Figure 8.

Proposed mechanisms for the effects of carvacrol on TBI-induced neuronal death and microglial activation. Schematic illustrations indicate the proposed action of carvacrol through inhibition of membrane-bound TRPM7 and intracellular vesicle-bound TRPM7 on neuronal death and microglial activation induced by TBI: (A) TBI induces the release of pre-synaptic zinc into the synapse, which translocates into the post-synaptic neurons through the TRPM7 channel. Increased zinc translocation contributes to the production of ROS. Increased ROS induces the activation of both membrane- and M7Vs-bound TRPM7, leading to the accumulation of free zinc in the cytosol, contributing to further ROS production. Eventually, zinc and ROS induce further neuronal injury; (B) carvacrol blocks the TRPM7 channels, leading to less translocation of zinc into the post-synaptic neurons after TBI. Inhibition of ROS production further leads to less activation of TRPM7, which is also blocked by carvacrol. Reduction in zinc reflux and ROS production reduces neuronal death; (C) synaptically released zinc gives rise to its influx into nearby microglia through TRPM7 channels, and this triggers microglial activation; (D) inhibition of TRPM7 by carvacrol can result in the suppression of zinc influx, thereby blocking microglial activation.