Faculty Collaboration Database

Deficiency of telomerase activity aggravates the blood-brain barrier disruption and neuroinflammatory responses in a model of experimental stroke. J Neurosci Res 2010 Oct;88(13):2859-68

Date

06/22/2010

Pubmed ID

20564349

Pubmed Central ID

PMC2919635

DOI

10.1002/jnr.22450

Scopus ID

2-s2.0-77957224445 (requires institutional sign-in at Scopus site)   32 Citations

Abstract

Epidemiology and genetic studies indicate that patients with telomere length shorter than average are at higher risk of dying from heart disease or stroke. Telomeres are located at the ends of eukaryotic chromosomes, which demonstrate progressive length reduction in most somatic cells during aging. The enzyme telomerase can compensate for telomere loss during cell replication. The present study sought to investigate the contribution of telomerase to stroke and blood-brain barrier (BBB) dysfunction. Telomerase reverse transcriptase knockout (TERT(-/-)) mice and littermate controls with normal TERT expression were subjected to a 24-hr permanent middle cerebral artery occlusion (pMCAO). The stroke outcomes were assessed in terms of neurological scores and infarct volumes. In addition, we evaluated oxidative stress, permeability across the BBB, and integrity of tight junctions in brain microvessels. Neurological testing revealed that TERT(-/-) mice showed enhanced deficits compared with controls. These changes were associated with a greater infarct volume. The expression of tight junction protein ZO-1 decreased markedly in ischemic hemispheres of TERT(-/-) mice. The brain microvessels of TERT(-/-) mice also were more susceptible to oxidative stress, revealing higher superoxide and lower glutathione levels compared with mice with normal TERT expression. Importantly, TERT deficiency potentiated the production of inflammatory mediators, such as tumor necrosis factor-alpha, interleukin-1 beta, and intercellular adhesion molecule-1, in the ischemic hemispheres of mice with pMCAO. Our study suggests that TERT deficiency can predispose to the development of stroke in an experimental model of this disease.

Author List

Zhang B, Chen L, Swartz KR, Bruemmer D, Eum SY, Huang W, Seelbach M, Choi YJ, Hennig B, Toborek M

Author

Karin R. Swartz MD Assistant Dean, Professor in the Neurosurgery department at Medical College of Wisconsin

MESH terms used to index this publication - Major topics in bold

Animals
Blood-Brain Barrier
Brain
Brain Infarction
Cytokines
Disease Models, Animal
Encephalitis
Gene Expression Regulation
Glutathione
Infarction, Middle Cerebral Artery
Mice
Mice, Knockout
Microvessels
Nervous System Diseases
Oxidative Stress
Proto-Oncogene Proteins
RNA, Messenger
Statistics, Nonparametric
Superoxides
Telomerase