Inducible nitric oxide synthase is an endogenous neuroprotectant after traumatic brain injury in rats and mice

Elizabeth H. Sinz, Patrick M. Kochanek, C. Edward Dixon, Robert S B Clark, Joseph A. Carcillo, Simon C. Watkins, Joanne Schiding, Timothy M. Carlos, Timothy R. Billiar

Research output: Contribution to journalArticle

Abstract

Introduction: Inducible nitric oxide synthase (iNOS) is upregulated by cytokines and is detected in brain during the acute inflammatory response to traumatic brain injury (TBI).1 In sepsis models, iNOS-derived nitric oxide (NO) prevents apoptosis in hepatocytes2 while in stroke, it is detrimental.3 We studied the role of iNOS in TBI using two methods; 1) treatment of rats with iNOS inhibitors aminoguanidine (AG) or N-iminoethyl-D-lysine (NIL), and 2) assessment of knockout mice lacking the gene for iNOS (knockout, -/-). Methods: Male Sprague-Dawley rats (n=10/grp), underwent controlled cortical impact (CCI) with secondary hypoxemia (FiO2 = 0.11 for 30 min).4 After injury, Alzet pumps were implanted SQ to deliver AG (∼180 mg/kg/d), NIL (∼60 mg/kg/d) or saline vehicle. In male mice (n=8/grp), CCI was performed in iNOS (-/-) and wild type (+/+) littermates. Outcome parameters included motor function and memory acquisition (Morris water maze [MWM], as well as histology (contusion volume and hippocampal neuron counts). Results: In rats, treatment with AG or NIL exacerbated damage in CA1 and CA3 (p < 0.05 vs vehicle) but did not expand the contusion. iNOS (/-) mice showed markedly increased latency in MWM (p < 0.05 vs +/+) after CCI. Conclusion: An endogenous neuroprotectant role for iNOS-derived nitric oxide after TBI is strongly supported.

Original languageEnglish (US)
Pages (from-to)A36
JournalCritical care medicine
Volume26
Issue number1 SUPPL.
StatePublished - Dec 1 1998

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Neuroprotective Agents
Nitric Oxide Synthase Type II
Lysine
Contusions
Nitric Oxide
Traumatic Brain Injury
Water
Knockout Mice
Sprague Dawley Rats
Sepsis
Histology
Stroke
Apoptosis
Cytokines
Neurons
Wounds and Injuries
Brain
Therapeutics
Genes
pimagedine

All Science Journal Classification (ASJC) codes

  • Critical Care and Intensive Care Medicine

Cite this

Sinz, E. H., Kochanek, P. M., Edward Dixon, C., Clark, R. S. B., Carcillo, J. A., Watkins, S. C., ... Billiar, T. R. (1998). Inducible nitric oxide synthase is an endogenous neuroprotectant after traumatic brain injury in rats and mice. Critical care medicine, 26(1 SUPPL.), A36.
Sinz, Elizabeth H. ; Kochanek, Patrick M. ; Edward Dixon, C. ; Clark, Robert S B ; Carcillo, Joseph A. ; Watkins, Simon C. ; Schiding, Joanne ; Carlos, Timothy M. ; Billiar, Timothy R. / Inducible nitric oxide synthase is an endogenous neuroprotectant after traumatic brain injury in rats and mice. In: Critical care medicine. 1998 ; Vol. 26, No. 1 SUPPL. pp. A36.
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Sinz, EH, Kochanek, PM, Edward Dixon, C, Clark, RSB, Carcillo, JA, Watkins, SC, Schiding, J, Carlos, TM & Billiar, TR 1998, 'Inducible nitric oxide synthase is an endogenous neuroprotectant after traumatic brain injury in rats and mice', Critical care medicine, vol. 26, no. 1 SUPPL., pp. A36.

Inducible nitric oxide synthase is an endogenous neuroprotectant after traumatic brain injury in rats and mice. / Sinz, Elizabeth H.; Kochanek, Patrick M.; Edward Dixon, C.; Clark, Robert S B; Carcillo, Joseph A.; Watkins, Simon C.; Schiding, Joanne; Carlos, Timothy M.; Billiar, Timothy R.

In: Critical care medicine, Vol. 26, No. 1 SUPPL., 01.12.1998, p. A36.

Research output: Contribution to journalArticle

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T1 - Inducible nitric oxide synthase is an endogenous neuroprotectant after traumatic brain injury in rats and mice

AU - Sinz, Elizabeth H.

AU - Kochanek, Patrick M.

AU - Edward Dixon, C.

AU - Clark, Robert S B

AU - Carcillo, Joseph A.

AU - Watkins, Simon C.

AU - Schiding, Joanne

AU - Carlos, Timothy M.

AU - Billiar, Timothy R.

PY - 1998/12/1

Y1 - 1998/12/1

N2 - Introduction: Inducible nitric oxide synthase (iNOS) is upregulated by cytokines and is detected in brain during the acute inflammatory response to traumatic brain injury (TBI).1 In sepsis models, iNOS-derived nitric oxide (NO) prevents apoptosis in hepatocytes2 while in stroke, it is detrimental.3 We studied the role of iNOS in TBI using two methods; 1) treatment of rats with iNOS inhibitors aminoguanidine (AG) or N-iminoethyl-D-lysine (NIL), and 2) assessment of knockout mice lacking the gene for iNOS (knockout, -/-). Methods: Male Sprague-Dawley rats (n=10/grp), underwent controlled cortical impact (CCI) with secondary hypoxemia (FiO2 = 0.11 for 30 min).4 After injury, Alzet pumps were implanted SQ to deliver AG (∼180 mg/kg/d), NIL (∼60 mg/kg/d) or saline vehicle. In male mice (n=8/grp), CCI was performed in iNOS (-/-) and wild type (+/+) littermates. Outcome parameters included motor function and memory acquisition (Morris water maze [MWM], as well as histology (contusion volume and hippocampal neuron counts). Results: In rats, treatment with AG or NIL exacerbated damage in CA1 and CA3 (p < 0.05 vs vehicle) but did not expand the contusion. iNOS (/-) mice showed markedly increased latency in MWM (p < 0.05 vs +/+) after CCI. Conclusion: An endogenous neuroprotectant role for iNOS-derived nitric oxide after TBI is strongly supported.

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Sinz EH, Kochanek PM, Edward Dixon C, Clark RSB, Carcillo JA, Watkins SC et al. Inducible nitric oxide synthase is an endogenous neuroprotectant after traumatic brain injury in rats and mice. Critical care medicine. 1998 Dec 1;26(1 SUPPL.):A36.