Therapeutic potential of an anti-high mobility group box-1 monoclonal antibody in epilepsy.
Brain inflammation is a major factor in epilepsy, and the high mobility group box-1 (HMGB1) protein is known to contribute significantly to the generation of seizures. Here, we investigated the therapeutic potential of an anti-HMGB1 monoclonal antibody (mAb) in epilepsy. anti-HMGB1 mAb attenuated both acute seizure models (maximal electroshock seizure, pentylenetetrazole-induced and kindling-induced), and chronic epilepsy model (kainic acid-induced) in a dose-dependent manner. Meanwhile, the anti-HMGB1 mAb also attenuated seizure activities of human brain slices obtained from surgical resection from drug-resistant epilepsy patients. The mAb showed an anti-seizure effect with a long-term manner and appeared to be minimal side effects at even very high dose (no disrupted physical EEG rhythm and no impaired basic physical functions, such as body growth rate and thermoregulation). This anti-seizure effect of mAb results from its inhibition of translocated HMGB1 from nuclei following seizures, and the anti-seizure effect was absent in toll-like receptor 4 knockout (TLR4-/-) mice. Interestingly, the anti-HMGB1 mAb also showed a disease-modifying anti-epileptogenetic effect on epileptogenesis after status epileptics, which is indicated by reducing seizure frequency and improving the impaired cognitive function. These results indicate that the anti-HMGB1 mAb should be viewed as a very promising approach for the development of novel therapies to treat refractory epilepsy.
Department of Pharmacology, Key Laboratory of Medical Neurobiology of the Ministry of Health of China, College of Pharmaceutical Sciences, Zhejiang University, Hangzhou, China.
Junli
J
Zhao
Department of Pharmacology, Key Laboratory of Medical Neurobiology of the Ministry of Health of China, College of Pharmaceutical Sciences, Zhejiang University, Hangzhou, China.
Yi
Y
Wang
Department of Pharmacology, Key Laboratory of Medical Neurobiology of the Ministry of Health of China, College of Pharmaceutical Sciences, Zhejiang University, Hangzhou, China.
Cenglin
C
Xu
Department of Pharmacology, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama, Japan.
Keyue
K
Liu
Department of Pharmacology, Key Laboratory of Medical Neurobiology of the Ministry of Health of China, College of Pharmaceutical Sciences, Zhejiang University, Hangzhou, China.
Ying
Y
Wang
Department of Pharmacology, Key Laboratory of Medical Neurobiology of the Ministry of Health of China, College of Pharmaceutical Sciences, Zhejiang University, Hangzhou, China.
Liying
L
Chen
Epilepsy Center, Second Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, China.
Xiaohua
X
Wu
Epilepsy Center, Second Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, China.
Feng
F
Gao
Epilepsy Center, Second Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, China.
Yi
Y
Guo
Epilepsy Center, Second Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, China.
Junming
J
Zhu
Epilepsy Center, Second Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, China.
Shuang
S
Wang
Department of Pharmacology, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama, Japan.
Masahiro
M
Nishibori
Department of Pharmacology, Key Laboratory of Medical Neurobiology of the Ministry of Health of China, College of Pharmaceutical Sciences, Zhejiang University, Hangzhou, China; Epilepsy Center, Second Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, China. Electronic address: chenzhong@zju.edu.cn.
Zhong
Z
Chen
D000818:Animals; D000911:Antibodies, Monoclonal / Q000008:administration & dosage*; D000927:Anticonvulsants / Q000008:administration & dosage*; D001921:Brain / Q000187:drug effects* / Q000276:immunology / Q000503:physiopathology; D004827:Epilepsy / Q000139:chemically induced / Q000188:drug therapy* / Q000276:immunology*; D024243:HMGB1 Protein / Q000276:immunology* / Q000378:metabolism; D006801:Humans; D007608:Kainic Acid / Q000008:administration & dosage; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D051197:Toll-Like Receptor 4 / Q000235:genetics
D000911:Antibodies, Monoclonal; D000927:Anticonvulsants; D024243:HMGB1 Protein; C585491:HMGB1 protein, human; C582808:HMGB1 protein, mouse; C493487:Tlr4 protein, mouse; D051197:Toll-Like Receptor 4; D007608:Kainic Acid
Epilepsy; HMGB1; Monoclonal antibody