Toll-like receptor 4 is associated with seizures following ischemia with hyperglycemia

Yanling Liang, Zhigang Lei, Hui Zhang, Zhiqiang Xu, Qiliang Cui, Zao C. Xu

Research output: Contribution to journalArticle

15 Scopus citations


Seizures are a common sequel of cerebral ischemia, and hyperglycemia markedly increases the onset of seizures following an ischemic insult. However, the underlying mechanism of seizures is unclear. The toll-like receptor 4 (TLR4) pathway is known to be involved in temporal lobe epilepsy. The present study investigated the potential involvement of TLR4 in the pathogenesis of seizures following cerebral ischemia with hypergly-cemia. Fifteen minutes of global ischemia was produced in adult Wistar rats using a 4-vessel occlusion method. Hyperglycemia was induced via an intraperitoneal injection of glucose 15 min prior to ischemia. We determined that 56.7% of the hyperglycemic rats, but none of the normoglycemic rats, developed tonic-clonic seizures within 12 h after ischemia. TLR4 was mildly expressed in a few cells in the control hippocampus, primarily in interneurons, and was localized in the cytoplasm. The TLR4-positive cells were significantly increased 3-12 h after ischemia. In the hyperglycemic ischemia group, TLR4-positive cells were further increased in quantity and intensity, with a peak at 3 h after ischemia relative to the normoglycemic group. There was no difference in the expression of TLR4 between the hyperglycemic ischemia and LPS groups or between the hyperglycemic non-ischemia and control groups. Western blot analysis consistently exhibited an increase in TLR4 protein levels in the CA3 region 3 h after hyperglycemic ischemia. High mobility group box 1 (HMGB1) (an endogenous ligand of TLR4) was localized in the nucleus of neuronal cells throughout the hippocampus in the control animals. We observed a dramatic decrease in HMGB1 immunostaining at 3 h after hyperglycemic ischemia that gradually returned to control levels. These results suggest that the TLR4 pathway is associated with seizures following global ischemia with hyperglycemia, which provides a new direction for the study of the pathogenesis of seizures that result from hyperglycemic ischemia.

Original languageEnglish (US)
Pages (from-to)75-84
Number of pages10
JournalBrain research
Issue number1
StatePublished - Jan 1 2014


  • Diabetes
  • HMGB1
  • Hyperactivity
  • Post-ischemic seizures Inflammation
  • Toll-like receptor 4

ASJC Scopus subject areas

  • Neuroscience(all)
  • Molecular Biology
  • Clinical Neurology
  • Developmental Biology

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