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

Abstract

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 0.2[Formula: see text]g/kg (AOM-0.2[Formula: see text]g), 0.4[Formula: see text]g/kg (AOM-0.4[Formula: see text]g), or 0.8[Formula: see text]g/kg (AOM-0.8[Formula: see text]g) at MCAo initiation. The AOM-0.4[Formula: see text]g and AOM-0.8[Formula: see text]g 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-0.8[Formula: see text]g on the aforementioned protein expression, whereas treatment with SP600125 — a JNK inhibitor — exerted protective effects similar to those of AOM-0.8[Formula: see text]g. Treatment with 0.4 or 0.8[Formula: see text]g/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.