Hyperhomocysteinemia alters cytokine gene expression, cytochrome c oxidase activity and oxidative stress in striatum and cerebellum of rodents

Life Sci. 2021 Jul 15:277:119386. doi: 10.1016/j.lfs.2021.119386. Epub 2021 Mar 24.

Abstract

Aims: Homocysteine has been linked to neurodegeneration and motor function impairments. In the present study, we evaluate the effect of chronic mild hyperhomocysteinemia on the motor behavior (motor coordination, functional performance, and muscular force) and biochemical parameters (oxidative stress, energy metabolism, gene expression and/or protein abundance of cytokine related to the inflammatory pathways and acetylcholinesterase) in the striatum and cerebellum of Wistar male rats.

Main methods: Rodents were submitted to one injection of homocysteine (0.03 μmol Hcy/g of body weight) between 30th and 60th postnatal days twice a day. After hyperhomocysteinemia induction, rats were submitted to horizontal ladder walking, beam balance, suspension, and vertical pole tests and/or euthanized to brain dissection for biochemical and molecular assays.

Key findings: Chronic mild hyperhomocysteinemia did not alter motor function, but induced oxidative stress and impaired mitochondrial complex IV activity in both structures. In the striatum, hyperhomocysteinemia decreased TNF-α gene expression and increased IL-1β gene expression and acetylcholinesterase activity. In the cerebellum, hyperhomocysteinemia increased gene expression of TNF-α, IL-1β, IL-10, and TGF-β, while the acetylcholinesterase activity was decreased. In both structures, hyperhomocysteinemia decreased acetylcholinesterase protein abundance without altering total p-NF-κB, NF-κB, Nrf-2, and cleaved caspase-3.

Significance: Chronic mild hyperhomocysteinemia compromises several biochemical/molecular parameters, signaling pathways, oxidative stress, and chronic inflammation in the striatum and cerebellum of rats without impairing motor function. These alterations may be related to the mechanisms in which hyperhomocysteinemia has been linked to movement disorders later in life and neurodegeneration.

Keywords: Cholinergic system; Cleaved caspase-3; Cytochrome c oxidase; Mild hyperhomocysteinemia; Motor coordination; NF-κB gene; Nrf-2 gene.

MeSH terms

  • Animals
  • Cerebellum / metabolism
  • Cerebellum / pathology*
  • Corpus Striatum / metabolism
  • Corpus Striatum / pathology*
  • Cytokines / genetics
  • Cytokines / metabolism*
  • Electron Transport Complex IV / metabolism*
  • Energy Metabolism
  • Gene Expression Regulation
  • Homocysteine / metabolism
  • Hyperhomocysteinemia / physiopathology*
  • Male
  • Mitochondria / metabolism
  • Mitochondria / pathology
  • Oxidative Stress*
  • Rats
  • Rats, Wistar

Substances

  • Cytokines
  • Homocysteine
  • Electron Transport Complex IV