Abstract
BackgroundPost-ischemic inflammation is a crucial component in stroke pathology in the early phase of cerebral ischemia–reperfusion (I/R) injury. Inflammation caused by microglia, astrocytes, and necrotic cells, produces pro-inflammatory mediators and exacerbates cerebral I/R injury. This study evaluated the effects of the Alpinia oxyphylla Miq [Yi Zhi Ren (YZR)] extract on cerebral infarction at 1 day after 90 min of transient middle cerebral artery occlusion (MCAo) and investigated the molecular mechanisms underlying the regulation of c-Jun N-terminal kinase (JNK)-mediated inflammatory cascades in the penumbral cortex. Rats were intraperitoneally injected with the YZR extract at the doses of 0.2 g/kg (YZR-0.2 g), 0.4 g/kg (YZR-0.4 g), or 0.8 g/kg (YZR-0.8 g) at MCAo onset.ResultsYZR-0.4 g and YZR-0.8 g treatments markedly reduced cerebral infarction, attenuated neurological deficits, and significantly downregulated the expression of phospho-apoptosis signal-regulating kinase 1 (p-ASK1)/ASK1, tumor necrosis factor receptor-associated factor 3 (TRAF3), TRAF3-interacting JNK-activating modulator (T3JAM), ionized calcium-binding adapter molecule 1 (Iba1), p-JNK/JNK, inducible nitric oxide synthase, cyclooxygenase-2, tumor necrosis factor-α, toll-like receptor 4 (TLR4), glial fibrillary acidic protein (GFAP), nuclear factor-kappa B (NF-κB), and interleukin-6 in the penumbral cortex at 1 day after reperfusion. SP600125 (SP), a selective JNK inhibitor, had the same effects. Furthermore, Iba1- and GFAP-positive cells were colocalized with TLR4, and colocalization of GFAP-positive cells was found with NF-κB in the nuclei.ConclusionYZR-0.4 g and YZR-0.8 g treatments exerted beneficial effects on cerebral ischemic injury by downregulating JNK-mediated signaling in the peri-infarct cortex. Moreover, the anti-infarction effects of YZR extract treatments were partially attributed to the downregulation of JNK-mediated TLR4/T3JAM- and ASK1-related inflammatory signaling pathways in the penumbral cortex at 1 day after reperfusion.
Highlights
Post-ischemic inflammation is a crucial component in stroke pathology in the early phase of cerebral ischemia–reperfusion (I/R) injury
Effects of Yi Zhi Ren (YZR) extract treatments on neurological function The Modified neurological severity score (mNSS) tests revealed that the Neurological deficit score (NDS) of motor, sensory, and beam balance functions were markedly higher in the Control group than in the Sham group and were markedly lower in the YZR-0.4 g and YZR-0.8 g groups than in the Control groups
Our results further revealed that amoeboid microglia and reactive astrocytes were predominantly expressed in the penumbral cortex, and activated microglia and reactive astrocytes were double labeled with toll-like receptor 4 (TLR4), whereas YZR-0.4 g and YZR-0.8 g treatments effectively downregulated the increased expression of TLR4, TLR4/ionized calcium-binding adapter molecule 1 (Iba1), and TLR4/glial fibrillary acidic protein (GFAP), and inhibited microglial and astrocytic activation in the peri-infarct region
Summary
Post-ischemic inflammation is a crucial component in stroke pathology in the early phase of cerebral ischemia–reperfusion (I/R) injury. During brain ischemic insult, activated microglia and reactive astrocytes predominantly express TLR4, which recognizes damageassociated molecular patterns (DAMPs), subsequently triggering downstream cascades through myeloid differentiation primary response gene 88 (MyD88)-dependent and toll/interleukin (IL)-1 receptor homology domaincontaining adaptor-inducing interferon-β (TRIF)dependent signaling pathways [6, 7]. These two pathways result in the activation of transcription factor nuclear factor-kappa B (NF-κB), which stimulates the production of pro-inflammatory mediators [6, 8]. JNK is considered a major stress-activated protein kinase and a promising candidate for activating microglia, and it induces neuroinflammation in response to I/R injury in in vitro and in vivo models [19]
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Free) 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a call
