Peroxisome proliferator-activated receptor-γ ligands reduce inflammation and infarction size in transient focal ischemia

Newly developed insulin-sensitizing agents, which target the nuclear receptor peroxisome proliferator-activated receptor-γ have recently been appreciated to exhibit potent anti-inflammatory actions. Since stroke is associated with an intense inflammatory response, we reasoned that these agents may a...

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Bibliographic Details
Published in:Neuroscience 2005, Vol.130 (3), p.685-696
Main Authors: Sundararajan, S., Gamboa, J.L., Victor, N.A., Wanderi, E.W., Lust, W.D., Landreth, G.E.
Format: Article
Language:English
Subjects:
Animals
Biological and medical sciences
Blood Glucose - metabolism
Brain Chemistry - drug effects
Brain Chemistry - genetics
Cell Count
Cerebrovascular Circulation - physiology
Chromans - therapeutic use
COX-2
Dose-Response Relationship, Drug
Encephalitis - drug therapy
Encephalitis - etiology
Encephalitis - pathology
Fundamental and applied biological sciences. Psychology
IL-1β
Immunohistochemistry
Infarction, Middle Cerebral Artery - drug therapy
Infarction, Middle Cerebral Artery - etiology
Infarction, Middle Cerebral Artery - pathology
iNOS
Ischemic Attack, Transient - drug therapy
Ischemic Attack, Transient - metabolism
Ischemic Attack, Transient - pathology
Ligands
Macrophages - drug effects
Male
Medical sciences
Microglia - drug effects
Middle Cerebral Artery - physiology
Nerve Tissue Proteins - biosynthesis
Nerve Tissue Proteins - genetics
Neurology
pioglitazone
PPAR gamma - drug effects
Psychomotor Performance - drug effects
Psychomotor Performance - physiology
Rats
Rats, Wistar
Reverse Transcriptase Polymerase Chain Reaction
RNA, Messenger - biosynthesis
RNA, Messenger - genetics
stroke
Thiazolidinediones - therapeutic use
troglitazone
Vascular diseases and vascular malformations of the nervous system
Vertebrates: nervous system and sense organs
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Summary:Newly developed insulin-sensitizing agents, which target the nuclear receptor peroxisome proliferator-activated receptor-γ have recently been appreciated to exhibit potent anti-inflammatory actions. Since stroke is associated with an intense inflammatory response, we reasoned that these agents may ameliorate injury from stroke. We report that administration of troglitazone or pioglitazone 24 h before and at the time of cerebral infarction dramatically reduced infarction volume and improved neurological function following middle cerebral artery occlusion in rats. Furthermore, we find that delayed therapy also significantly reduced infarct volume. The brains of the drug-treated animals displayed reduced inflammation as evidenced by decreased immunoreactivity for microglial/macrophage markers and reduced protein and mRNA for interleukin-1β, cyclooxygenase-2 and inducible nitric oxide synthase. We argue that the beneficial effects of these drugs are likely due to reduced expression of these inflammatory mediators, which are known to exacerbate ischemic injury following stroke. These results are of particular relevance to diabetic patients chronically treated with these agents who may benefit from the neuroprotective actions of these drugs.
ISSN:0306-4522
1873-7544
DOI:10.1016/j.neuroscience.2004.10.021