Cognitive deficits after systemic induction of inducible nitric oxide synthase: a randomised trial in rats

Background Nitric oxide acts as an important neurotransmitter as well as a sepsis mediator. During sepsis, high levels of nitric oxide, produced by the inducible form of the nitric oxide synthase (iNOS), may lead to disturbances concerning these conflicting roles and cause septic encephalopathy. To evaluate this theory, we aimed at first, to demonstrate cognitive dysfunction in a rat model based on systemic iNOS induction; second, to elucidate molecular mechanisms; and third, to prevent cognitive deficits in our sepsis model. Methods We used a rat systemic inflammation model that is based on the induction of iNOS by heat-killed Corynebacterium parvum in different doses (30 or 60 mg kg(-1)). NO(2)/NO(3) plasma levels were measured to prove iNOS induction. Cognitive performance was investigated. In brain tissue, NOS protein and NOS activity were determined. To prevent cognitive deficits, two groups of rats received L-N(6)-(1-Iminoethyl)-lysine (L-NIL), a specific iNOS inhibitor in the drinking water. Results The rats cognitive performance, that is, short-term memory as well as long-term memory was impaired in C. parvum rats with a peak at the third day after injection in the 60 mg kg(-1) group. At the same day, neuronal NOS (nNOS)-protein content in the prefrontal cortex was reduced in C. parvum rats. nNOS activity was also reduced in C. parvum rats. The cognitive deficit in short-term memory could be prevented by L-NIL. Conclusion We demonstrate early, reversible cognitive deficits in a rat model of systemic inflammation with increased systemic iNOS activity. As systemic inhibition of iNOS activity prevented rats from the deficit in short-term memory, an involvement of systemic iNOS induction in this deficit is likely. Whether the reduced nNOS-protein expression and nNOS activity are connected to systemic iNOS induction, however, remains unclear. Eur J Anaesthesiol 2011; 28: 655-663 Published online 11 July 2011