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TRPV1 Channel: A Potential Drug Target for Treating Epilepsy.

Nazıroğlu M - Curr Neuropharmacol (2015)

Bottom Line: Thus activation of TRPV1 by oxidative stress, resiniferatoxin, cannabinoid receptor (CB1) activators (i.e. anandamide) or capsaicin induced epileptic effects, and these effects could be reduced by appropriate inhibitors, including capsazepine (CPZ), 5'-iodoresiniferatoxin (IRTX), resolvins, and CB1 antagonists.It has been also reported that CPZ and IRTX reduced spontaneous excitatory synaptic transmission through modulation of glutaminergic systems and desensitization of TRPV1 channels in the hippocampus of rats.Immunocytochemical studies indicated that TRPV1 channel expression increased in the hippocampus of mice and patients with temporal lobe epilepsy.

View Article: PubMed Central - PubMed

Affiliation: Director of Neuroscience Research Center, Suleyman Demirel University, TR-32260, Isparta, Turkey. mustafanaziroglu@sdu.edu.tr.

ABSTRACT
Epilepsy has 2-3% incidence worldwide. However, present antiepileptic drugs provide only partial control of seizures. Calcium ion accumulation in hippocampal neurons has long been known as a major contributor to the etiology of epilepsy. TRPV1 is a calcium-permeable channel and mediator of epilepsy in the hippocampus. TRPV1 is expressed in epileptic brain areas such as CA1 area and dentate gyrus of the hippocampus. Here the author reviews the patent literature on novel molecules targeting TRPV1 that are currently being investigated in the laboratory and are candidates for future clinical evaluation in the management of epilepsy. A limited number of recent reports have implicated TRPV1 in the induction or treatment of epilepsy suggesting that this may be new area for potential drugs targeting this debilitating disease. Thus activation of TRPV1 by oxidative stress, resiniferatoxin, cannabinoid receptor (CB1) activators (i.e. anandamide) or capsaicin induced epileptic effects, and these effects could be reduced by appropriate inhibitors, including capsazepine (CPZ), 5'-iodoresiniferatoxin (IRTX), resolvins, and CB1 antagonists. It has been also reported that CPZ and IRTX reduced spontaneous excitatory synaptic transmission through modulation of glutaminergic systems and desensitization of TRPV1 channels in the hippocampus of rats. Immunocytochemical studies indicated that TRPV1 channel expression increased in the hippocampus of mice and patients with temporal lobe epilepsy. Taken together, findings in the current literature support a role for calcium ion accumulation through TRPV1 channels in the etiology of epileptic seizures, indicating that inhibition of TRPV1 in the hippocampus may possibly be a novel target for prevention of epileptic seizures.

No MeSH data available.


Related in: MedlinePlus

Possible molecular pathways of TRPV1 channel activation on epilepsy in hippocampal neurons. Convulsions in epilepsy canresults in augmented glutamate release, leading to Ca2+ uptake through NMDA receptor and TRP channels. Mitochondria were reported toaccumulate Ca2+ provided cytosolic Ca2+ rises, thereby leading to depolarization of mitochondrial membranes. At the extreme, Ca2+ entrycauses severe mitochondrial permeability transition or even the rupture of the mitochondrial membrane, substantial swelling of themitochondria with rupture of the outer membrane and release of apoptosis-inducing factors such as caspase 3 and 9. Anandamide, capsaicin,resiniferatoxin, nitric oxide (NO) and reactive oxygen species (ROS) induce Ca2+ accumulation through desensitization of TRPV1 channelsalthough pharmacological desensitization of TRPV1 channels through antagonists such as capsazepine (CPZ) and 5'-iodoresiniferatoxin(IRTX) contributes to an immediate reduction on neuronal excitability [78]. ROS enhance also spontaneous release of glutamate frompresynaptic terminals onto neurons through TRPV1 channel activation. The molecular pathway may be a cause of epileptic seizures and thesubject should urgently investigate.
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Figure 1: Possible molecular pathways of TRPV1 channel activation on epilepsy in hippocampal neurons. Convulsions in epilepsy canresults in augmented glutamate release, leading to Ca2+ uptake through NMDA receptor and TRP channels. Mitochondria were reported toaccumulate Ca2+ provided cytosolic Ca2+ rises, thereby leading to depolarization of mitochondrial membranes. At the extreme, Ca2+ entrycauses severe mitochondrial permeability transition or even the rupture of the mitochondrial membrane, substantial swelling of themitochondria with rupture of the outer membrane and release of apoptosis-inducing factors such as caspase 3 and 9. Anandamide, capsaicin,resiniferatoxin, nitric oxide (NO) and reactive oxygen species (ROS) induce Ca2+ accumulation through desensitization of TRPV1 channelsalthough pharmacological desensitization of TRPV1 channels through antagonists such as capsazepine (CPZ) and 5'-iodoresiniferatoxin(IRTX) contributes to an immediate reduction on neuronal excitability [78]. ROS enhance also spontaneous release of glutamate frompresynaptic terminals onto neurons through TRPV1 channel activation. The molecular pathway may be a cause of epileptic seizures and thesubject should urgently investigate.

Mentions: MN formulated the present hypothesis and was responsible for writing the report. The author wishes thanks to Prof. Dr. James W. Putney (NC, USA) for the critical revision of the manuscript and Bilal Çiğ (Ph.D. Student, Department of Neurosceince, Medical Faculty, Suleyman Demirel University) for preparation of Fig. 1.


