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Inducible nitric oxide synthase is an endogenous neuroprotectant after traumatic brain injury in rats and mice
Elizabeth H. Sinz, … , Donald W. Marion, Timothy R. Billiar
Elizabeth H. Sinz, … , Donald W. Marion, Timothy R. Billiar
Published September 1, 1999
Citation Information: J Clin Invest. 1999;104(5):647-656. https://doi.org/10.1172/JCI6670.
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Article

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

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Abstract

Nitric oxide (NO) derived from the inducible isoform of NO synthase (iNOS) is an inflammatory product implicated both in secondary damage and in recovery from brain injury. To address the role of iNOS in experimental traumatic brain injury (TBI), we used 2 paradigms in 2 species. In a model of controlled cortical impact (CCI) with secondary hypoxemia, rats were treated with vehicle or with 1 of 2 iNOS inhibitors (aminoguanidine and L-N-iminoethyl-lysine), administered by Alzet pump for 5 days and 1.5 days after injury, respectively. In a model of CCI, knockout mice lacking the iNOS gene (iNOS–/–) were compared with wild-type (iNOS+/+) mice. Functional outcome (motor and cognitive) during the first 20 days after injury, and histopathology at 21 days, were assessed in both studies. Treatment of rats with either of the iNOS inhibitors after TBI significantly exacerbated deficits in cognitive performance, as assessed by Morris water maze (MWM) and increased neuron loss in vulnerable regions (CA3 and CA1) of hippocampus. Uninjured iNOS+/+ and iNOS–/– mice performed equally well in both motor and cognitive tasks. However, after TBI, iNOS–/– mice showed markedly worse performance in the MWM task than iNOS+/+ mice. A beneficial role for iNOS in TBI is supported.

Authors

Elizabeth H. Sinz, Patrick M. Kochanek, C. Edward Dixon, Robert S.B. Clark, Joseph A. Carcillo, Joanne K. Schiding, Minzhi Chen, Stephen R. Wisniewski, Timothy M. Carlos, Debra Williams, Steven T. DeKosky, Simon C. Watkins, Donald W. Marion, Timothy R. Billiar

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Figure 1

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iNOS mRNA expression in rats and mice after TBI. iNOS mRNA was detected ...
iNOS mRNA expression in rats and mice after TBI. iNOS mRNA was detected using RT-PCR. (a) In rats, iNOS mRNA was increased in injured cortex at 2, 6, 24, and 72 hours, and in ipsilateral hippocampus at 2 and 6 hours after TBI plus secondary hypoxemic insult, compared with control (n = 2 animals per group). A 138-bp PCR product is seen. (b) In C57BL/6J mice, iNOS mRNA was increased in injured cortex at 24, 48, and 72 hours after TBI, compared with control (n = 3 animals per group). A 429-bp PCR product is seen. RT-PCR for actin confirmed equal loading of RNA. M, marker; C, uninjured control.

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