TY - JOUR
T1 - Inhibition of connexin hemichannels alleviates neuroinflammation and hyperexcitability in temporal lobe epilepsy
AU - Guo, Anni
AU - Zhang, Huiqi
AU - Li, Huanhuan
AU - Chiu, Arthur
AU - García-Rodríguez, Claudia
AU - Lagos, Carlos F.
AU - Sáez, Juan C.
AU - Lau, Chunyue Geoffrey
N1 - Funding Information:
ACKNOWLEDGMENTS. This work was supported by the Hong Kong Research Grants Council (RGC/ECS 21103818 to C.G.L. and RGC/GRF 11104320 and 11104521 to C.G.L.), Shenzhen General Basic Research Program (JCYJ20190808182203591 to C.G.L.), a grant from ITF-InnoHK, and internal funds from City University of Hong Kong (to C.G.L.) and Fondo Nacional de Desarrollo Científico y Tecnológico (FONDECYT) grant 1191329 (to J.C.S.), Project P09 from the Centro Interdisciplinario de Neurociencias de Valparáıso (to J.C.S.), and Fondo de Fomento al Desarrollo Científico y Tecnológico (FONDEF) project D07I1086 (to J.C.S.).
Funding Information:
This work was supported by the Hong Kong Research Grants Council (RGC/ECS 21103818 to C.G.L. and RGC/GRF 11104320 and 11104521 to C.G.L.), Shenzhen General Basic Research Program (JCYJ20190808182203591 to C.G.L.), a grant from ITF-InnoHK, and internal funds from City University of Hong Kong (to C.G.L.) and Fondo Nacional de Desarrollo Científico y Tecnológico (FONDECYT) grant 1191329 (to J.C.S.), Project P09 from the Centro Interdisciplinario de Neurociencias de Valparáíso (to J.C.S.), and Fondo de Fomento al Desarrollo Científico y Tecnológico (FONDEF) project D07I1086 (to J.C.S.).
Publisher Copyright:
Copyright © 2022 the Author(s).
PY - 2022/11/8
Y1 - 2022/11/8
N2 - Temporal lobe epilepsy (TLE) is one of the most common types of epilepsy, yet approximately one-third of patients are refractory to current anticonvulsive drugs, which target neurons and synapses. Astrocytic and microglial dysfunction is commonly found in epileptic foci and has been shown to contribute to neuroinflammation and hyperexcitability in chronic epilepsy. Accumulating evidence points to a key role for glial hemichannels in epilepsy, but inhibiting both connexin (Cx) gap junctions and hemichannels can lead to undesirable side effects because the former coordinate physiological functions of cell assemblies. It would be a great benefit to use an orally available small molecule to block hemichannels to alleviate epileptic symptoms. Here, we explored the effect of D4, a newly developed compound that inhibits the Cx hemichannels but not Cx gap junctions using the pilocarpine mouse model of TLE. In vitro application of D4 caused a near-complete reduction in the pilocarpine-induced cell membrane permeability associated with increased Cx hemichannel activity. Moreover, preadministration of D4 in vivo effectively reduced neuroinflammation and altered synaptic inhibition, which then enhanced the animal survival rate. Posttreatment with a single dose of D4 in vivo has prolonged effects on suppressing the activation of astrocytes and microglia and rescued the changes in neuroinflammatory and synaptic gene expression induced by pilocarpine. Collectively, these results indicate that targeting Cx hemichannels by D4 is an effective and promising strategy for treating epilepsy in which neuroinflammation plays a critical role.
AB - Temporal lobe epilepsy (TLE) is one of the most common types of epilepsy, yet approximately one-third of patients are refractory to current anticonvulsive drugs, which target neurons and synapses. Astrocytic and microglial dysfunction is commonly found in epileptic foci and has been shown to contribute to neuroinflammation and hyperexcitability in chronic epilepsy. Accumulating evidence points to a key role for glial hemichannels in epilepsy, but inhibiting both connexin (Cx) gap junctions and hemichannels can lead to undesirable side effects because the former coordinate physiological functions of cell assemblies. It would be a great benefit to use an orally available small molecule to block hemichannels to alleviate epileptic symptoms. Here, we explored the effect of D4, a newly developed compound that inhibits the Cx hemichannels but not Cx gap junctions using the pilocarpine mouse model of TLE. In vitro application of D4 caused a near-complete reduction in the pilocarpine-induced cell membrane permeability associated with increased Cx hemichannel activity. Moreover, preadministration of D4 in vivo effectively reduced neuroinflammation and altered synaptic inhibition, which then enhanced the animal survival rate. Posttreatment with a single dose of D4 in vivo has prolonged effects on suppressing the activation of astrocytes and microglia and rescued the changes in neuroinflammatory and synaptic gene expression induced by pilocarpine. Collectively, these results indicate that targeting Cx hemichannels by D4 is an effective and promising strategy for treating epilepsy in which neuroinflammation plays a critical role.
KW - antiepileptic drug
KW - connexon
KW - excitability
KW - seizure
UR - http://www.scopus.com/inward/record.url?scp=85141144583&partnerID=8YFLogxK
U2 - 10.1073/pnas.2213162119
DO - 10.1073/pnas.2213162119
M3 - Article
C2 - 36322757
AN - SCOPUS:85141144583
SN - 0027-8424
VL - 119
JO - Proceedings of the National Academy of Sciences of the United States of America
JF - Proceedings of the National Academy of Sciences of the United States of America
IS - 45
M1 - e2213162119
ER -