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High mobility group box 1 enhances hyperthermia-induced seizures and secondary epilepsy associated with prolonged hyperthermia-induced seizures in developing rats

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Abstract

Levels of high mobility group box 1 (HMGB1), an important inflammatory mediator, are high in the serum of febrile seizure (FS) patients. However, its roles in FS and secondary epilepsy after prolonged FS are poorly understood. We demonstrate HMGB1’s role in the pathogenesis of hyperthermia-induced seizures (HS) and secondary epilepsy after prolonged hyperthermia-induced seizures (pHS). In the first experiment, 14–15-day-old male rats were divided into four groups: high-dose HMGB1 (100 μg), moderate-dose (10 μg), low-dose (1 μg), and control. Each rat was administered HMGB1 intranasally 1 h before inducing HS. Temperature was measured at seizure onset with electroencephalography (EEG). In the second experiment, 10–11-day-old rats were divided into four groups: pHS + HMGB1 (10 μg), pHS, HMGB1, and control. HMGB1 was administered 24 h after pHS. Video-EEGs were recorded for 24 h at 90 and 120 days old; histological analysis was performed at 150 days old. In the first experiment, the temperature at seizure onset was significantly lower in the high- and moderate-dose HMGB1 groups than in the control group. In the second experiment, the incidence of spontaneous epileptic seizure was significantly higher in the pHS + HMGB1 group than in the other groups. Comparison between pHS + HMGB1 groups with and without epilepsy revealed that epileptic rats had significantly enhanced astrocytosis in the hippocampus and corpus callosum. In developing rats, HMGB1 enhanced HS and secondary epilepsy after pHS. Our findings suggest that HMGB1 contributes to FS pathogenesis and plays an important role in the acquired epileptogenesis of secondary epilepsy associated with prolonged FS.

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Acknowledgements

We are grateful to the staff of the Animal Center of ADRES of Ehime University for their gentle care of our animals and histological staining. This study was supported by a Grant-in-Aid for Scientific Research (C) from the Ministry of Education, Culture, Sports, Science and Technology, Japan (No. 25461553 & 16 K09990).

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Authors and Affiliations

  1. Department of Pediatrics, Ehime University Graduate School of Medicine, 454 Shitsukawa, Toon, Ehime, 791-0295, Japan

    Masanori Ito, Yusuke I. Shimizu, Yoshiaki Yano, Eiichi Ishii & Mitsumasa Fukuda

  2. Department of Molecular and Cellular Physiology, Ehime University Graduate School of Medicine, 454 Shitsukawa, Toon, Ehime, Japan

    Hisaaki Takahashi, Hajime Yano & Junya Tanaka

  3. Division of Pathophysiology, Faculty of Pharmaceutical Sciences, Hokuriku University, Taiyougaoka 1-1, Kanazawa, Ishikawa, 920-1181, Japan

    Hisaaki Takahashi

  4. Department of Pediatrics, Graduate School of Medical Sciences, Kyushu University, 3-1-1 Maidashi, Higashi-ku, Fukuoka, Japan

    Yoshito Ishizaki

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  1. Masanori Ito
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  2. Hisaaki Takahashi
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  3. Hajime Yano
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  4. Yusuke I. Shimizu
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Correspondence to Mitsumasa Fukuda.

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All experimental procedures conformed to the guidelines from the Ministry of Education of Japan and were approved by the animal experimental committee of Ehime University Graduate School of Medicine (No. TE-17-2).

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The authors declare that they have no conflict of interest.

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Ito, M., Takahashi, H., Yano, H. et al. High mobility group box 1 enhances hyperthermia-induced seizures and secondary epilepsy associated with prolonged hyperthermia-induced seizures in developing rats. Metab Brain Dis 32, 2095–2104 (2017). https://doi.org/10.1007/s11011-017-0103-4

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  • DOI: https://doi.org/10.1007/s11011-017-0103-4

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