Abstract
BackgroundOur previous study found that suppression of TRPM7 reduced neuronal death in adult rat ischemic brain injury. It was reported that carvacrol blocked TRPM7 and attenuated brain injury in an adult rat MCAO model. The effects of carvacrol on neonatal stroke remain unknown. This study investigated the effects of carvacrol on neuronal injury and behavioral impairment after hypoxia-ischemia in neonatal mice and the potential signaling pathway underlying these effects.ResultsCarvacrol inhibited TRPM7 current in HEK293 cells over-expressing TRPM7 and TRPM7-like current in hippocampal neurons in a dose-dependent manner. Carvacrol (>200 μM) reduced OGD-induced neuronal injury in cortical neurons. 24 hours after HI, TRPM7 protein level in the ipsilateral hemisphere was significantly higher than in the contralateral hemisphere. Carvacrol (30 and 50 mg/kg) pre-treatment reduced brain infarct volume 24 hours after HI in a dose-dependent manner. Carvacrol pre-treatment also improved neurobehavioral outcomes. Furthermore, animals pre-treated with carvacrol had fewer TUNEL-positive cells in the brain compared to vehicle-treated animals 3 days after HI. Carvacrol pre-treatment also increased Bcl-2/Bax and p-Akt/t-Akt protein ratios and decreased cleaved caspase-3 protein expression 24 hours after HI.ConclusionsCarvacrol pre-treatment protects against neonatal hypoxic-ischemic brain injury by reducing brain infarct volume, promoting pro-survival signaling and inhibiting pro-apoptotic signaling, as well as improving behavioral outcomes. The neuroprotective effect may be mediated by the inhibition of TRPM7 channel function. Carvacrol is a potential drug development target for the treatment of neonatal stroke.
Highlights
Our previous study found that suppression of to intracellular ionicTransient receptor potential melastatin 7 (TRPM7) reduced neuronal death in adult rat ischemic brain injury
Carvacrol inhibits TRPM7 currents in HEK293 cells and hippocampal neurons First, we performed whole-cell patch-clamp experiments to examine the effect of carvacrol on TRPM7 current in HEK293 cells over-expressing TRPM7 and on TRPM7-like native currents in mouse hippocampal neurons
We showed that carvacrol pre-incubation for 30 minutes significantly reduced Propidium iodide (PI) fluorescence intensity in a dosedependent manner (200-800 μM concentration) compared to that of vehicle-treat group
Summary
Our previous study found that suppression of TRPM7 reduced neuronal death in adult rat ischemic brain injury. It was reported that carvacrol blocked TRPM7 and attenuated brain injury in an adult rat MCAO model. This study investigated the effects of carvacrol on neuronal injury and behavioral impairment after hypoxia-ischemia in neonatal mice and the potential signaling pathway underlying these effects. Hypoxic-ischemic injury or stroke in mammalian brains elicits delayed neuronal death (DND) [1]. Previous studies have considered glutamate excitotoxicity as a key mechanism in stroke [2]. Non-glutamate mechanisms have attracted more attention in stroke research. TRPM7 is a Ca2+-permeable, nonselective cation channel that has recently gained attention as a potential cation influx pathway involved in ischemic neuronal injury. Subsequent reports have revealed that TRPM7 mRNA and protein expression increase in the brain after cerebral ischemic injury and in hippocampal neurons subjected to
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