Valacyclovir treatment ameliorates the persistently increased pentylenetetrazol-induced seizure susceptibility in mice with herpes simplex virus type 1 infection.
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.
Department of Pharmacology, College of Medicine, National Cheng-Kung University, Tainan 701, Taiwan.
Hung-Ming
HM
Wu
Ying-Ching
YC
Liang
Shun-Hua
SH
Chen
Chiung-Chun
CC
Huang
Shih-Heng
SH
Chen
Jing-Jane
JJ
Tsai
Ching-Liang
CL
Hsieh
Kuei-Sen
KS
Hsu
D000212:Acyclovir / Q000031:analogs & derivatives* / Q000627:therapeutic use*; D000818:Animals; D000998:Antiviral Agents / Q000627:therapeutic use; D001522:Behavior, Animal; D001835:Body Weight / Q000187:drug effects; D004198:Disease Susceptibility; D004305:Dose-Response Relationship, Drug; D004347:Drug Interactions; D004569:Electroencephalography / Q000379:methods; D004576:Electromyography / Q000379:methods; D006561:Herpes Simplex / Q000150:complications*; D018259:Herpesvirus 1, Human; D006624:Hippocampus / Q000503:physiopathology / Q000821:virology; D007150:Immunohistochemistry / Q000379:methods; D007239:Infections / Q000188:drug therapy; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D010433:Pentylenetetrazole / Q000633:toxicity; D011930:Reaction Time; D012640:Seizures / Q000139:chemically induced / Q000188:drug therapy* / Q000503:physiopathology / Q000821:virology; D013194:Staining and Labeling / Q000379:methods; D013997:Time Factors; D000077483:Valacyclovir; D014633:Valine / Q000031:analogs & derivatives* / Q000627:therapeutic use*; D017735:Virus Latency / Q000187:drug effects
D000998:Antiviral Agents; D014633:Valine; D000077483:Valacyclovir; D010433:Pentylenetetrazole; D000212:Acyclovir