IL-6 knockout mice are protected from cocaine-induced kindling behaviors; possible involvement of JAK2/STAT3 and PACAP signalings

Huynh Nhu Mai, Yoon Hee Chung, Eun Joo Shin, Naveen Sharma, Ji Hoon Jeong, Choon Gon Jang, Kuniaki Saito, Toshitaka Nabeshima, Dora Reglodi, Hyoung Chun Kim

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7 Citations (Scopus)


IL-6 has been recognized as an anticonvulsant against certain neuroexcitotoxicities. We aimed to investigate on the interactive role between IL-6 and PACAP in cocaine-induced kindling behaviors. Although we found that cocaine (45 mg/kg, i.p./day x 5) significantly increased IL-6 and TNF-α expression, it resulted in a decrease in IFN-γ expression. We observed that the cocaine-induced increase in IL-6 expression was more pronounced than that in TNF-α expression. Genetic depletion of IL-6 significantly activated cocaine kindling behaviors. This phenomenon was also consistently observed in WT mice that received a neutralizing IL-6 receptor antibody. Cocaine-treated IL-6 knockout mice exhibited significantly decreased PACAP and PACAP receptor (PAC1R) mRNA levels and significantly increased TNF-α gene expression. TNF-α knockout mice were protected from cocaine kindling via an up-regulation of IL-6, phospho-JAK2/STAT3, PACAP, and PAC1R levels, which produced anti-apoptotic effects. Recombinant IL-6 protein (rIL-6, 2 μg, i.v./mouse/day x 5) also up-regulated phospho-JAK2/STAT3, PACAP, and PAC1R mRNA levels, leading to anti-apoptotic effects in IL-6 knockout mice. Consistently, AG490, a JAK2/STAT3 inhibitor, and PACAP 6–38, a PAC1 receptor antagonist, counteracted rIL-6-mediated protection. Combined, our results suggest that IL-6 gene requires up-regulation of phospho-JAK2/STAT3, PACAP, and PAC1R and down-regulation of the TNF-α gene to modulate its anticonvulsive/neuroprotective potential.

Original languageEnglish
Pages (from-to)249-263
Number of pages15
JournalFood and Chemical Toxicology
Publication statusPublished - Jun 1 2018



  • Cocaine-induced kindling (convulsive) behaviors
  • Hippocampus
  • Interleukin-6 knockout mice
  • JAK2/STAT3
  • Pituitary adenylate cyclase-activating polypeptide
  • Tumor necrosis factor-α knockout mice

ASJC Scopus subject areas

  • Food Science
  • Toxicology

Cite this

Mai, H. N., Chung, Y. H., Shin, E. J., Sharma, N., Jeong, J. H., Jang, C. G., Saito, K., Nabeshima, T., Reglodi, D., & Kim, H. C. (2018). IL-6 knockout mice are protected from cocaine-induced kindling behaviors; possible involvement of JAK2/STAT3 and PACAP signalings. Food and Chemical Toxicology, 116, 249-263.