MRI detects protective effects of DAPT treatment with modulation of microglia/macrophages at subacute and chronic stages following cerebral ischemia

Mol Med Rep. 2017 Oct;16(4):4493-4500. doi: 10.3892/mmr.2017.7200. Epub 2017 Aug 9.

Abstract

Notch homolog 1 (Notch 1) signaling is regarded as a potential therapeutic target for modulating the inflammatory response and exhibiting neuroprotective effects in cerebral injury following stroke. N-[N-(3,5-difluorophenacetyl)-1-alanyl]-S-phenylglycine t‑butylester (DAPT) efficiently inhibits activation of the Notch 1 signaling pathway in microglia and may protect brain tissue from ischemic damage. However, the temporal proliferation and morphological alterations of microglia/macrophages throughout progression of the disease, as well as the comprehensive alterations of the whole brain following DAPT treatment, remain to be elucidated. The present study evaluated the temporal proliferation and the morphological alterations of microglia/macrophages over the period of the subacute and chronic stages, in addition to dynamic alterations of brain tissue, using the magnetic resonance imaging (MRI) method, following DAPT treatment. Sprague‑Dawley rats (n=40) were subjected to 90 min of middle cerebral artery occlusion and were treated with DAPT (n=20) or acted as controls with no treatment (n=20). The two groups of rats underwent MRI scans prior to the induction of stroke symptoms and at 24 h, 7, 14, 21 and 28 days following the stroke. A total of five rats from each group were sacrificed at 7, 14, 21 and 28 days following induction of stroke. Compared with control rats, the MRI data of the ipsilateral striatum in treated rats revealed ameliorated brain edema at the subacute stage and recovered brain tissue at the chronic stage. In addition to this, treatment attenuated the round‑shape and promoted a ramified‑shape of microglia/macrophages. The present study confirmed the protective effect of DAPT treatment by dynamically monitoring the cerebral alterations and indicated the possibility of DAPT treatment to alter microglial characteristics to induce a protective effect, via inhibition of the Notch signaling pathway.

MeSH terms

  • Animals
  • Brain Ischemia / diagnosis*
  • Brain Ischemia / drug therapy
  • Brain Ischemia / metabolism*
  • Dipeptides / drug effects*
  • Image Processing, Computer-Assisted
  • Macrophages / drug effects*
  • Macrophages / metabolism*
  • Magnetic Resonance Imaging*
  • Microglia / drug effects*
  • Microglia / metabolism*
  • Protective Agents / pharmacology
  • Rats
  • Receptors, Notch / metabolism
  • Signal Transduction

Substances

  • Dipeptides
  • N-(N-(3,5-difluorophenacetyl)alanyl)phenylglycine tert-butyl ester
  • Protective Agents
  • Receptors, Notch