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(Stroke. 2005;36:2226.)
© 2005 American Heart Association, Inc.

Original Contributions

Neuroinflammation and Both Cytotoxic and Vasogenic Edema Are Reduced in Interleukin-1 Type 1 Receptor-Deficient Mice Conferring Neuroprotection

Jelena Lazovic, PhD; Anirban Basu, PhD; Hsiao-Wen Lin; Raymond P. Rothstein; J. Kyle Krady, PhD; Michael B. Smith, PhD Steven W. Levison, PhD

From the Departments of Neural and Behavioral Sciences and Radiology (J.L., A.B., J.K.K., M.B.S., S.W.L.), Pennsylvania State University College of Medicine, Hershey, PA; National Brain Research Center (A.B.), Gurgaon, India; and Department of Neurology and Neuroscience (H-W.L., R.P.R., S.W.L.), University of Medicine and Dentistry, New Jersey-New Jersey Medical School, Newark, NJ.

Correspondence to Steven W. Levison, Laboratory for Regenerative Neurobiology, Department of Neurology and Neuroscience, University of Medicine and Dentistry, New Jersey-New Jersey Medical School, 185 South Orange Ave, H-506, Newark, NJ 07101-170. E-mail Steve.Levison{at}umdnj.edu

Background and Purpose— Interleukin-1 (IL-1) is a proinflammatory cytokine implicated in multiple neurodegenerative diseases, including stroke. However, to date, there is no consensus regarding which receptor(s) mediates the detrimental effects of IL-1. We hypothesized that abrogating IL-1 type 1 receptor (IL-1R1) signaling would reduce edema, chemokine expression, and leukocyte infiltration; lower levels of iNOS; and, consequently, decrease free radical damage after mild hypoxia/ischemia (H/I), thus preserving brain cells.

Methods— IL-1R1 null mice and wild-type mice were subjected to a mild H/I insult. MRI was used to measure the area affected at 30 minutes and 48 hours after H/I. An RNAse protection assay was used to evaluate changes in chemokine mRNA expression. RT-PCR was used to assess inducible nitric oxide synthase (iNOS) and endothelial nitric oxide synthase mRNA levels. Immunohistochemistry was used to assess leukocyte infiltration. Western blots were used to assess iNOS and glutamate aspartate transporter protein levels.

Results— IL-1R1 null mice had reduced cytotoxic and vasogenic edema. The volume of hyperintense signal on T₂-weighted images was reduced on average by 90% at 48 hours after H/I. The induction of multiple chemokine mRNAs was significantly reduced in IL-1R1 null mice compared with wild-type mice at 18 and 72 hours after H/I, which correlated with fewer infiltrating CD3+ leukocytes. Levels of iNOS protein and mRNA (but not glutamate aspartate transporter) were significantly reduced in the IL-1R1 mouse brain.

Conclusions— These findings indicate that abrogating IL-1R1 signaling could protect brain cells subsequent to a mild stroke by reducing edema and immune cell recruitment, as well as by limiting iNOS-mediated free radical damage.

Key Words: cytokines • interleukin-1 • inducible nitric oxide synthase • inflammation • leukocytes • microglia • stroke

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