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Abstract
Transient receptor potential melastatin 7 (TRPM7) is an ion channel that mediates monovalent cations out of cells, as well as the entry of divalent cations, such as zinc, magnesium, and calcium, into the cell. It has been reported that inhibitors of TRPM7 are neuroprotective in various neurological diseases. Previous studies in our lab suggested that seizure-induced neuronal death may be caused by the excessive release of vesicular zinc and the subsequent accumulation of zinc in the neurons. However, no studies have evaluated the effects of carvacrol and 2-aminoethoxydiphenyl borate (2-APB), both inhibitors of TRPM7, on the accumulation of intracellular zinc in dying neurons following seizure. Here, we investigated the therapeutic efficacy of carvacrol and 2-APB against pilocarpine-induced seizure. Carvacrol (50 mg/kg) was injected once per day for 3 or 7 days after seizure. 2-APB (2 mg/kg) was also injected once per day for 3 days after seizure. We found that inhibitors of TRPM7 reduced seizure-induced TRPM7 overexpression, intracellular zinc accumulation, and reactive oxygen species production. Moreover, there was a suppression of oxidative stress, glial activation, and the blood–brain barrier breakdown. In addition, inhibitors of TRPM7 remarkably decreased apoptotic neuron death following seizure. Taken together, the present study demonstrates that TRPM7-mediated zinc translocation is involved in neuron death after seizure. The present study suggests that inhibitors of TRPM7 may have high therapeutic potential to reduce seizure-induced neuron death.
Highlights
Epilepsy is a neurological disorder characterized by unpredictable seizure behavior [1,2,3]
We found that carvacrol treatment revealed a significant decrease in the percentage of neuronal nuclei (NeuN)+Caspase-3+ cells among NeuN+ cells after status epilepticus (SE) compared to the vehicle-treated SE group
Fluoro-Jade B (FJB) staining showed that 2-aminoethoxydiphenyl borate (2-APB) treatment significantly reduced the number of degenerating neurons. These findings indicate that 2-APB treatment reduces the accumulation of intracellular free zinc by inhibiting the overexpression of the Transient receptor potential melastatin 7 (TRPM7) channel, which occurs in the hippocampal cornu Ammonis 1 (CA1) following pilocarpine-induced SE, thereby causing a reduction
Summary
Epilepsy is a neurological disorder characterized by unpredictable seizure behavior [1,2,3]. The anticipated mechanisms that may diffuse the spread and recruitment of neurons produce an increase in K+ concentration outside of the cell and an increase in Ca2+ in the presynaptic terminals [7]. These mechanisms may blunt hyperpolarization and depolarize proximate neurons, as well as increase neurotransmitter release. Another mechanism of epilepsy that occurs after brain injury is an imbalance between neuronal excitation and inhibition, such as the up-regulation of excitatory circuits or the down-regulation of inhibitory circuits [8,9]. Many survivors of severe epileptic seizures still show neuronal damage and cognitive impairment, while the rate of cure is significantly lower [13,14]
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