TRPV1 Channel: A Potential Drug Target for Treating Epilepsy.

Nazıroğlu M - Curr Neuropharmacol (2015)

Possible molecular pathways of TRPV1 channel activation on epilepsy in hippocampal neurons. Convulsions in epilepsy canresults in augmented glutamate release, leading to Ca2+ uptake through NMDA receptor and TRP channels. Mitochondria were reported toaccumulate Ca2+ provided cytosolic Ca2+ rises, thereby leading to depolarization of mitochondrial membranes. At the extreme, Ca2+ entrycauses severe mitochondrial permeability transition or even the rupture of the mitochondrial membrane, substantial swelling of themitochondria with rupture of the outer membrane and release of apoptosis-inducing factors such as caspase 3 and 9. Anandamide, capsaicin,resiniferatoxin, nitric oxide (NO) and reactive oxygen species (ROS) induce Ca2+ accumulation through desensitization of TRPV1 channelsalthough pharmacological desensitization of TRPV1 channels through antagonists such as capsazepine (CPZ) and 5'-iodoresiniferatoxin(IRTX) contributes to an immediate reduction on neuronal excitability [78]. ROS enhance also spontaneous release of glutamate frompresynaptic terminals onto neurons through TRPV1 channel activation. The molecular pathway may be a cause of epileptic seizures and thesubject should urgently investigate.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4598436&req=5

Figure 1: Possible molecular pathways of TRPV1 channel activation on epilepsy in hippocampal neurons. Convulsions in epilepsy canresults in augmented glutamate release, leading to Ca2+ uptake through NMDA receptor and TRP channels. Mitochondria were reported toaccumulate Ca2+ provided cytosolic Ca2+ rises, thereby leading to depolarization of mitochondrial membranes. At the extreme, Ca2+ entrycauses severe mitochondrial permeability transition or even the rupture of the mitochondrial membrane, substantial swelling of themitochondria with rupture of the outer membrane and release of apoptosis-inducing factors such as caspase 3 and 9. Anandamide, capsaicin,resiniferatoxin, nitric oxide (NO) and reactive oxygen species (ROS) induce Ca2+ accumulation through desensitization of TRPV1 channelsalthough pharmacological desensitization of TRPV1 channels through antagonists such as capsazepine (CPZ) and 5'-iodoresiniferatoxin(IRTX) contributes to an immediate reduction on neuronal excitability [78]. ROS enhance also spontaneous release of glutamate frompresynaptic terminals onto neurons through TRPV1 channel activation. The molecular pathway may be a cause of epileptic seizures and thesubject should urgently investigate.
Mentions: MN formulated the present hypothesis and was responsible for writing the report. The author wishes thanks to Prof. Dr. James W. Putney (NC, USA) for the critical revision of the manuscript and Bilal Çiğ (Ph.D. Student, Department of Neurosceince, Medical Faculty, Suleyman Demirel University) for preparation of Fig. 1.

Bottom Line: Thus activation of TRPV1 by oxidative stress, resiniferatoxin, cannabinoid receptor (CB1) activators (i.e. anandamide) or capsaicin induced epileptic effects, and these effects could be reduced by appropriate inhibitors, including capsazepine (CPZ), 5'-iodoresiniferatoxin (IRTX), resolvins, and CB1 antagonists.It has been also reported that CPZ and IRTX reduced spontaneous excitatory synaptic transmission through modulation of glutaminergic systems and desensitization of TRPV1 channels in the hippocampus of rats.Immunocytochemical studies indicated that TRPV1 channel expression increased in the hippocampus of mice and patients with temporal lobe epilepsy.

View Article: PubMed Central - PubMed

Affiliation: Director of Neuroscience Research Center, Suleyman Demirel University, TR-32260, Isparta, Turkey. mustafanaziroglu@sdu.edu.tr.

ABSTRACT
Epilepsy has 2-3% incidence worldwide. However, present antiepileptic drugs provide only partial control of seizures. Calcium ion accumulation in hippocampal neurons has long been known as a major contributor to the etiology of epilepsy. TRPV1 is a calcium-permeable channel and mediator of epilepsy in the hippocampus. TRPV1 is expressed in epileptic brain areas such as CA1 area and dentate gyrus of the hippocampus. Here the author reviews the patent literature on novel molecules targeting TRPV1 that are currently being investigated in the laboratory and are candidates for future clinical evaluation in the management of epilepsy. A limited number of recent reports have implicated TRPV1 in the induction or treatment of epilepsy suggesting that this may be new area for potential drugs targeting this debilitating disease. Thus activation of TRPV1 by oxidative stress, resiniferatoxin, cannabinoid receptor (CB1) activators (i.e. anandamide) or capsaicin induced epileptic effects, and these effects could be reduced by appropriate inhibitors, including capsazepine (CPZ), 5'-iodoresiniferatoxin (IRTX), resolvins, and CB1 antagonists. It has been also reported that CPZ and IRTX reduced spontaneous excitatory synaptic transmission through modulation of glutaminergic systems and desensitization of TRPV1 channels in the hippocampus of rats. Immunocytochemical studies indicated that TRPV1 channel expression increased in the hippocampus of mice and patients with temporal lobe epilepsy. Taken together, findings in the current literature support a role for calcium ion accumulation through TRPV1 channels in the etiology of epileptic seizures, indicating that inhibition of TRPV1 in the hippocampus may possibly be a novel target for prevention of epileptic seizures.

No MeSH data available.


Related in: MedlinePlus