Significance
Although symptomatic medications are available, many temporal lobe epilepsy (TLE) patients remain unresponsive to treatment and new drug targets are needed. Connexin-based gap junctions and hemichannels in brain glial cells are implicated in TLE, but blocking gap junctions can lead to undesirable side effects. Here, we studied the effect of a small organic molecule called D4, which selectively blocks connexin hemichannels, and tested its efficacy in treating TLE using a mouse model. In vivo application of D4 strongly suppresses TLE-induced hemichannel activity and neuroinflammation, curbs TLE seizures, and increases the survival rate. Thus, targeted blockade of brain connexin hemichannels with D4 is a potentially effective strategy to treat TLE symptoms and neuropathology.
Abstract
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….
