1400W, a Potent Selective Inducible NOS Inhibitor, Improves Histopathological Outcome Following Traumatic Brain Injury in Rats

There are conflicting data regarding the role of nitric oxide (NO) produced by inducible NO synthase (iNOS) in the pathophysiology of traumatic brain injury (TBI). In this report, we evaluated the effect of a potent selective (iNOS) inhibitor, 1400W, on histopathological outcome following TBI in a rat model of lateral fluid percussion brain injury. First, to design an appropriate treatment protocol, the parallel time courses of iNOS and neuronal NOS (nNOS) gene expression, protein synthesis, and activity were investigated. Early induction of iNOS gene was observed in the cortex of injured rats, from 6 to 72 h with a peak at 24 h. Similarly, iNOS protein was detected from 24 to 72 h and de novo synthesized iNOS was functionally active, as measured by Ca2+-independent NOS activity. The kinetic studies of nNOS showed discrepancies, since nNOS gene expression and protein synthesis were constant in the cortex of injured rats from 24 to 72 h, while Ca2+-dependent constitutive NOS activity was markedly decreased at 24 h, persisting up to 72 h. Second, treatment with 1400W, started as a bolus of 20 mg kg-1 (s.c.) at 18 h post-TBI, followed by s.c.-infusion at a rate of 2.2 mg kg-1 h-1 between 18 and 72 h, reduced by 64% the brain lesion volume at 72 h. However, the same treatment paradigm initiated 24 h post-TBI did not have any effect. In conclusion, administration of a selective iNOS inhibitor, 1400W, even delayed by 18 h improves histopathological outcome supporting a detrimental role for iNOS induction after TBI.