Abstract
Neuroinflammation is one of the important factors aggravating brain injury after ischemic stroke. We aimed to investigate the effects of cerebrolysin (CBL) on neuroinflammation in vivo and in vitro and the underlying mechanisms. The gene expressions of pro-inflammatory factors and anti-inflammatory factors were analyzed by real time PCR in rat transient middle cerebral artery occlusion (tMCAO) model, lipopolysaccharides-induced neuroinflammatory mice model and LPS-treated mouse primary microglia cells. The neuroprotective effects of CBL were evaluated by infarct size, Longa test and Rotarod test for long-term functional recovery in rats subjected to ischemia. The role of CREB/PGC-1α pathway in anti-neuroinflammatory effect of CBL was also determined by real time PCR and Western blotting. In the tMCAO model, administration of CBL at 3 h post-ischemia reduced infarct volume, promoted long-term functional recovery, decreased the gene expression of pro-inflammatory factors and increased the gene expression of anti-inflammatory factors. Correspondingly, in LPS-induced neuroinflammatory mice model, CBL treatment attenuated sickness behavior, decreased the gene expression of pro-inflammatory factors, and increased the gene expression of anti-inflammatory factors. In in vitro and in vivo experiments, CBL increased the protein expression levels of PGC-1α and phosphorylated CREB to play anti-inflammatory effect. Additionally, the application of the specific CREB inhibitor, 666-15 compound could effectively reverse the anti-inflammatory effect of CBL in primary mouse microglia cells and anti-ischemic brain injury of CBL in rats subjected to tMCAO. In conclusion, CBL ameliorated cerebral ischemia injury through reducing neuroinflammation partly via the activation of CREB/PGC-1α pathway and may play a therapeutic role as anti-neuroinflammatory agents in the brain disorders associated with neuroinflammation.
Highlights
Ischemic stroke is a major type of stroke causing brain injury without effective treatment worldwide
Thereby, in order to make sure whether the treatment with CBL can display neuroprotective effects in rats after transient middle cerebral artery occlusion (tMCAO) operation, the percentage of the infarct size and neurobehavioral score were analyzed by TTC staining and Longa test, respectively
Neuroinflammation plays an important role in ischemic stroke, in which the pro-inflammatory phenotype of microglia release pro-inflammatory mediators, producing neurotoxicity, and antiinflammatory phenotype of microglia release anti-inflammatory mediators to promote neurogenesis and functional recovery (Voet et al, 2018)
Summary
Ischemic stroke is a major type of stroke causing brain injury without effective treatment worldwide. A meta-analysis of nine randomized clinical trials showed that CBL has a beneficial effect on early global neurological deficits in patients with acute ischemic stroke and safety aspects comparable to placebo (Bornstein et al, 2018). Previous studies have indicated that CBL administration could help improve neurological recovery, promote neurite outgrowth, resulting in treating acute ischemia stroke, traumatic brain injury, subarachnoid hemorrhage, and Alzheimer’s disease (Ubhi et al, 2013; Zhang et al, 2015; Park et al, 2018; Sadigh-Eteghad et al, 2018). Whether CBL administrated after ischemia has beneficial effects on ischemic brain injury and neurological deficits with detailed molecular mechanisms needs to be determined. Investigating the behavioral functional recovery and underlying mechanisms of CBL is beneficial for discovery of a series of drugs for the treatment of stroke
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