Neuroprotective and neurorestorative therapy represent two major drug intervention strategies for ischemic stroke. Multiple factors such as excitotoxicity, inflammation, angiogenesis, and neurogenesis are the main pathological processes that underlie acute and chronic ischemic brain injury. Furthermore, their intimate interactions mediate blood-brain barrier permeability, increase neurovascular unit structural damage as well as a hemorrhagic transformation during ischemic stroke. We aimed to review the current understandings of the underlying mechanisms of neuroprotection and neurorestoration in ischemic stroke. Notably, traditional Chinese medicine (TCM) has notable advantages in the comprehensive treatment and overall regulation of multi-site and multi-target diseases. Therefore, we reviewed the recent advances in natural compounds from medicinal herbs that possess the bioactivities of simultaneously promoting neuroprotection (e.g., excitotoxicity, oxidative stress, apoptosis, inflammation, and autophagy) and neurorestoration (e.g., angiogenesis, neurogenesis, and axonal sprouting) following brain ischemia injury. These natural compounds were divided into glycosides (astragaloside IV, gastrodin, ginsenoside Rg1 and salidroside), flavonoids (baicalin, icariin, puerarin and breviscapine), phenols (resveratrol, curcumin and salvianolic acid B), and terpenes (ginkgolide B and catalpol). We found that all compounds exhibited anti-brain ischemia activities in vivo and in vitro experiments by promoting neuroprotection and, or neurorestoration. This review tracks and summarizes the progress of the past five years to explore the active compounds and the underlying molecular mechanisms of TCMs that produce pro-neuroprotection and pro-neurorestoration. Additionally, we provide another basis of reference supporting the advantages of TCMs, which could ultimately lead to the development of precise clinical medications for ischemic stroke treatment.

S: Background: Many neurological diseases involve neuroinflammation, during which overproduction of cytokines by immune cells, especially microglia, can aggregate neuronal death. Ferroptosis is a recently discovered cell metabolism-related form of cell death and RSL3 is a well-known inducer of cell ferroptosis. Here, we aimed to investigate the effects of RSL3 in neuroinflammation and sensitivity of different type of microglia and macrophage to ferroptosis. Methods: Here, we used quantitative RT-PCR analysis and ELISA analysis to analyze the production of proinflammatory cytokine production of microglia and macrophages after lipopolysaccharides (LPS) stimulation. We used CCK8, LDH, and flow cytometry analysis to evaluate the sensitivity of different microglia and macrophages to RSL3-induced ferroptosis. Western blot was used to test the activation of inflammatory signaling pathway and knockdown efficiency. SiRNA-mediated interference was conducted to knockdown GPX4 or Nrf2 in BV2 microglia. Intraperitoneal injection of LPS was performed to evaluate systemic inflammation and neuroinflammation severity in in vivo conditions. Results: We found that ferroptosis inducer RSL3 inhibited lipopolysaccharides (LPS)-induced inflammation of microglia and peritoneal macrophages (PMs) in a cell ferroptosis-independent manner, whereas cell ferroptosis-conditioned medium significantly triggered inflammation of microglia and PMs. Different type of microglia and macrophages showed varied sensitivity to RSL3-induced ferroptosis. Mechanistically, RSL3 induced Nrf2 protein expression to inhibit RNA Polymerase II recruitment to transcription start site of proinflammatory cytokine genes to repress cytokine transcription, and protect cells from ferroptosis. Furthermore, simultaneously injection of RSL3 and Fer-1 ameliorated LPS-induced neuroinflammation in in vivo conditions. Conclusions: These data revealed the proinflammatory role of ferroptosis in microglia and macrophages, identified RSL3 as a novel inhibitor of LPS-induced inflammation, and uncovered the molecular regulation of microglia and macrophage sensitivity to ferroptosis. Thus, targeting ferroptosis in diseases by using RSL3 should consider both the pro-ferroptosis effect and the anti-inflammation effect to achieve optimal outcome.

Neuroinflammation is a secondary response following ischemia stroke. Arginine is a non-essential amino acid that has been shown to inhibit acute inflammatory reaction. In this study we show that arginine treatment decreases neuronal death after rat cerebral ischemia/reperfusion (I/R) injury and improves functional recovery of stroke animals. We also show that arginine suppresses inflammatory response in the ischemic brain tissue and in the cultured microglia after OGD insult. We further provide evidence that the levels of HIF-1α and LDHA are increased after rat I/R injury and that arginine treatment prevents the elevation of HIF-1α and LDHA after I/R injury. Arginine inhibits inflammatory response through suppression of HIF-1α and LDHA in the rat ischemic brain tissue and in the cultured microglia following OGD insult, and protects against ischemic neuron death after rat I/R injury by attenuating HIF-1α/LDHA-mediated inflammatory response. Together, these results indicate a possibility that arginine-induced neuroprotective effect may be through the suppression of HIF-1α/LDHA-mediated inflammatory response in microglia after cerebral ischemia injury.

Background/Aims: Enriched environment (EE) has been reported to exert neuroprotective effect in animal models of ischemic stroke. However, the underlying mechanism remains unclear. The purpose of this study was to investigate the effect of EE treatment on neuronal apoptosis in the periinfarct cortex after cerebral ischemia/reperfusion (I/R) injury. Methods: The cerebral I/R injury was established by middle cerebral artery occlusion (MCAO). A set of behavioral tests including the modified neurological severity score (mNSS), limb-placing test and foot-fault test were conducted. The infarct volume and the neuronal survival rate were evaluated by Nissl staining. The morphology and ultrastructure of ischemic neurons was examined by transmission electron microscopy. Neuronal apoptosis was assessed by double labeling of TdT-mediated dUTP-biotin nick end labeling (TUNEL) with NeuN. The expressions of apoptosis-related proteins were tested by western blotting and immunohistochemical labeling. Results: EE treatment improved neurological function, reduced infarct volume, increased neuronal survival rate and alleviated the morphological and ultrastructural damage of neurons (especially mitochondria) after I/R injury. EE treatment reduced the neuronal apoptosis, increased B cell lymphoma/leukemia-2 (Bcl-2) protein levels while decreased Bcl-2-associated X protein (Bax), cytochrome c, caspase-3 expressions and Bax/Bcl-2 ratio in the periinfarct cortex after cerebral I/R injury. Conclusion: Our findings suggest that EE treatment inhibits neuronal apoptosis in the periinfarct cortex after focal cerebral I/R injury, which may be one of the possible mechanisms underlying the neuroprotective effects of EE.

The journal focuses on neuroimmunology and neuroinflammation, and the coverage extends to other basic and clinical studies related to neuroscience including molecular biology, psychology, pathology, physiology, endocrinology, pharmacology, oncology, etc.