capsazepine and Epilepsy

Calcium ion accumulation into the cytosol of the hippocampus and dorsal root ganglion (DRG) are main reasons in etiology of epilepsy. Transient receptor potential vanilloid type 1 (TRPV1) channel is a cation-permeable calcium channel found in the DRG and hippocampus. Although previous studies implicate TRPV1 channels in the generation of epilepsy, suppression of ongoing seizures by TRPV1 antagonists has not yet been investigated. We tested the effects of TRPV1-specific antagonists, capsazepine (CPZ) and 5'-iodoresiniferatoxin (IRTX) on the modulation of calcium accumulation, apoptosis and anticonvulsant properties in the hippocampus and DRG of pentylentetrazol (PTZ) and capsaicin (CAP) administrated rats. Forty rats were divided into five groups as follows; control, PTZ, CAP+PTZ, IRTX, and IRTX+PTZ. Fura-2 and patch-clamp experiments were performed on neurons dissected from treated animals by CAP and CPZ. PTZ and CAP+PTZ administrations increased intracellular free Ca(2+) concentrations, TRPV1 current densities, apoptosis, caspase 3 and 9 values although the values were reduced by IRTX and CPZ treatments. Latency time was extended by application CPZ and IRTX although CAP produced acceleration of epileptic seizures. Taken together, these results support a role for TRPV1 channels in the inhibition of apoptosis, epileptic seizures and calcium accumulation, indicating that TRPV1 inhibition may possibly be a novel target in the DRG and hippocampus for prevention of epileptic seizures and peripheral pain.

Topics: Animals; Apoptosis; Calcium; Capsaicin; Diterpenes; Epilepsy; Ganglia, Spinal; Hippocampus; Male; Neurons; Pentylenetetrazole; Rats; Rats, Wistar; TRPV Cation Channels

Incidence rates of epilepsy and use of Wi-Fi worldwide have been increasing. TRPV1 is a Ca(2+) permeable and non-selective channel, gated by noxious heat, oxidative stress and capsaicin (CAP). The hyperthermia and oxidant effects of Wi-Fi may induce apoptosis and Ca(2+) entry through activation of TRPV1 channel in epilepsy. Therefore, we tested the effects of Wi-Fi (2.45 GHz) exposure on Ca(2+) influx, oxidative stress and apoptosis through TRPV1 channel in the murine dorsal root ganglion (DRG) and hippocampus of pentylentetrazol (PTZ)-induced epileptic rats. Rats in the present study were divided into two groups as controls and PTZ. The PTZ groups were divided into two subgroups namely PTZ + Wi-Fi and PTZ + Wi-Fi + capsazepine (CPZ). The hippocampal and DRG neurons were freshly isolated from the rats. The DRG and hippocampus in PTZ + Wi-Fi and PTZ + Wi-Fi + CPZ groups were exposed to Wi-Fi for 1 hour before CAP stimulation. The cytosolic free Ca(2+), reactive oxygen species production, apoptosis, mitochondrial membrane depolarization, caspase-3 and -9 values in hippocampus were higher in the PTZ group than in the control although cell viability values decreased. The Wi-Fi exposure induced additional effects on the cytosolic Ca(2+) increase. However, pretreatment of the neurons with CPZ, results in a protection against epilepsy-induced Ca(2+) influx, apoptosis and oxidative damages. In results of whole cell patch-clamp experiments, treatment of DRG with Ca(2+) channel antagonists [thapsigargin, verapamil + diltiazem, 2-APB, MK-801] indicated that Wi-Fi exposure induced Ca(2+) influx via the TRPV1 channels. In conclusion, epilepsy and Wi-Fi in our experimental model is involved in Ca(2+) influx and oxidative stress-induced hippocampal and DRG death through activation of TRPV1 channels, and negative modulation of this channel activity by CPZ pretreatment may account for the neuroprotective activity against oxidative stress.

Topics: Animals; Apoptosis; Calcium; Capsaicin; Caspase 3; Electromagnetic Radiation; Epilepsy; Ganglia, Spinal; Hippocampus; Male; Neurons; Oxidative Stress; Rats; TRPV Cation Channels

Transient receptor potential vanilloid 1 (TRPV1) is a cation-permeable ion channel found in the peripheral and central nervous systems. The membrane surface expression of TRPV1 is known to occur in neuronal cell bodies and sensory neuron axons. TRPV1 receptors are also expressed in the hippocampus, the main epileptogenic region in the brain. Although, previous studies implicate TRPV1 channels in the generation of epilepsy, suppression of ongoing seizures by TRPV1 antagonists has not yet been attempted. Here, we evaluate the role of TRPV1 channels in the modulation of epileptiform activity as well as the anti-convulsant properties of capsazepine (CZP), an established TRPV1 competitive antagonist, using in vitro and in vivo models. To this end, we used 4-aminopyridine (4-AP) to trigger seizure-like activity. We found that CZP suppressed 4-AP induced epileptiform activity in vitro (10-100μM) and in vivo (50mg/kg s.c.). In contrast, capsaicin enhanced 4-AP induced epileptiform activity in vitro (1-100μM) and triggered bursting activity in vivo (100μM dialysis perfusion), which was abolished by the TRPV1 antagonist CZP. To further investigate the mechanisms of TRPV1 modulation, we studied the effect of capsaicin and CZP on evoked potentials. Capsaicin (1-100μM) and CZP (10-100μM) increased and decreased, respectively, the amplitude of extracellular field evoked potentials in a concentration-dependent manner. Additional in vitro studies showed that the effect of the TRPV1 blocker on evoked potentials was similar whether the response was orthodromic or antidromic, suggesting that the effect involves interference with membrane depolarization on cell bodies and axons. The fact that CZP could act directly on axons was confirmed by decreased amplitude of the compound action potential and by an increased delay of both the antidromic potentials and the axonal response. Histological studies using transgenic mice also show that, in addition to the known neural expression, TRPV1 channels are widely expressed in alvear oligodendrocytes in the hippocampus. Taken together, these results indicate that activation of TRPV1 channels leads to enhanced excitability, while their inhibition can effectively suppress ongoing electrographic seizures. These results support a role for TRPV1 channels in the suppression of convulsive activity, indicating that antagonism of TRPV1 channels particularly in axons may possibly be a novel target for effective acute suppression of seizures.

Topics: 4-Aminopyridine; Animals; Anticonvulsants; Capsaicin; Convulsants; Disease Models, Animal; Epilepsy; Evoked Potentials; Mice; Mice, Inbred C57BL; Mice, Transgenic; TRPV Cation Channels