The protective effect of nordihydroguaiaretic acid on cerebral ischemia/reperfusion injury is mediated by the JNK pathway

Nordihydroguaiaretic acid (NDGA) is a powerful antioxidant and/or lipoxygenase (LOX) inhibitor which is isolated from Larrea tridentate. NDGA has been shown to have neuroprotective effects both in vitro and in vivo experiments. However, little is known regarding NDGA's protective mechanism in ischemia/reperfusion (I/R) injury. We therefore investigated the potential protective effects of NDGA and explored the underlying mechanisms. Oxygen-glucose deprivation (OGD) was performed in cultured rat cortical neurons for 60 min. The effect of NDGA on OGD induced cell death and apoptosis was examined at 24 h after reperfusion. Western blot was used to analyze the expression of p-c-jun and p-JNK. Exogenous 5-, 12-, 15-hydroxyeicosatetraenoic acid (HETE) was added respectively to the cells to investigate the contribution of the products of LOX to the c-Jun N-terminal protein kinase (JNK) pathway. Rats were injected intraperitoneally with NDGA before being subjected to middle cerebral artery occlusion (MCAO). At 24 h after reperfusion, neurological deficit, brain infarct volume and the expression of p-c-jun and p-JNK were measured. The results showed that NDGA increased cell viability and inhibited apoptosis after OGD in neurons. NDGA suppressed the expression of p-c-jun and p-JNK in cortical neurons, whereas exogenous 12-, 15-HETE attenuated this effect. NDGA improved neurological deficit, reduced infarct volumes, and downregulated the overexpression of p-c-jun and p-JNK after MCAO and reperfusion. In conclusion, these results suggest that NDGA's protective effect against I/R injury is mediated by the suppression of JNK pathway. This effect is probably due to its 12/15-LOX inhibitor property.

► NDGA increases cell viability and inhibited apoptosis after OGD in neurons.
► NDGA suppresses the expression of p-c-jun and p-JNK in cortical neurons.
► 12-, 15-HETE attenuates the effect of NDGA on p-c-jun and p-JNK in neurons.
► NDGA improved neurological deficit and reduced infarct volumes of rats after MCAO.
► NDGA downregulates the expression of p-c-jun and p-JNK after MCAO and reperfusion.