Abstract
Inflammation is considered as a major contributor to brain injury following cerebral ischemia. The therapeutic potential of both MLC601/MLC901, which are herbal extract preparations derived from Chinese Medicine, has been reported both in advanced stroke clinical trials and also in animal and cellular models. The aim of this study was to investigate the effects of MLC901 on the different steps of post-ischemic inflammation in focal ischemia in mice. In vivo injury was induced by 60 minutes of middle cerebral artery occlusion (MCAO) followed by reperfusion. MLC901 was administered in post-treatment 90 min after the onset of ischemia and once a day during reperfusion. MLC901 treatment resulted in a reduction in infarct volume, a decrease of Blood Brain Barrier leakage and brain swelling, an improvement in neurological scores and a reduction of mortality rate at 24 hours after MCAO. These beneficial effects of MLC901 were accompanied by an inhibition of astrocytes and microglia/macrophage activation, a drastically decreased neutrophil invasion into the ischemic brain as well as by a negative regulation of pro-inflammatory mediator expression (cytokines, chemokines, matrix metalloproteinases). MLC901 significantly inhibited the expression of Prx6 as well as the transcriptional activity of NFκB and the activation of Toll-like receptor 4 (TLR4) signaling, an important pathway in the immune response in the ischemic brain. MLC901 effects on the neuroinflammation cascade induced by cerebral ischemia probably contribute, in a very significant way, in its potential therapeutic value.
Highlights
The focal hypoperfusion of the brain induced by ischemic stroke leads to excitotoxic cell death, to oxidative damage and to inflammation[1]
Cerebral ischemia triggers activation of Toll-like receptors (TLR)[2], via endogenous ligands[2] of the danger-associated molecular patterns (DAMPS), that are released from ischemic tissues[10]
The neuroprotective and neuroregenerative properties of the two mixtures have been reported to be comparable[36]. These preclinical studies have pointed out a marked beneficial effect of MLC901 on activation of ATP-sensitive potassium channels[41], a process known to be neuroprotective against stroke[42] as well on the repair process including neurogenesis, neurite outgrowth and angiogenesis[36,43]
Summary
The focal hypoperfusion of the brain induced by ischemic stroke leads to excitotoxic cell death, to oxidative damage and to inflammation[1]. The ischemia-induced activation of both microglia and astocytes[2] leads to release of pro-inflammatory cytokines such as interleukin 1 β (IL-1β) and tumor necrosis factor α (TNFα)[4,5,6] as well as of chemokines[7,8] These pro-inflammatory mediators facilitate BBB damage that favors the migration of circulating leukocytes into the ischemic brain[3]. A recent extension study of the CHIMES trial (CHIMES-E) revealed that a 3-month treatment with MLC601 improved the functional outcome for up to 2 years among patients with stroke of intermediate severity[22,32] All these clinical results are encouraging to pursue further exploration of MLC601 and MLC901 as a new efficient therapeutic strategy against stroke. These preclinical studies have pointed out a marked beneficial effect of MLC901 on activation of ATP-sensitive potassium channels[41], a process known to be neuroprotective against stroke[42] as well on the repair process including neurogenesis, neurite outgrowth and angiogenesis[36,43]
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