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

Nitric oxide (NO) derived from the inducible isoform of NO synthase (iNOS) is an inflammatory product implicated both in secondary damage and in recov ery from brain injury. To address the role of iNOS in experimental traumati c brain injury (TBI), we used in paradigms in 2 species. In a model of cont rolled cortical impact (CCI) with secondary hypoxemia, rats were treated wi th vehicle or with 1 of 2 iNOS inhibitors (aminoguanidine and L-N-iminoethy l-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 (m otor and cognitive) during the first 20 days after injury, and histopatholo gy at 21 days, were assessed in both studies. Treatment of rats with either of the iNOS inhibitors after TBI significantly exacerbated deficits in cog nitive performance, as assessed by Morris water maze (MWM) and increased ne uron loss in vulnerable regions (CA3 and CA1) of hippocampus. Uninjured iNO S(+/+) and iNOS(-/-) mice performed equally well in both motor and cognitiv e tasks. However, after TBI, iNOS(-/-) mice showed markedly worse performan ce in the MWM task than iNOS(+/+) mice. A beneficial role for iNOS in TBI i s supported.