Abstract
Over the last two decades, evidence supporting the concept of zinc-induced neuronal death has been introduced, and several intervention strategies have been investigated. Vesicular zinc is released into the synaptic cleft, where it then translocates to the cytoplasm, which leads to the production of reactive oxygen species and neurodegeneration. Carvacrol inhibits transient receptor potential melastatin 7 (TRPM7), which regulates the homeostasis of extracellular metal ions, such as calcium and zinc. In the present study, we test whether carvacrol displays any neuroprotective effects after global cerebral ischemia (GCI), via a blockade of zinc influx. To test our hypothesis, we used eight-week-old male Sprague–Dawley rats, and a GCI model was induced by bilateral common carotid artery occlusion (CCAO), accompanied by blood withdrawal from the femoral artery. Ischemic duration was defined as a seven-minute electroencephalographic (EEG) isoelectric period. Carvacrol (50 mg/kg) was injected into the intraperitoneal space once per day for three days after the onset of GCI. The present study found that administration of carvacrol significantly decreased the number of degenerating neurons, microglial activation, oxidative damage, and zinc translocation after GCI, via downregulation of TRPM7 channels. These findings suggest that carvacrol, a TRPM7 inhibitor, may have therapeutic potential after GCI by reducing intracellular zinc translocation.
Highlights
Transient cerebral ischemia results from decreased blood flow into the brain, primarily through blood vessels, such as the bilateral common carotid artery and vertebral artery
The results showed that Fluoro-Jade B (FJB)-stained hippocampal neurons emerged in the Subi, Cornus Ammonis 1 (CA1), and Cornus Ammonis 2 (CA2) regions (Figure 1A)
Administration of carvacrol showed an approximate 54% reduction in the number of FJB (+) neurons in the Subi (GCI vehicle, 191.1 ± 8.7; global cerebral ischemia (GCI) carvacrol, 88.4 ± 15.4), 67% in the CA1 (GCI vehicle, 159.4 ± 21.6; GCI carvacrol, 53.7 ± 20.2), and 65% in the CA2 (GCI vehicle, 181.2 ± 6.3; GCI carvacrol, 65.1 ± 54.3) region, when compared to the vehicle group
Summary
Transient cerebral ischemia results from decreased blood flow into the brain, primarily through blood vessels, such as the bilateral common carotid artery and vertebral artery. In the case of neurological injury, toxic levels of chelatable zinc can be released from the synaptic vesicle, and can dissociate from intracellular proteins This phenomenon contributes to neuronal death and causes zinc-induced neurotoxicity [17,18]. In a past in vitro study, under oxygen-glucose deprived conditions, an increase in Ca2+ entry that led to neuronal cell death was observed In another preceding study, the use of glutamate receptor inhibitors and voltage-gated Ca2+ channel blockers as neuroprotective agents was established [27]. By using TRPM7 shRNA viral vectors [29], it was demonstrated that ischemic cell death mechanisms were regulated by TRPM7 These findings suggested that, alongside voltage-gated calcium channels and the glutamate receptor-like proton-sensitive channel, the TRPM7 channel has a critical role in mediating ischemic brain injury. We suggest that carvacrol may be an ideal therapeutic tool for preventing global cerebral ischemia-induced neuronal death
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