Zileuton Reduces Inflammatory Reaction and Brain Damage Following Permanent Cerebral Ischemia in Rats

Abstract

5-Lipoxygenase inhibitor zileuton has been demonstrated to attenuate ischemic brain damage in rats of permanent focal cerebral ischemia in previous work. To further investigate the mechanism underlying zileuton's neuroprotection, adult male Sprague-Dawley rats underwent permanent middle cerebral artery occlusion (MCAO), then received treatment with zileuton or vehicle after the onset of ischemia. Neurological deficit, cerebral infarction, and morphological characteristic were measured 6 and 24 h after MCAO. The enzymatic activity of myeloperoxidase (MPO) was assessed 6 and 24 h after MCAO and the lipid peroxidation levels were evaluated by malondialdehyde assay. Expression of nuclear factor-kappa B (NF-kappaB) p65 in rat brain was detected by immunohistochemistry and Western blot. Expression of inducible nitric oxide synthase (iNOS) in rat brain was determined by RT-PCR and Western blot. Nitric oxide production in rat brain was also measured 24 h after MCAO. The concentration of TNF-alpha and IL-1beta in serum were detected by ELISA. Zileuton significantly reduced neurological deficit scores, cerebral infarct volume, MPO activity, and the lipid peroxidation levels. It also inhibited the expression of NF-kappaB and decreased the expression and activity of iNOS in rat brain. In addition, zileuton attenuated the release of TNF-alpha and IL-1beta in serum. Our results suggest that zileuton reduces inflammatory reaction and brain damage in a rat model of permanent focal cerebral ischemia. The neuroprotective effect of zileuton in cerebral ischemia might be associated with the inhibition of inflammatory reaction.

Neuroinflammatory response to experimental stroke is inhibited by eriodictyol

“…In agreement to this result Tu et al [61] demonstrated that enzymatic activity of MPO was increased at 6 h after pMCAO with a peak at 24 h, especially in the cortex. Wang et al [62] found that increased MPO activity persist longer in the cortex than in the striatum and can still be found in the cortex after 120 h. The treatment with Etyol significantly protected ischemic animals against the increase in MPO activity.…”

5-Lipoxygenase Inhibitors Attenuate TNF-α-Induced Inflammation in Human Synovial Fibroblasts

“…Developing novel 5-LOX inhibitor or 5-LOX/COX-2 dual inhibitor is a therapeutic strategy to treat inflammatory diseases including arthritis [45]. Neuro-inflammation of brain damage induced by permanent cerebral ischemia and renal ischemia-reperfusion injury can be protected by treatment of zileuton, a 5-LOX inhibitor [46], [47]. 5-LOX inhibitor, NDGA is reported to attenuate ovalbumin-induced lung inflammation in rats [48].…”

Baicalin Inhibits TLR2/4 Signaling Pathway in Rat Brain Following Permanent Cerebral Ischemia

“…Several studies have reported that proinflammatory cytokines, including TNF-α and IL-1β are elevated in serum in the early phase of acute ischemic stroke [26,27].…”