Luteoloside attenuates neuroinflammation in focal cerebral ischemia in rats via regulation of the PPARγ/Nrf2/NF-κB signaling pathway

Int Immunopharmacol. 2019 Jan;66:309-316. doi: 10.1016/j.intimp.2018.11.044. Epub 2018 Nov 29.

Abstract

Luteoloside, a flavonoid compound, has been reported to have anti-inflammatory, anti-oxidative, antibacterial, antiviral, anticancer, and cardioprotective effects, among others, but its neuroprotective effects have rarely been studied. The purpose of this study was to investigate the protective effect of luteoloside on cerebral ischemia and explore its potential mechanism. Middle cerebral artery occlusion (MCAO) was performed to investigate the effects of luteoloside on cerebral ischemia-reperfusion (I/R). Male Sprague-Dawley rats were randomly divided into six groups: sham, MCAO, luteoloside (20 mg/kg, 40 mg/kg, 80 mg/kg) and nimodipine (4 mg/kg). The results showed that luteoloside alleviated neurologic deficits and cerebral edema as well as improved cerebral infarction and histopathological changes in MCAO rats. Luteoloside significantly inhibited I/R-induced neuroinflammation, as demonstrated by reduced levels of interleukin-1β (IL-1β), tumor necrosis factor-α (TNF-α), inducible nitric oxide synthase (iNOS) and cyclooxygenase-2 (COX-2) in the brain tissues of MCAO rats. Furthermore, our results demonstrated that luteoloside significantly suppressed the activation of nuclear factor-kappa B (NF-κB) signaling, upregulated the protein expression of peroxisome proliferator activated receptor gamma (PPARγ) and increased NF-E2-related factor (Nrf2) nuclear accumulation in MCAO rats. Collectively, our findings suggested that luteoloside played a crucial neuroprotective role by inhibiting NF-κB signaling in focal cerebral ischemia in rats. Furthermore, PPARγ and Nrf2 were also important for the anti-inflammatory effect of luteoloside. In addition, our data suggested that luteoloside might be an effective treatment for cerebral ischemia and other neurological disorders.

Keywords: Cerebral ischemia; Luteoloside; NF-κB signaling; Neuroinflammation; Nrf2; PPARγ.

MeSH terms

  • Animals
  • Anti-Inflammatory Agents / therapeutic use*
  • Brain Ischemia / drug therapy*
  • Cells, Cultured
  • Cyclooxygenase 2 / metabolism
  • Disease Models, Animal
  • Glucosides / therapeutic use*
  • Humans
  • Infarction, Middle Cerebral Artery / drug therapy*
  • Interleukin-1beta / metabolism
  • Luteolin / therapeutic use*
  • Male
  • NF-E2-Related Factor 2 / metabolism
  • NF-kappa B / metabolism
  • Neurogenic Inflammation / drug therapy*
  • Nitric Oxide Synthase Type II / metabolism
  • PPAR gamma / metabolism
  • Rats
  • Rats, Sprague-Dawley
  • Signal Transduction
  • Tumor Necrosis Factor-alpha / metabolism

Substances

  • Anti-Inflammatory Agents
  • Glucosides
  • Interleukin-1beta
  • NF-E2-Related Factor 2
  • NF-kappa B
  • Nfe2l2 protein, rat
  • PPAR gamma
  • Tumor Necrosis Factor-alpha
  • luteolin-7-glucoside
  • Nitric Oxide Synthase Type II
  • Cyclooxygenase 2
  • Luteolin