Nicotine attenuates oxidative stress, activation of redox-regulated transcription factors and induction of proinflammatory genes in compressive spinal cord trauma.
Pathophysiology of neurodegeneration following spinal cord injury (SCI) involves alterations of cellular redox status, activation of transcription factors and induction of proinflammatory genes. In addition, recent evidence indicates that nicotine can induce potent neuroprotective effects. To study the influence of nicotine on the redox signaling pathways in relationship to SCI, moderate contusions of spinal cords at the level of T-10 were induced in rats treated or untreated with nicotine. Cellular oxidative stress, DNA binding activity of redox-responsive transcription factors (AP-1, NF-kappaB and CREB) as well as mRNA levels of inflammatory genes (MCP-1 and TNF-alpha) were determined in the thoracic and lumbar regions of the spinal cords. Nicotine was administrated 2 h after the SCI in a single i.p. injection at the dose of 0.35, 3.5 or 7 mg/kg, and rats were sacrificed 3 h following such an injection. Spinal cord trauma was associated with a significant increase in oxidative stress, and activation of NF-kappaB, AP-1 and CREB, as well as overexpression of MCP-1 and TNF-alpha in both the thoracic and lumbar regions. Nicotine administration following the SCI markedly attenuated, especially in the lumbar region, these oxidative and proinflammatory responses. These protective effects of nicotine were fully reversed by inhibition of neuronal nicotinic receptors by mecamylamine. The present results indicate that nicotine administration can attenuate the oxidative injury to spinal cords and suggest that neuronal nicotinic receptors can be attractive targets for neuroprotective therapy.
Ravikumar
R
R
Department of Surgery, University of Kentucky, Lexington, KY 40536, USA.
Flora
Govinder
G
Geddes
James W
JW
Hennig
Bernhard
B
Toborek
Michal
M
D000818:Animals; D001667:Binding, Competitive / Q000187:drug effects / Q000235:genetics; D018932:Chemokine CCL2 / Q000378:metabolism; D017362:Cyclic AMP Response Element-Binding Protein / Q000378:metabolism; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D005786:Gene Expression Regulation / Q000187:drug effects / Q000235:genetics; D007249:Inflammation / Q000188:drug therapy* / Q000235:genetics / Q000378:metabolism; D018836:Inflammation Mediators / Q000378:metabolism*; D008297:Male; D016328:NF-kappa B / Q000187:drug effects / Q000378:metabolism; D009538:Nicotine / Q000494:pharmacology* / Q000627:therapeutic use; D018733:Nicotinic Antagonists / Q000494:pharmacology; D010084:Oxidation-Reduction; D018384:Oxidative Stress / Q000187:drug effects* / Q000502:physiology; D012333:RNA, Messenger / Q000187:drug effects / Q000378:metabolism; D051381:Rats; D020318:Rats, Long-Evans; D011978:Receptors, Nicotinic / Q000187:drug effects / Q000378:metabolism; D013117:Spinal Cord Compression / Q000188:drug therapy* / Q000235:genetics / Q000378:metabolism; D018808:Transcription Factor AP-1 / Q000378:metabolism; D014157:Transcription Factors / Q000187:drug effects* / Q000235:genetics; D016896:Treatment Outcome; D014409:Tumor Necrosis Factor-alpha / Q000187:drug effects / Q000378:metabolism; D015854:Up-Regulation / Q000187:drug effects / Q000235:genetics
C491766:Ccl2 protein, rat; D018932:Chemokine CCL2; D017362:Cyclic AMP Response Element-Binding Protein; D018836:Inflammation Mediators; D016328:NF-kappa B; D018733:Nicotinic Antagonists; D012333:RNA, Messenger; D011978:Receptors, Nicotinic; D018808:Transcription Factor AP-1; D014157:Transcription Factors; D014409:Tumor Necrosis Factor-alpha; D009538:Nicotine