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Front Neurosci. 2017 Oct 26;11:583. doi: 10.3389/fnins.2017.00583. eCollection 2017.

Neuroprotective Effect of β-Caryophyllene on Cerebral Ischemia-Reperfusion Injury via Regulation of Necroptotic Neuronal Death and Inflammation: In Vivo and in Vitro.

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Chongqing Key Laboratory of Biochemistry and Molecular Pharmacology, School of Pharmacy, Chongqing Medical University, Chongqing, China.
Chongqing Research Center for Pharmaceutical Engineering, School of Pharmacy, Chongqing Medical University, Chongqing, China.
School of Pharmacy, Chongqing Medical and Pharmaceutical College, Chongqing, China.


Necrotic cell death is a hallmark feature of ischemic stroke and it may facilitate inflammation by releasing intracellular components after cell-membrane rupture. Previous studies reported that β-caryophyllene (BCP) mitigates cerebral ischemia-reperfusion (I/R) injury, but the underlying mechanism remains unclear. We explored whether BCP exerts a neuroprotective effect in cerebral I/R injury through inhibiting necroptotic cell death and inflammation. Primary neurons with and without BCP (0.2, 1, 5, 25 μM) treatment were exposed to oxygen-glucose deprivation and re-oxygenation (OGD/R). Neuron damage, neuronal death type and mixed lineage kinase domain-like (MLKL) protein expression were assessed 48 h after OGD/R. Furthermore, mice underwent I/R procedures with or without BCP (8, 24, 72 mg/kg, ip.). Neurologic dysfunction, cerebral infarct volumes, cell death, cytokine levels, necroptosis core molecules, and HMGB1-TLR4 signaling were determined at 48 h after I/R. BCP (5 μM) significantly reduced necroptotic neurons and MLKL protein expression following OGD/R. BCP (24, 72 mg/kg, ip.) reduced infarct volumes, neuronal necrosis, receptor-interaction protein kinase-1 (RIPK1), receptor-interaction protein kinase-3 (RIPK3) expression, and MLKL phosphorylation after I/R injury. BCP also decreased high-mobility group box 1 (HMGB1), toll-like receptor 4 (TLR4), interleukin-1β (IL-1β), and tumor necrosis factor-α (TNF-α) levels. Thus, BCP alleviates ischemic brain damage potentially by inhibiting necroptotic neuronal death and inflammatory response. This study suggests a novel application for BCP as a neuroprotective agent.


high-mobility group box 1; inflammation; ischemia-reperfusion injury; necroptosis; oxygen-glucose deprivation and re-oxygenation; β-caryophyllene

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