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    • To verify this hypothesis OGD was adopted to mimic cerebral

    2019-04-22

    To verify this hypothesis, OGD was adopted to mimic cerebral ischemic injury in rat cortical astrocyte-neuron co-cultures in the present study. This co-cultures system allows us to manipulate astrocytes and neurons respectively, and simultaneously allows the two kinds of cells to exchange soluble mediators freely. Thus, the astrocyte-neuron co-cultures system was particularly suitable for the need of the present study. And 4-h OGD was chosen as lethal OGD in the present study that caused widespread neuronal death, which were similar to the previous studies (Romera et al., 2007; Sisalli et al., 2014). Above all, it was observed that lethal OGD caused obvious down-regulation of GLT-1 protein from 6 h to 48 h that was consistent with our in vivo result, except for a transient elevation from 0 min to 30 min by western blot in the present study. Consistently, other studies reported that GLT-1 expression is up-regulated at the early phase, but is down-regulated at the late phase after MCAO in rats (Rao et al., 1998; Torp et al., 1995). Resent study showed that the up-regulation of GLT-1 in early ischemia may be mediated by mTOR-Akt-NF-κB cascade in astrocytes suffered OGD (Ji et al., 2013). Numerous studies have indicated that lethal OGD decreased GLT-1 protein and mRNA levels in cultured astrocytes (Lu et al., 2017; Qi et al., 2018; Yu et al., 2017). Moreover, up-regulated GLT-1 expression by histamine alleviated the OGD-induced neuronal death, and this protective effect was abolished by GLT-1 selective inhibitor dihydrokainate (DHK) (Fang et al., 2014). So, it was widely accepted that the down-regulation of GLT-1 mediated the neuronal injury induced by lethal OGD. However, the mechanism that involved in the down-regulation of GLT-1 in lethal OGD is not clear yet. In the end, the present study observed whether depressing p38 MAPK function by SB203580 could attenuate the cerebral ischemic injury via regulating the expression of GLT-1 in vivo. At first, it was observed that pre-administration of SB203580 by intracerebroventricular injection dose-dependently protected neurons from ischemic injury induced by global smad ischemia for 8 min in CA1 hippocampus. Similar to our results, intraventricular administration of SB203580 significantly attenuated the edema and infarct volumes in the cortex after 90-min MCAO in rats (Nito et al., 2008). Then, we observed the effect of SB203580 on the down-regulation of GLT-1 after the lethal ischemia. The result showed that SB203580 reversed the down-regulation of GLT-1 expression in CA1 hippocampus at 6 h and 2d after the global brain ischemia. To our knowledge, although there are a few studies have focused on the neuroprotection of p38 MAPK via up-regulating GLT-1 (Zhang et al., 2017; Yu et al., 2017; Qi et al., 2018), it is the first time to report that excessive activation of p38 MAPK was responsible for the down-regulation of GLT-1 which took charge of cerebral ischemic injury in rats. The more detailed mechanisms of p38 MAPK bi-directional regulating GLT-1 expression in cerebral ischemic tolerance and ischemic injury still need to be further studied.
    Introduction Heat shock proteins (HSPs) are induced in response to environmental stresses such as heat stress and pathological conditions [1]. HSPs are generally characterized as molecular chaperones to prevent aggregation of proteins and restore proteostasis [1]. HSPs have recently been classified into seven families on the basis of their molecular weights, named HSPH (HSP110), HSPC (HSP90), HSPA (HSP70), HSPD/E (HSP60/HSP10), CCT (TRiC), DNAJ (HSP40) and HSPB (small HSPs) [1], [2]. HSP27 which belongs to the HSPB family, is an ATP-independent molecular chaperone [1]. HSP27 binds to misfolded proteins and subsequently transfer them to ATP-dependent HSPs such as HSPC (HSP90) and HSPA (HSP70) for protein refolding or to the protein degradation systems including proteasomes or autophagosomes [1]. The functions of HSP27 are post-translationally modified by phosphorylation [1]. It is recognized that HSP27 in its unphosphorylated form exists as large oligomers, whereas its phosphorylation develops the conformational changes leading to the dissociation into small oligomers such as dimers or monomer [1]. On the other hand, HSP90 (HSPC), an ATP-dependent molecular chaperone, is widely expressed in numerous types of unstressed cells and represents 1-2% of total cellular proteins, which is elevated to 4-6% by stresses [2], [3]. HSP90 also plays a cytoprotective role due to the inhibition of apoptosis [2]. It has been shown that HSP90 is abnormally overexpressed in many types of cancers since the cancer cells need chaperones for their survival, and that HSP90-dependent client proteins are involved in a variety of oncogenic pathways [4], [5]. Therefore, inhibition of HSP90 functions has become as one of the leading strategies for anticancer chemotherapeutics [4], [5].