Cannabidiol inhibits febrile seizure by modulating AMPA receptor kinetics through its interaction with the N-terminal domain of GluA1/GluA2

Yongzhou Yu; Zuxiao Yang; Baohua Jin; Xia Qin; Xiaoque Zhu; Jiahui Sun; Lifang Huo; Ri Wang; Yongyun Shi; Zhanfeng Jia; Yun Stone Shi; Shifeng Chu; Dezhi Kong; Wei Zhang

doi:10.1016/j.phrs.2020.105128

Cannabidiol inhibits febrile seizure by modulating AMPA receptor kinetics through its interaction with the N-terminal domain of GluA1/GluA2

Pharmacol Res. 2020 Nov:161:105128. doi: 10.1016/j.phrs.2020.105128. Epub 2020 Aug 15.

Authors

Yongzhou Yu¹, Zuxiao Yang¹, Baohua Jin¹, Xia Qin¹, Xiaoque Zhu¹, Jiahui Sun², Lifang Huo¹, Ri Wang¹, Yongyun Shi³, Zhanfeng Jia⁴, Yun Stone Shi², Shifeng Chu⁵, Dezhi Kong⁶, Wei Zhang⁷

Affiliations

¹ Department of Pharmacology of Chinese Materia Medica, Institution of Chinese Integrative Medicine, The Key Laboratory of New Drug Pharmacology and Toxicology, Hebei Medical University, Shijiazhuang, Hebei Province, 050017, China.
² State Key Laboratory of Pharmaceutical Biotechnology and MOE Key Laboratory of Model Animal for Disease Study, Model Animal Research Center, Nanjing University, Nanjing, 210061, China.
³ Department of Orthopaedics, Luhe People's Hospital Affiliated to Yangzhou University, Nanjing, 211500, China.
⁴ Department of Pharmacology, Center for Innovative Drug Research and Evaluation, Institute of Medical Science and Health, The Key Laboratory of Neural and Vascular Biology, Ministry of Education, The Key Laboratory of New Drug Pharmacology and Toxicology, Hebei Medical University, Shijiazhuang, Hebei Province, 050017, China.
⁵ State Key Laboratory of Bioactive Substances and Functions of Natural Medicines, Institute of Materia Medica, Neuroscience Center, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, 100050, China.
⁶ Department of Pharmacology of Chinese Materia Medica, Institution of Chinese Integrative Medicine, The Key Laboratory of New Drug Pharmacology and Toxicology, Hebei Medical University, Shijiazhuang, Hebei Province, 050017, China. Electronic address: kongdezhi@hebmu.edu.cn.
⁷ Department of Pharmacology of Chinese Materia Medica, Institution of Chinese Integrative Medicine, The Key Laboratory of New Drug Pharmacology and Toxicology, Hebei Medical University, Shijiazhuang, Hebei Province, 050017, China. Electronic address: weizhang@hebmu.edu.cn.

PMID: 32805354
DOI: 10.1016/j.phrs.2020.105128

Abstract

Cannabidiol (CBD) is a major phytocannabinoid in Cannabis sativa. CBD is being increasingly reported as a clinical treatment for neurological diseases. Febrile seizure is one of the most common diseases in children with limited therapeutic options. We investigated possible therapeutic effects of CBD on febrile seizures and the underlying mechanism. Use of a hyperthermia-induced seizures model revealed that CBD significantly prolonged seizure latency and reduced the severity of thermally-induced seizures. Hippocampal neuronal excitability was significantly decreased by CBD. Further, CBD significantly reduced the α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptor (AMPAR) mediated evoked excitatory postsynaptic currents (eEPSCs) and the amplitude and frequency of miniature EPSCs (mEPSCs). Furthermore, CBD significantly accelerated deactivation in GluA1 and GluA2 subunits. Interestingly, CBD slowed receptor recovery from desensitization of GluA1, but not GluA2. These effects on kinetics were even more prominent when AMPAR was co-expressed with γ-8, the high expression isoform 8 of transmembrane AMPAR regulated protein (TARPγ8) in the hippocampus. The inhibitory effects of CBD on AMPAR depended on its interaction with the distal N-terminal domain of GluA1/GluA2. CBD inhibited AMPAR activity and reduced hippocampal neuronal excitability, thereby improving the symptoms of febrile seizure in mice. The putative binding site of CBD in the N-terminal domain of GluA1/GluA2 may be a drug target for allosteric gating modulation of AMPAR.

Keywords: AMPA receptor; AP5 (PubChem CID: 52974251); Bicuculline (PubChem CID: 10237); CBD; CBD (PubChem CID: 644019); CNQX (PubChem CID: 3721046); CTZ (PubChem CID: 2910); Febrile seizure; L-glutamate monosodium (PubChem CID: 23672308); N-terminal domain; NBQX (PubChem CID: 6098006); PTX (PubChem CID: 31304); QX314 (PubChem CID: 3925); TTX (PubChem CID: 6324668).

Publication types

Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't

MeSH terms

Animals
Anticonvulsants / metabolism
Anticonvulsants / pharmacology*
Brain Waves / drug effects*
CA1 Region, Hippocampal / drug effects*
CA1 Region, Hippocampal / metabolism
CA1 Region, Hippocampal / physiopathology
Cannabidiol / metabolism
Cannabidiol / pharmacology*
Disease Models, Animal
Excitatory Amino Acid Antagonists / metabolism
Excitatory Amino Acid Antagonists / pharmacology*
Excitatory Postsynaptic Potentials / drug effects
HEK293 Cells
Humans
Hyperthermia / complications*
Ion Channel Gating / drug effects
Kinetics
Mice
Mice, Inbred C57BL
Miniature Postsynaptic Potentials / drug effects
Models, Molecular
Protein Binding
Reaction Time / drug effects
Receptors, AMPA / antagonists & inhibitors*
Receptors, AMPA / genetics
Receptors, AMPA / metabolism
Seizures, Febrile / etiology
Seizures, Febrile / metabolism
Seizures, Febrile / physiopathology
Seizures, Febrile / prevention & control*

Substances

Anticonvulsants
Excitatory Amino Acid Antagonists
Receptors, AMPA
Cannabidiol
glutamate receptor ionotropic, AMPA 2
glutamate receptor ionotropic, AMPA 1

Grants and funding

P41 GM103311/GM/NIGMS NIH HHS/United States