 axotomies. These suggest that close, but not distant, axotomy enhanced NO production, which appeared to be cytotoxic since blocking NO synthesis with N-nitro- l-arginine methyl ester reduced brainstem axotomy-induced rubrospinal cell loss. On the other hand, the mitochondrial Mn-superoxide dismutase, which competes with NO to prevent the formation of the cytotoxic free radical peroxynitrite, was notably reduced after brainstem but almost unaltered following C2 axotomy. Meanwhile, the cytosolic Cu/Zn-superoxide dismutase was not altered following C2 but increased after brainstem axotomy. Ultrastructurally, in rubrospinal neurons more mitochondria became swollen following brainstem than C2 axotomy. Based on these, we proposed that besides the NO-overproduction-induced toxicity, superoxide-loading-induced mitochondrial damage also added to hampering the survival of the closely axotomized neurons.
Liu
P-H
PH
Department of Anatomy, College of Medicine, Tzu-Chi University, No. 701, Section 3, Chung Yan Road, 970, Hualien, Taiwan, Republic of China.
Tsai
H-Y
HY
Chung
Y-W
YW
Wang
Y-J
YJ
Tseng
G-F
GF
D000818:Animals; D001369:Axons / Q000473:pathology / Q000502:physiology*; D019771:Axotomy / Q000379:methods; D019703:Calcineurin / Q000378:metabolism; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005260:Female; D005609:Free Radicals / Q000378:metabolism*; D007124:Immunoenzyme Techniques; D019331:NG-Nitroarginine Methyl Ester / Q000494:pharmacology; D009474:Neurons / Q000378:metabolism* / Q000648:ultrastructure; D009569:Nitric Oxide / Q000037:antagonists & inhibitors / Q000096:biosynthesis; D019001:Nitric Oxide Synthase / Q000037:antagonists & inhibitors / Q000378:metabolism; D052248:Nitric Oxide Synthase Type I; D051381:Rats; D017208:Rats, Wistar; D012012:Red Nucleus / Q000187:drug effects / Q000378:metabolism* / Q000473:pathology; D013116:Spinal Cord / Q000187:drug effects / Q000378:metabolism* / Q000473:pathology; D013119:Spinal Cord Injuries / Q000378:metabolism* / Q000473:pathology; D013482:Superoxide Dismutase / Q000378:metabolism; D013997:Time Factors; D015854:Up-Regulation
D004791:Enzyme Inhibitors; D005609:Free Radicals; D009569:Nitric Oxide; D019001:Nitric Oxide Synthase; D052248:Nitric Oxide Synthase Type I; C496322:Nos1 protein, rat; D013482:Superoxide Dismutase; D019703:Calcineurin; D019331:NG-Nitroarginine Methyl Ester