Neuroprotective Effect of Lipoxin A4 Methyl Ester in a Rat Model of Permanent Focal Cerebral Ischemia

Abstract

Neuroprotective effect of lipoxin A(4) methyl ester (LXA(4) ME) was tested in a rat model of permanent middle cerebral artery occlusion. LXA(4) ME was administrated through intracerebroventricular injection immediately after middle cerebral artery was occluded. Administration of LXA(4) ME ameliorated neurological deficit, reduced infarct volume, attenuated histological damage, and decreased number of apoptotic neuron induced by ischemic insult. These neuroprotective effects of LXA(4) ME were associated with inhibition of neutrophil infiltration, lipid peroxidation, and astrocyte activation. In addition, LXA(4) ME also attenuated proinflammatory cytokines (TNF-alpha and IL-1beta) production. These data suggest that LXA(4) ME protects neuron against permanent cerebral ischemia by inhibiting inflammatory responses.

A Lipoxin A4 Analog Ameliorates Blood–Brain Barrier Dysfunction and Reduces MMP-9 Expression in a Rat Model of Focal Cerebral Ischemia–Reperfusion Injury

“…In particular, during transient global cerebral ischemia, the MMP-induced degradation of perineuronal matrix proteins plays a role in anoikis-type neuronal cell death (Lee et al 2008). Importantly, our previous reports have shown that LXA 4 ME can inhibit neuronal apoptosis induced by transient or permanent cerebral ischemia insult Wu et al 2010). Considering these reports, we propose that the LXA 4 ME-mediated attenuation of neuronal apoptosis may be partly due to the inhibition of MMP-9 expression and activity.…”

“…The rats were randomly assigned to sham, MCAO, or LXA 4 ME groups. After MCAO, rats in the LXA 4 ME group received an intracerebroventricular injection of 5 μL LXA 4 ME (0.3 nM), as described in our previous reports Wu et al 2010). Briefly, injections were performed with a Hamilton syringe using a 27-gauge needle.…”

“…We recently reported that LXA 4 ME protects the brain against cerebral ischemia-reperfusion injury and permanent cerebral ischemic infarction in a rat model Wu et al 2010). To our knowledge, however, there are no previous studies examining the effects of LXA 4 ME on BBB permeability and MMP activity following transient focal cerebral ischemia-reperfusion.…”

Targeting resolution of neuroinflammation after ischemic stroke with a lipoxin A4 analog: Protective mechanisms and long‐term effects on neurological recovery

“…Furthermore, we observed a trend towards significantly higher IL‐10 and IL‐4 expression at 48 hr, indicating that BML‐111 may be maximally effective at reducing pro‐inflammatory cytokines and increasing anti‐inflammatory cytokines 48 hr after stroke. Lipoxin A 4 and its analogs have been shown to attenuate IL‐1β and TNF‐α levels 6 and 24 hr post‐stroke while increasing IL‐10 and TGFβ levels when injected into the brain at the time of occlusion in a tMCAO model (Y. Wu et al., 2010; Ye et al., 2010). We did not observe any changes in cytokine and chemokine levels 24 hr post‐ischemia.…”

“…Direct injections of LXA 4 into the brain immediately after the onset of ischemia reduced stroke size, blood–brain barrier (BBB) breakdown, and neuroinflammatory factors in rats (L. Wu et al., 2013; Wu, Miao, et al., 2012; Wu, Wang, et al., 2012; Wu et al., 2010; Ye et al., 2010). Recently, we showed for the first time that two post‐ischemic injections of BML‐111 (1 mg/kg; i.v.)…”