Valacyclovir treatment ameliorates the persistently increased pentylenetetrazol-induced seizure susceptibility in mice with herpes simplex virus type 1 infection

Hung Ming Wu, Ying Ching Liang, Shun-hua Chen, Chiung Chun Huang, Shih Heng Chen, Jing Jane Tsai, Ching Liang Hsieh, Kuei-Sen Hsu

Research output: Contribution to journalArticle

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Abstract

Herpes simplex virus type 1 (HSV-1) is an important pathogen related to epilepsy. We have shown previously that corneal inoculation of mice with HSV-1 causes acute spontaneous behavioral and electrophysiological seizures and increases hippocampal excitability and kainite-induced seizure susceptibility. In this study, we aimed to determine whether early-life HSV-1 infection in mice might cause short- and long-term enhanced susceptibility to pentylenetetrazol (PTZ)-induced seizures and to evaluate whether early antiviral drug therapy was effectively ameliorating this deficit. Seizure threshold was calculated by the latency of onset of the myoclonic jerk, generalized clonus, and maximal tonic-clonic convulsion. We demonstrate that the localization of viral antigens was predominantly within the bilateral temporal areas (amygdala, piriform, and entorhinal cortex) of HSV-1-infected mice. We also present evidence that mice of all HSV-1-infected groups had a shorter latency and higher severity to PTZ-induced seizures than in age-matched, mock-infected controls. Treatment of HSV-1-infected mice with valacyclovir, a potent inhibitor of HSV-1 replication, produced a dose-dependent decrease in the signs of neurological deficits, pathological damages, and PTZ-induced seizure severity. Our results are consistent with the hypothesis that early-life HSV-1 infection leads to persistent enhancement of neuronal excitability in limbic circuits, which could result in an overall increased propensity to induce seizures later in life. Additionally, prompt optimal antiviral therapy effectively decreases seizure susceptibility in HSV-1-infected mice by limiting the level of viral replication and inflammatory response induced by virus. The present study provides not only experimental evidence, but also a new therapeutic strategy in HSV-1-associated human epilepsy.

Original languageEnglish
Pages (from-to)66-77
Number of pages12
JournalExperimental Neurology
Volume189
Issue number1
DOIs
Publication statusPublished - 2004 Sep 1

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valacyclovir
Pentylenetetrazole
Human Herpesvirus 1
Virus Diseases
Seizures
Therapeutics
Antiviral Agents
Epilepsy
Tonic-Clonic Epilepsy
Entorhinal Cortex
Myoclonus

All Science Journal Classification (ASJC) codes

  • Neurology
  • Developmental Neuroscience

Cite this

Wu, Hung Ming ; Liang, Ying Ching ; Chen, Shun-hua ; Huang, Chiung Chun ; Chen, Shih Heng ; Tsai, Jing Jane ; Hsieh, Ching Liang ; Hsu, Kuei-Sen. / Valacyclovir treatment ameliorates the persistently increased pentylenetetrazol-induced seizure susceptibility in mice with herpes simplex virus type 1 infection. In: Experimental Neurology. 2004 ; Vol. 189, No. 1. pp. 66-77.
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abstract = "Herpes simplex virus type 1 (HSV-1) is an important pathogen related to epilepsy. We have shown previously that corneal inoculation of mice with HSV-1 causes acute spontaneous behavioral and electrophysiological seizures and increases hippocampal excitability and kainite-induced seizure susceptibility. In this study, we aimed to determine whether early-life HSV-1 infection in mice might cause short- and long-term enhanced susceptibility to pentylenetetrazol (PTZ)-induced seizures and to evaluate whether early antiviral drug therapy was effectively ameliorating this deficit. Seizure threshold was calculated by the latency of onset of the myoclonic jerk, generalized clonus, and maximal tonic-clonic convulsion. We demonstrate that the localization of viral antigens was predominantly within the bilateral temporal areas (amygdala, piriform, and entorhinal cortex) of HSV-1-infected mice. We also present evidence that mice of all HSV-1-infected groups had a shorter latency and higher severity to PTZ-induced seizures than in age-matched, mock-infected controls. Treatment of HSV-1-infected mice with valacyclovir, a potent inhibitor of HSV-1 replication, produced a dose-dependent decrease in the signs of neurological deficits, pathological damages, and PTZ-induced seizure severity. Our results are consistent with the hypothesis that early-life HSV-1 infection leads to persistent enhancement of neuronal excitability in limbic circuits, which could result in an overall increased propensity to induce seizures later in life. Additionally, prompt optimal antiviral therapy effectively decreases seizure susceptibility in HSV-1-infected mice by limiting the level of viral replication and inflammatory response induced by virus. The present study provides not only experimental evidence, but also a new therapeutic strategy in HSV-1-associated human epilepsy.",
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Valacyclovir treatment ameliorates the persistently increased pentylenetetrazol-induced seizure susceptibility in mice with herpes simplex virus type 1 infection. / Wu, Hung Ming; Liang, Ying Ching; Chen, Shun-hua; Huang, Chiung Chun; Chen, Shih Heng; Tsai, Jing Jane; Hsieh, Ching Liang; Hsu, Kuei-Sen.

In: Experimental Neurology, Vol. 189, No. 1, 01.09.2004, p. 66-77.

Research output: Contribution to journalArticle

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