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TRPV1 antagonist capsazepine suppresses 4-AP-induced epileptiform activity in vitro and electrographic seizures in vivo.

ABSTRACT: 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 (10-100?M) and in vivo (50mg/kg s.c.). In contrast, capsaicin enhanced 4-AP induced epileptiform activity in vitro (1-100?M) and triggered bursting activity in vivo (100?M 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 (1-100?M) and CZP (10-100?M) 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.

SUBMITTER: Gonzalez-Reyes LE

PROVIDER: S-EPMC4104534 | biostudies-literature | 2013 Dec

REPOSITORIES: biostudies-literature

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TRPV1 antagonist capsazepine suppresses 4-AP-induced epileptiform activity in vitro and electrographic seizures in vivo.

Gonzalez-Reyes Luis E LE Ladas Thomas P TP Chiang Chia-Chu CC Durand Dominique M DM

Experimental neurology 20131018

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 att ...[more]

PMID: 24145133

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Project description:Background: Neonatal encephalopathy is caused by a wide variety of acute brain insults in newborns and presents with a spectrum of neurologic dysfunction, such as consciousness disturbance, seizures, and coma. The increased excitability in the neonatal brain appears to be highly susceptible to seizures after a variety of insults, and seizures may be the first clinical sign of a serious neurologic disorder. Subtle seizures are common in the neonatal period, and abnormal clinical paroxysmal events may raise the suspicion of neonatal seizures. Continuous video electroencephalographic (EEG) monitoring is the gold standard for the diagnosis of neonatal seizures. The aim of this study was to identify the prevalence of electrographic seizures and the impact of monitoring in neonates with a high risk of encephalopathy. Methods: We conducted this prospective cohort study in a tertiary neonatal intensive care unit over a 4-year period. Neonates with a high risk of encephalopathy who were receiving continuous video EEG monitoring were eligible. The patients were divided into 2 groups: (1) acute neonatal encephalopathy (ANE) and (2) other high-risk encephalopathy conditions (OHRs). The neonates’ demographic characteristics, etiologies, EEG background feature, presence of electrographic seizures and the impact of monitoring were analyzed. Results: A total of 71 neonates with a high risk of encephalopathy who received continuous video EEG monitoring were enrolled. In this consecutive cohort, 42 (59.2%) were monitored for ANE and 29 (40.8%) were monitored for OHRs. At the time of starting EEG monitoring, 54 (76.1%) of the neonates were term infants. The median gestational age at monitoring was 39 weeks (interquartile range, 37–41 weeks). The median total EEG monitoring duration was 64.7 h (interquartile range, 22.2–72.4 h). Electrographic seizures were captured in 25 of the 71 (35.2%) neonates, of whom 20 (80%) had electrographic-only seizures without clinical correlation. Furthermore, of these 20 neonates, 13 (65%) developed electrographic status epilepticus. Electrographic seizures were most commonly found in the ANE group (17, 40.5%) than in the OHRs group (8, 27.6%) (p = 0.013). Besides, normal/mild abnormality and inactive EEG background were less electrographic seizure than moderate and major abnormality EEG background (2 of 30, 6.7% vs. 23 of 41, 56.1%, p < 0.001). Finally, continuous video EEG monitoring excluded the diagnosis of electrographic seizures in two-thirds of the monitored neonates who had paroxysmal events mimicking seizures and led to a change in clinical management in 39.4% of the neonates. Conclusions: Our findings showed that monitoring could accurately detect seizures, and that it could be used to guide seizure medication management. Therefore, continuous video EEG monitoring has important clinical management implications in neonates with a high risk of encephalopathy.

Project description:OBJECTIVE:We previously discovered a role for the extracellular domain of the transmembrane protein semaphorin 4D (Sema4D) as a fast-acting, selective, and positive regulator of functional γ-aminobutyric acid (GABA)ergic synapse formation in hippocampal neuronal culture. We also demonstrated that Sema4D treatment increases inhibitory tone and suppresses hyperexcitability in an organotypic hippocampal slice culture model of epilepsy. Here, we investigate the ability of Sema4D to promote GABAergic synapse formation and suppress seizure activity in vivo in adult mice. METHODS:We performed a 3-hour, intrahippocampal infusion of Sema4D or control protein into the CA1 region of adult mice. To quantify GABAergic presynaptic bouton density, we performed immunohistochemistry on hippocampal tissue sections isolated from these animals using an antibody that specifically recognizes the glutamic acid decarboxylase isoform 65 protein (GAD65), which is localized to presynaptic GABAergic boutons. To assess seizure activity, we employed 2 in vivo mouse models of epilepsy, intravenous (iv) pentylenetetrazol (PTZ) and hippocampal electrical kindling, in the presence or absence of Sema4D treatment. We monitored seizure activity by behavioral observation or electroencephalography (EEG). To assay the persistence of the Sema4D effect, we monitored seizure activity and measured the density of GAD65-positive presynaptic boutons 3 or 48 hours after Sema4D infusion. RESULTS:Sema4D-treated mice displayed an elevated density of GABAergic presynaptic boutons juxtaposed to hippocampal pyramidal neuron cell bodies, consistent with the hypothesis that Sema4D promotes the formation of new inhibitory synapses in vivo. In addition, Sema4D acutely suppressed seizures in both the PTZ and electrical kindling models. When we introduced a 48-hour gap between Sema4D treatment and the seizure stimulus, seizure activity was indistinguishable from controls. Moreover, immunohistochemistry on brain sections or hippocampal slices isolated 3 hours, but not 48 hours, after Sema4D treatment displayed an increase in GABAergic bouton density, demonstrating temporal correlation between the effects of Sema4D on seizures and GABAergic synaptic components. SIGNIFICANCE:Our findings suggest a novel approach to treating acute seizures: harnessing synaptogenic molecules to enhance connectivity in the inhibitory network.

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TRPV1 antagonist capsazepine suppresses 4-AP-induced epileptiform activity in vitro and electrographic seizures in vivo.

Publications

TRPV1 antagonist capsazepine suppresses 4-AP-induced epileptiform activity in vitro and electrographic seizures in vivo.

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