Abstract
More than 30% of patients with epilepsy are refractory and have inadequate seizure control. Focal cortical cooling (FCC) suppresses epileptiform discharges (EDs) in patients with refractory focal cortical epilepsy. However, little is known about the mechanism by which FCC inhibits seizures at 15°C, and FCC treatment is highly invasive. Therefore, new antiepileptic drugs are needed that produce the same effects as FCC but with different mechanisms of action. To address this need, we focused on transient receptor potential melastatin 8 (TRPM8), an ion channel that detects cold, which is activated at 15°C. We examined whether TRPM8 activation suppresses penicillin G (PG)-induced EDs in anesthetized rats. Icilin, a TRPM8 and TRP Ankyrin 1 agonist, was administered after PG injection, and a focal electrocorticogram (ECoG) and cortical temperature were recorded for 4 h. We measured spike amplitude, duration, firing rate, and power density in each band to evaluate the effects of icilin. PG-induced EDs and increased delta, theta, alpha, and beta power spectra were observed in the ECoG. Icilin suppressed EDs while maintaining cortical temperature. In particular, 3.0-mM icilin significantly suppressed PG-induced spike amplitude, duration, and firing rate and improved the increased power density of each band in the EDs to the level of basal activity in the ECoG. These suppressive effects of 3.0-mM icilin on EDs were antagonized by administering N-(3-aminopropyl)-2-[(3-methylphenyl) methoxy]-N-(2-thienylmethyl)-benzamide hydrochloride (AMTB), a selective TRPM8 inhibitor. Our results suggest that TRPM8 activation in epileptic brain regions may be a new therapeutic approach for patients with epilepsy.
Highlights
The lifetime prevalence of epilepsy is 7.60 per 1,000 people (Fiest et al, 2017), and more than 30% of patients with epilepsy have inadequate control of seizures (Kwan and Brodie, 2000)
An in vivo study showed that all bands in the power density spectra of penicillin G (PG)-induced epileptiform discharges (EDs) were suppressed by Focal cortical cooling (FCC) to 15°C (Kida et al, 2012), a temperature at which the transient receptor potential (TRP) melastatin 8 (TRPM8) channel is activated (Peier et al, 2002)
Administrated intracortically icilin at the dose of 3 μM suppressed the amplitude of EDs in C57BL/6 mouse, while administrated intracortically icilin at the dose of 3 μM did not affect the ECoG for PG-induced EDs in TRPM8 knockout (TRPM8KO) mouse
Summary
The lifetime prevalence of epilepsy is 7.60 per 1,000 people (Fiest et al, 2017), and more than 30% of patients with epilepsy have inadequate control of seizures (Kwan and Brodie, 2000). Because the percentage of patients with epilepsy who develop refractory epilepsy positively correlates with the number of seizures before treatment with antiepileptic drugs (Kwan and Brodie, 2000), it is important. ED Suppression by Icilin to reduce the number of seizures to prevent refractory epilepsy Given these issues, we proposed that refractory epilepsy can be treated by focal cortical cooling (FCC) to 15°C to 25°C (Nomura et al, 2014). A TRPM8 and TRP Ankyrin 1 agonist, reduced the amplitude of glutamatergic excitatory postsynaptic currents (EPSCs) in an electrophysiological study (Wrigley et al, 2009). These reports suggest that TRPM8 activation is involved in the suppressive effect of FCC on epilepsy. The antiepileptic effects of TRPM8 activation in the somatosensory cortex are unknown
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