Delayed treatment with nimesulide reduces measures of oxidative stress following global ischemic brain injury in gerbils

TL;DR

This study demonstrates that delayed administration of nimesulide reduces oxidative stress markers and neuronal degeneration in gerbils after global ischemic brain injury, indicating its neuroprotective potential within a wide therapeutic window.

Contribution

It shows that nimesulide, a cyclooxygenase-2 inhibitor, can attenuate oxidative stress and neuronal damage after ischemia even when administered hours later.

Findings

Nimesulide reduces hippocampal oxidative stress markers.

Delayed treatment still offers neuroprotection.

Fewer degenerating neurons observed with nimesulide.

Abstract

Metabolism of arachidonic acid by cyclooxygenase is one of the primary sources of reactive oxygen species in the ischemic brain. Neuronal overexpression of cyclooxygenase-2 has recently been shown to contribute to neurodegeneration following ischemic injury. In the present study, we examined the possibility that the neuroprotective effects of the cyclooxygenase-2 inhibitor nimesulide would depend upon reduction of oxidative stress following cerebral ischemia. Gerbils were subjected to 5 min of transient global cerebral ischemia followed by 48 h of reperfusion and markers of oxidative stress were measured in hippocampus of gerbils receiving vehicle or nimesulide treatment at three different clinically relevant doses (3, 6 or 12 mg/kg). Compared with vehicle, nimesulide significantly (P<0.05) reduced hippocampal glutathione depletion and lipid peroxidation, as assessed by the levels of malondialdehyde (MDA), 4-hydroxy-alkenals (4-HDA) and lipid hydroperoxides levels, even when the treatment was delayed until 6 h after ischemia. Biochemical evidences of nimesulide neuroprotection were supported by histofluorescence findings using the novel marker of neuronal degeneration Fluoro-Jade B. Few Fluoro-Jade B positive cells were seen in CA1 region of hippocampus in ischemic animals treated with nimesulide compared with vehicle. These results suggest that nimesulide may protect neurons by attenuating oxidative stress and reperfusion injury following the ischemic insult with a wide therapeutic window of protection.