Nerolidol ameliorates cyclophosphamide-induced oxidative stress, neuroinflammation and cognitive dysfunction: Plausible role of Nrf2 and NF- κB

Life Sci. 2019 Nov 1;236:116867. doi: 10.1016/j.lfs.2019.116867. Epub 2019 Sep 11.

Abstract

Aim: Cyclophosphamide (CP) is a potent anticancer and immunosuppressant drug. Studies have shown significant oxidative stress and cognitive impairment but neuroinflammatory and histological aberrations with its administration is underexplored. Nerolidol (NER) is a lipophilic bioactive molecule with antioxidant and anti-inflammatory properties but it has not been explored for neuroprotective potential in CP-induced neurotoxic manifestations. Therefore, in the present study, we aimed to evaluate the neuroprotective potential of NER in CP-induced neuroinflammation and associated comorbid conditions like depression and cognitive dysfunctions.

Materials and method: In-silico study using Schrödinger software was used to assess the binding affinity of NER with Nrf2. In the In vivo study, NER 200 and 400 mg/kg p.o. were given from 1st day to 14th day. CP 200 mg/kg, i.p., was administered on the 7th day. After 24 h of the last dosing, neurobehavioral tests like spontaneous body alternation, passive avoidance and forced swim test were performed. On completion of study, mice were sacrificed, hippocampus and cortex were removed for biochemical estimations, histopathology and immunohistochemistry of p65 NF- κB and Nrf2.

Key findings: In-silico study showed significant binding of NER into the pocket domain of Nrf2. In-vivo study showed protective effect of NER against CP-induced neuroinflammation, oxidative stress, cognitive impairment and structural abnormalities in the hippocampus and cortex regions.

Significance: Findings of the study suggested that NER is a potential therapeutic molecule which can mitigate CP-induced neurotoxic manifestations via Nrf2 and NF-κB pathway. However, more detailed studies are needed to explicate the mechanism underlying its neuroprotective effect.

Keywords: Cresyl Violet staining; Hippocampus; Molecular docking; Neurotoxicity; Sesquiterpene.

MeSH terms

  • Animals
  • Cognitive Dysfunction / chemically induced
  • Cognitive Dysfunction / metabolism
  • Cognitive Dysfunction / pathology
  • Cognitive Dysfunction / prevention & control*
  • Cyclophosphamide / toxicity*
  • Gene Expression Regulation
  • Hippocampus / drug effects
  • Hippocampus / metabolism
  • Immunosuppressive Agents / toxicity
  • Inflammation / chemically induced
  • Inflammation / metabolism
  • Inflammation / pathology
  • Inflammation / prevention & control*
  • Male
  • Mice
  • NF-E2-Related Factor 2 / genetics
  • NF-E2-Related Factor 2 / metabolism*
  • NF-kappa B / genetics
  • NF-kappa B / metabolism*
  • Neuroprotective Agents
  • Neurotoxicity Syndromes / etiology
  • Neurotoxicity Syndromes / metabolism
  • Neurotoxicity Syndromes / pathology
  • Neurotoxicity Syndromes / prevention & control*
  • Oxidative Stress / drug effects*
  • Sesquiterpenes / pharmacology*
  • Signal Transduction

Substances

  • Immunosuppressive Agents
  • NF-E2-Related Factor 2
  • NF-kappa B
  • Neuroprotective Agents
  • Nfe2l2 protein, mouse
  • Sesquiterpenes
  • Cyclophosphamide
  • nerolidol