Stepwise occlusion of the carotid arteries of the rat: MRI assessment of the effect of donepezil and hypoperfusion-induced brain atrophy and white matter microstructural changes

PLoS One. 2018 May 31;13(5):e0198265. doi: 10.1371/journal.pone.0198265. eCollection 2018.

Abstract

Bilateral common carotid artery occlusion (BCCAo) in the rat is a widely used animal model of vascular dementia and a valuable tool for preclinical pharmacological drug testing, although the varying degrees of acute focal ischemic lesions it induces could interfere with its translational value. Recently, a modification to the BCCAo model, the stepwise occlusion of the two carotid arteries, has been introduced. To acquire objective translatable measures, we used longitudinal multimodal magnetic resonance imaging (MRI) to assess the effects of semi-chronic (8 days) donepezil treatment in this model, with half of the Wistar rats receiving the treatment one week after the stepwise BCCAo. With an ultrahigh field MRI, we measured high-resolution anatomy, diffusion tensor imaging, cerebral blood flow measurements and functional MRI in response to whisker stimulation, to evaluate both the structural and functional effects of the donepezil treatment and stepwise BCCAo up to 5 weeks post-occlusion. While no large ischemic lesions were detected, atrophy in the striatum and in the neocortex, along with widespread white matter microstructural changes, were found. Donepezil ameliorated the transient drop in the somatosensory BOLD response in distant cortical areas, as detected 2 weeks after the occlusion but the drug had no effect on the long term structural changes. Our results demonstrate a measurable functional MRI effect of the donepezil treatment and the importance of diffusion MRI and voxel based morphometry (VBM) analysis in the translational evaluation of the rat BCCAo model.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Brain Ischemia / complications
  • Carotid Artery, Common / diagnostic imaging*
  • Carotid Artery, Common / drug effects
  • Carotid Artery, Common / physiopathology
  • Carotid Stenosis / complications
  • Carotid Stenosis / diagnostic imaging
  • Carotid Stenosis / pathology*
  • Carotid Stenosis / physiopathology*
  • Cerebrovascular Circulation / drug effects*
  • Diffusion Tensor Imaging*
  • Donepezil
  • Indans / pharmacology*
  • Male
  • Oxygen / blood
  • Piperidines / pharmacology*
  • Rats
  • Rats, Wistar
  • White Matter / drug effects
  • White Matter / pathology*

Substances

  • Indans
  • Piperidines
  • Donepezil
  • Oxygen

Grants and funding

The study was supported by Gedeon Richter Plc., the Hungarian National Research, Development and Innovation Office (KMOP-1.1.5-08-2009-0001, KTIA_NAP_13-1-2013-0001), the National Brain Research Program (Grant No. KTIA_13_NAP-A-II/20. and KTIA 13 NAP-A-II/3) and an EU-funded Hungarian grant EFOP-3.6.1-16-2016-00008. The funders provided support in the form of salaries for authors [G.Ny, A.C, T.S, Zs.S, D.G, P.D], 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.