Hesperidin alleviates chronic restraint stress and lipopolysaccharide-induced Hippocampus and Frontal cortex damage in mice: Role of TLR4/NF-κB, p38 MAPK/JNK, Nrf2/ARE signaling

Neurochem Int. 2020 Nov:140:104835. doi: 10.1016/j.neuint.2020.104835. Epub 2020 Aug 24.

Abstract

Stress and lipopolysaccharide (LPS) animal models are used for screening antidepressants and anxiolytic drugs. However, the lacunae for their combination (Restraint stress; RS and LPS) impacting inflammation, apoptosis and antioxidant signaling have not been explored. The present study investigated RS + LPS-induced neurobehavioral and neurochemical anomalies in hippocampus (HIP) and frontal cortex (FC) of mice. Furthermore, citrus-derived flavanone glycoside (Hesperidin; HSP) neuroprotective ability was also confirmed in this model. Male Balb/c mice were given RS (for 28 days) and LPS (single dose, 0.83 mg/kg, i.p.) on 28th day. RS + LPS challenge caused neurobehavioral deficits in mice as evaluated over elevated plus maze (EPM), open field test (OFT), light-dark box test, tail suspension test (TST), forced swim test (FST), sucrose preference test (SPT). Moreover, RS + LPS caused alteration via enhanced oxido-nitrosative stress, proinflammatory cytokines level (serum, HIP, FC), lower antioxidants (GSH, SOD, CAT), increased IBA-1, GFAP, TLR4/NF-κB, p38MAPK/JNK while decreased Nrf2/BDNF/HO-1 expression in HIP and FC of mice. The 21 days (8-28th day), HSP (50 and 100 mg/kg, p.o.) treatment significantly alleviated the anxiety and depressive-like behavior and reversed neurochemical, histopathological changes. HSP exerted the neuroprotective effect via its anti-inflammatory, anti-apoptotic, antioxidant and neurogenesis potential in treating psychiatric illness alone or associated with other diseases.

Keywords: Chronic restraint stress; Hesperidin; Lipopolysaccharide; Nrf2/ARE signaling; TLR4/NF-κB; p38 MAPK/JNK.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Chronic Disease
  • Dose-Response Relationship, Drug
  • Frontal Lobe / drug effects
  • Frontal Lobe / metabolism
  • Hesperidin / pharmacology
  • Hesperidin / therapeutic use*
  • Hippocampus / drug effects
  • Hippocampus / metabolism
  • Lipopolysaccharides / toxicity
  • MAP Kinase Signaling System / drug effects
  • MAP Kinase Signaling System / physiology
  • Male
  • Mice
  • Mice, Inbred BALB C
  • NF-E2-Related Factor 2 / antagonists & inhibitors*
  • NF-E2-Related Factor 2 / metabolism
  • NF-kappa B / antagonists & inhibitors*
  • NF-kappa B / metabolism
  • Restraint, Physical / adverse effects
  • Restraint, Physical / psychology
  • Stress, Psychological / drug therapy*
  • Stress, Psychological / metabolism
  • Stress, Psychological / psychology
  • Toll-Like Receptor 4 / antagonists & inhibitors*
  • Toll-Like Receptor 4 / metabolism
  • p38 Mitogen-Activated Protein Kinases / antagonists & inhibitors*
  • p38 Mitogen-Activated Protein Kinases / metabolism

Substances

  • Lipopolysaccharides
  • NF-E2-Related Factor 2
  • NF-kappa B
  • Nfe2l2 protein, rat
  • Tlr4 protein, rat
  • Toll-Like Receptor 4
  • Hesperidin
  • p38 Mitogen-Activated Protein Kinases