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.