Targeting central β2 receptors ameliorates streptozotocin-induced neuroinflammation via inhibition of glycogen synthase kinase3 pathway in mice

Prog Neuropsychopharmacol Biol Psychiatry. 2018 Aug 30:86:65-75. doi: 10.1016/j.pnpbp.2018.05.010. Epub 2018 May 18.

Abstract

Alzheimer's disease (AD) is portrayed by progressive cognitive decline and pathological deposition of amyloid plaques as well as neurofibrillary tangles. Most of AD cases are sporadic, resulting from overlap of various environmental and genetic factors. Intra-cerebroventricular injection of streptozotocin (STZ) leads to insulin resistance brain state accompanied by memory decline, oxidative stress, and neuro-degeneration which mimic the pathologies associated with sporadic Alzheimer's disease (SAD). In the current study, protective effects of formoterol in STZ-induced SAD were studied. Formoterol-induced improvement in cognition was confirmed using Morris water maze and Y maze together with histopathological evidences. Moreover, prominent declines in oxidative stress, neuro-inflammation, and apoptotic parameters were recorded upon its injection in STZ-induced SAD mouse model. This was manifested by the decrement of malondialdehyde, hydrogen peroxide, interleukin-1β, interleukin-6, tumor necrosis factor-α, and caspase-3levels contrary to reduced glutathione and interleukin-10 increments. Formoterol also reversed STZ-induced alteration in acetylcholine and glutamate levels. Furthermore, it could be concluded that formoterol was capable of combating STZ-induced neuro-inflammation and retarding the development of the main pathological hallmarks of AD through glycogen synthase kinase-3 deactivation.

Keywords: Fomoterol; Mice; Neuro-inflammation; STZ; Sporadic Alzheimer's disease.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adrenergic beta-2 Receptor Agonists / pharmacology*
  • Alzheimer Disease / drug therapy
  • Alzheimer Disease / metabolism
  • Alzheimer Disease / pathology
  • Animals
  • Anti-Inflammatory Agents, Non-Steroidal / pharmacology*
  • Antioxidants / pharmacology
  • Brain / drug effects
  • Brain / metabolism
  • Brain / pathology
  • Disease Models, Animal
  • Dose-Response Relationship, Drug
  • Formoterol Fumarate / pharmacology*
  • Glycogen Synthase Kinase 3 / metabolism*
  • Inflammation / drug therapy*
  • Inflammation / metabolism
  • Inflammation / pathology
  • Male
  • Maze Learning / drug effects
  • Mice
  • Motor Activity / drug effects
  • Neuroprotective Agents / pharmacology
  • Oxidative Stress / drug effects
  • Random Allocation
  • Receptors, Adrenergic, beta-2 / metabolism
  • Signal Transduction

Substances

  • Adrenergic beta-2 Receptor Agonists
  • Anti-Inflammatory Agents, Non-Steroidal
  • Antioxidants
  • Neuroprotective Agents
  • Receptors, Adrenergic, beta-2
  • Glycogen Synthase Kinase 3
  • Formoterol Fumarate