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This review summarizes the currently known biochemical neuroadaptive mechanisms of remote ischemic conditioning. In particular, it focuses on the significance of the pro-adaptive effects of remote ischemic conditioning which allow for the prevention of the neurological and cognitive impairments associated with hippocampal dysregulation after brain damage. The neuroimmunohumoral pathway transmitting a conditioning stimulus, as well as the molecular basis of the early and delayed phases of neuroprotection, including anti-apoptotic, anti-oxidant, and anti-inflammatory components, are also outlined. Based on the close interplay between the effects of ischemia, especially those mediated by interaction of hypoxia-inducible factors (HIFs) and steroid hormones, the involvement of the hypothalamic–pituitary–adrenocortical system in remote ischemic conditioning is also discussed. [ABSTRACT FROM AUTHOR]

S100 calcium-binding protein A8 (S100A8), a danger-associated molecular pattern, has emerged as an important mediator of the pro-inflammatory response. Some S100 proteins play a prominent role in neuroinflammatory disorders and increase the secretion of pro-inflammatory cytokines in microglial cells. The aim of this study was to determine whether S100A8 induced neuronal apoptosis during cerebral hypoxia and elucidate its mechanism of action. In this study, we reported that the S100A8 protein expression was increased in mouse neuronal and microglial cells when exposed to hypoxia, and induced neuroinflammation and neuronal apoptosis. S100A8, secreted from neurons under hypoxia, activated the secretion of tumor necrosis factor (TNF-α) and interleukin-6 (IL-6) through phosphorylation of extracellular-signal-regulated kinase (ERK) and c-Jun N-terminal kinase (JNK) in microglia. Also, phosphorylation of ERK via the TLR4 receptor induced the priming of the NLRP3 inflammasome. The changes in Cyclooxygenase-2 (COX-2) expression, a well-known inflammatory activator, were regulated by the S100A8 expression in microglial cells. Knockdown of S100A8 levels by using shRNA revealed that microglial S100A8 expression activated COX-2 expression, leading to neuronal apoptosis under hypoxia. These results suggested that S100A8 may be an important molecule for bidirectional microglia-neuron communication and a new therapeutic target for neurological disorders caused by microglial inflammation during hypoxia. [ABSTRACT FROM AUTHOR]