Neuroprotective Effects of Alpinia oxyphylla Miq against Mitochondria-Related Apoptosis by the Interactions between Upregulated p38 MAPK Signaling and Downregulated JNK Signaling in the Subacute Phase of Cerebral Ischemia-Reperfusion in Rats

Apoptosis in the penumbra region is the major cell death mechanism occurring during ischemia-reperfusion injury's early phase. Here, we evaluated how the Alpinia oxyphylla Miq (AOM) affects mitochondria-related apoptosis 3 days after transient middle cerebral artery occlusion (MCAo) and examined the mechanisms underlying the regulation of MAPK-mediated mitochondria-related apoptotic signaling in the peri-infarct cortex in rats. The rats were administered the AOM extract intraperitoneally at doses of 0.2g/kg (AOM-0.2g), 0.4g/kg (AOM-0.4g), or 0.8g/kg (AOM-0.8g) at MCAo initiation. The AOM-0.4g and AOM-0.8g significantly ameliorated apoptotic cell death and considerably downregulated cytochrome c (cyto c) and cleaved caspase-3 immunoreactivity 3 days after reperfusion. Simultaneously, they significantly downregulated cytosolic p-JNK/JNK, cathepsin B/actin, cyto c/actin, Smac/DIABLO/actin, cleaved caspase-3/actin, and AIF/actin and mitochondrial p53/HSP60 and Bax/HSP60 fractions but upregulated cytosolic p-p38 MAPK/p38 MAPK, p-p90RSK/actin, p-Bad/Bad, p-CREB/actin, and XIAP/actin and cytosolic and mitochondrial Bcl-2/Bax and Bcl-xL/Bax fractions in the peri-infarct cortex. Pretreatment with SB203580 - a p38 MAPK inhibitor - completely abrogated the effects of AOM-0.8g on the aforementioned protein expression, whereas treatment with SP600125 - a JNK inhibitor - exerted protective effects similar to those of AOM-0.8g. Treatment with 0.4 or 0.8g/kg AOM has neuroprotective effects against mitochondria-related apoptosis by suppressing cyto c, Smac/DIABLO, and AIF release from the mitochondria to cytosol. The anti-mitochondria related apoptotic effects of the AOM extract are attributable to the interactions between upregulated p38 MAPK/p90RSK-mediated p-Bad and CREB signaling and downregulated JNK/cathepsin B-mediated Bax and p53 signaling in the peri-infarct cortex 3 days after transient MCAo.

Automated summary

This study found that Alpinia oxyphylla Miq (AOM) has a protective effect against cell apoptosis after transient middle cerebral artery occlusion (MCAo), and it achieves this by regulating the signaling pathways within the cells. AOM inhibits mitochondria-related apoptosis and promotes cell survival.