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Anticonvulsant agent DPP4 inhibitor sitagliptin downregulates CXCR3/RAGE pathway on seizure models

Yunli Liu1, Baohua Hou1, Yusong Zhang2

  • 1Department of Pathophysiology, School of Basic Medical Sciences, Wuhan University, Wuhan, China.

Experimental Neurology
|June 10, 2018
PubMed

Insights

Sitagliptin, a DPP4 inhibitor, shows anticonvulsant effects by reducing seizure severity and epileptiform activity. It acts by downregulating the CXCL4/CXCR3 axis and the RAGE-JAK2/STAT3 pathway, suggesting potential as a novel epilepsy treatment.

Area of Science:

  • Neuroscience
  • Pharmacology

Background:

  • Epilepsy is a common neurological disorder with complex causes.
  • Dipeptidyl peptidase IV (DPP4) is potentially involved in epilepsy pathogenesis.
  • The anticonvulsant effects and mechanisms of the DPP4 inhibitor sitagliptin are not fully understood.

Purpose of the Study:

  • To investigate the anticonvulsant effect of sitagliptin.
  • To elucidate the underlying molecular mechanisms of sitagliptin's action in epilepsy.

Main Methods:

  • Utilized a pentylenetetrazole (PTZ)-induced rat model of epilepsy.
  • Performed electroencephalography (EEG) recordings and patch-clamp electrophysiology.
  • Analyzed the expression of RAGE, JAK2, STAT3, CXCL4, and CXCR3.

Main Results:

  • Sitagliptin significantly reduced seizure severity in PTZ-treated rats.
  • Sitagliptin decreased epileptiform activity as measured by EEG and patch-clamp.
  • Sitagliptin downregulated the RAGE-JAK2/STAT3 pathway and decreased CXCL4/CXCR3 expression.
  • CXCR3 was identified as upstream of the RAGE-JAK2/STAT3 pathway.

Conclusions:

  • Sitagliptin exhibits a notable anticonvulsant effect.
  • The mechanism involves downregulating the CXCL4/CXCR3 axis and subsequently the RAGE-JAK2/STAT3 pathway.
  • Sitagliptin represents a promising candidate for a novel anticonvulsant therapy.
Keywords:
CXCR3DPP4RAGESeizureSitagliptin

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