The increase in TNF-alpha levels is implicated in NF-kappaB activation and inducible nitric oxide synthase expression...

The underlying mechanisms by which physical or psychological stress causes neurodegeneration are still unknown. We have demonstrated that the high-output and long-lasting synthesizing source of nitric oxide (NO), inducible NO synthase (iNOS), is expressed in brain cortex after three weeks of repeated stress and that its overexpression accounts for the neurodegenerative changes found in this situation. Now we have found that a short duration of stress (immobilization for 6 h) also induces the expression of iNOS in brain cortex in adult male rats. In order to elucidate the possible mechanisms involved in iNOS expression, we have studied the role of the cytokine tumor necrosis factor-alpha (TNF-alpha) released in brain during stress. We have shown that there is an increase in soluble TNF-alpha levels after 1 h of stress in cortex and that this is preceded by an increase in TNF-alpha-convertase (TACE) activity in brain cortex as soon as 30 min after immobilization. Stress-induced increase in both TACE activity and TNF-alpha levels seems to be mediated by excitatory amino acids since they can be blocked by MK-801 (dizocilpine) (0.2 mg/kg i.p.), an antagonist of the N-methyl-D-aspartate subtype of glutamate receptor. In order to study the role of TACE and TNF-alpha in iNOS induction, a group of animals were i.p. injected with the preferred TACE inhibitor BB1101 (2 and 10 mg/kg). Indeed, BB1101 inhibited iNOS expression induced by six hours of stress. In addition, we studied the role of the transcription factor nuclear factor kappaB (NF-kappaB), which is required for iNOS expression. We have found that the administration of the TACE inhibitor BB1101 inhibited the stress-stimulated translocation of NF-kappaB to the nucleus. Taken together, these findings indicate that glutamate receptor activation induces TACE up-regulation and subsequent increase in TNF-alpha levels, and this account for stress-induced iNOS expression via NF-kappaB activation, supporting a possible neuroprotective role for specific TACE inhibitors in this situation.