Troxerutin flavonoid has neuroprotective properties and increases neurite outgrowth and migration of neural stem cells from the subventricular zone

PLoS One. 2020 Aug 14;15(8):e0237025. doi: 10.1371/journal.pone.0237025. eCollection 2020.

Abstract

Troxerutin (TRX) is a water-soluble flavonoid which occurs commonly in the edible plants. Recent studies state that TRX improves the functionality of the nervous system and neutralizes Amyloid-ß induced neuronal toxicity. In this study, an in vitro assay based upon Neural stem cell (NSCs) isolated from the subventricular zone of the postnatal balb/c mice was established to explore the impact of TRX on individual neurogenesis processes in general and neuroprotective effect against ß-amyloid 1-42 (Aß42) induced inhibition in differentiation in particular. NSCs were identified exploiting immunostaining of the NSCs markers. Neurosphere clonogenic assay and BrdU/Ki67 immunostaining were employed to unravel the impact of TRX on proliferation. Differentiation experiments were carried out for a time span lasting from 48 h to 7 days utilizing ß-tubulin III and GFAP as neuronal and astrocyte marker respectively. Protective effects of TRX on Aß42 induced depression of NSCs differentiation were determined after 48 h of application. A neurosphere migration assay was carried out for 24 h in the presence and absence of TRX. Interestingly, TRX enhanced neuronal differentiation of NSCs in a dose-dependent manner after 48 h and 7 days of incubation and significantly enhanced neurite growth. A higher concentration of TRX also neutralized the inhibitory effects of Aß42 on neurite outgrowth and length after 48 h of incubation. TRX significantly stimulated cell migration. Overall, TRX not only promoted NSCs differentiation and migration but also neutralized the inhibitory effects of Aß42 on NSCs. TRX, therefore, offers an interesting lead structure from the perspective of drug design especially to promote neurogenesis in neurological disorders i.e. Alzheimer's disease.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Amyloid beta-Protein Precursor / pharmacology
  • Animals
  • Astrocytes / metabolism
  • Cell Differentiation / drug effects
  • Cell Movement / drug effects
  • Cell Proliferation / drug effects
  • Cells, Cultured
  • Flavonoids / pharmacology
  • Hydroxyethylrutoside / analogs & derivatives*
  • Hydroxyethylrutoside / metabolism
  • Hydroxyethylrutoside / pharmacology
  • Lateral Ventricles / drug effects
  • Lateral Ventricles / metabolism
  • Male
  • Mice
  • Mice, Inbred BALB C
  • Neural Stem Cells / drug effects
  • Neural Stem Cells / metabolism
  • Neurites / drug effects*
  • Neurogenesis
  • Neuronal Outgrowth / physiology*
  • Neurons / metabolism
  • Neuroprotection
  • Neuroprotective Agents / metabolism
  • Neuroprotective Agents / pharmacology

Substances

  • Amyloid beta-Protein Precursor
  • Flavonoids
  • Hydroxyethylrutoside
  • Neuroprotective Agents
  • troxerutin

Grants and funding

We are very thankful to The University of Applied Sciences, Kaiserslautern, Germany and The Higher Education Commission Government of Pakistan (Ref. PD/OS-II/Batch-VI/Germany/2015/77159/17755) for providing financial support in the execution of the present project. These funding agencies provided support in term of stipend for authors and expenses concerning chemicals but did not have any additional role in the study design, data collection and analysis, decision to publish, or preparation of the manuscript. Additionally, Ursapharm Arzneimittel GmbH provided support in the form of salary for author PM, but did not have any additional role in the study design, data collection and analysis, decision to publish, or preparation of the manuscript. The specific roles of these authors are articulated in the ‘author contributions’ section.