Identification of New Therapeutic Targets by Genome-Wide Analysis of Gene Expression in the Ipsilateral Cortex of Aged Rats after Stroke

• Authors: Ana-Maria Buga, University of Medicine; Claus Jürgen Scholz, University of Wurzburg; Senthil Kumar, College of Veterinary Medicine; James Herndon Jr., Emory University; Dragos Alexandru, University of Medicine; Gabriel Radu Cojocaru, University of Medicine; Thomas Dandekar, Biocenter Am Hubland; Aurel Popa-Wagner, University of Medicine
• Journal Title: PLoS ONE
• Volume: Volume 7, Number 12
• Publisher: Public Library of Science | 2012-12-12, Pages e50985-e50985
• Type of Work: Article | Final Publisher PDF
• Publisher DOI: http://doi.org/10.1371/journal.pone.0050985
• Subjects: Biology, Neuroscience; Biology, Genetics
• Keywords: Science & Technology; Multidisciplinary Sciences; Science & Technology - Other Topics; CORTICOTROPIN-RELEASING HORMONE; COLONY-STIMULATING FACTOR; CEREBRAL-ISCHEMIA; RECEPTOR; BRAIN; PROTEIN; INHIBITOR; MOUSE; GAMMA; DIFFERENTIATION; Stroke; Gene expression; Age groups; Central nervous system; Gene regulation; Drug research and development; Apoptosis; Neurotransmission

Abstract

Background: Because most human stroke victims are elderly, studies of experimental stroke in the aged rather than the young rat model may be optimal for identifying clinically relevant cellular responses, as well for pinpointing beneficial interventions. Methodology/Principal Findings: We employed the Affymetrix platform to analyze the whole-gene transcriptome following temporary ligation of the middle cerebral artery in aged and young rats. The correspondence, heat map, and dendrogram analyses independently suggest a differential, age-group-specific behaviour of major gene clusters after stroke. Overall, the pattern of gene expression strongly suggests that the response of the aged rat brain is qualitatively rather than quantitatively different from the young, i.e. the total number of regulated genes is comparable in the two age groups, but the aged rats had great difficulty in mounting a timely response to stroke. Our study indicates that four genes related to neuropathic syndrome, stress, anxiety disorders and depression (Acvr1c, Cort, Htr2b and Pnoc) may have impaired response to stroke in aged rats. New therapeutic options in aged rats may also include Calcrl, Cyp11b1, Prcp, Cebpa, Cfd, Gpnmb, Fcgr2b, Fcgr3a, Tnfrsf26, Adam 17 and Mmp14. An unexpected target is the enzyme 3-hydroxy-3-methylglutaryl-Coenzyme A synthase 1 in aged rats, a key enzyme in the cholesterol synthesis pathway. Post-stroke axonal growth was compromised in both age groups. Conclusion/Significance: We suggest that a multi-stage, multimodal treatment in aged animals may be more likely to produce positive results. Such a therapeutic approach should be focused on tissue restoration but should also address other aspects of patient post-stroke therapy such as neuropathic syndrome, stress, anxiety disorders, depression, neurotransmission and blood pressure.