Identification of Guaifenesin–Andrographolide as a Novel Combinatorial Drug Therapy for Epilepsy Using Network Virtual Screening and Experimental Validation

Combinatorial drug therapy has attracted
substantial attention
as an emerging strategy for the treatment of diseases with complex
pathological mechanisms. We previously developed a potentially universal
computational screening approach for combination drugs and used this
approach to successfully identify some beneficial combinations for
the treatment of heart failure. Herein, this screening approach was
used to identify novel combination drugs for the treatment of epilepsy
in an approved drug library. The combination of guaifenesin–andrographolide
was first discovered as a promising therapy with synergistic anticonvulsant
activities in maximal electroshock (MES)- and subcutaneous pentylenetetrazol
(sc-PTZ)-induced epilepsy models in vivo. The studies of network analysis,
fluorescence imaging, and N-methyl-d-aspartate
(NMDA)-induced cytotoxicity further revealed that guaifenesin–andrographolide
might synergistically affect NMDA receptors and then alleviate the
pathogenesis of epilepsy. Therefore, we report that the combination
of guaifenesin–andrographolide exerts effects against epilepsy
through a novel synergistic mechanism and is thus a potential treatment
for epilepsy, providing a promising mechanism for the design of novel
combinatorial drug treatments against epilepsy.