Effects of chronic overexpression of interleukin-1 receptor antagonist in a model of permanent focal cerebral ischemia in mouse.
Interleukin-1 receptor antagonist (IL-1ra) has been shown previously to have neuroprotective effects in animal models of stroke. The effects of chronic overexpression of human soluble IL-1ra (hsIL-1ra) were studied in a mouse model of permanent focal cerebral ischemia. A transgenic mouse strain (Tg hsIL-1ra+/-) has been developed using the promoter for glial fibrillary acidic protein (GFAP) to limit the overexpression to the CNS. Analysis of the neurological scores, infarct volume and edema formation revealed no differences between Tg hsIL-1ra+/- and wild-type (WT) mice. The cerebral ischemia resulted in pronounced astrocyte proliferation and microglial activation, as well as induction of inflammatory markers in both Tg hsIL-1ra+/- and WT mice, with no major differences between the two genotypes. Interestingly, hsIL-1ra expression in astrocytes was reduced in infarcted areas as compared to non-ischemic regions and sham-operated controls. In conclusion, transgenic overexpression of hsIL1-ra was not neuroprotective in this cerebral ischemia model, possibly due to insufficient levels for protection against the extensive lesion, or an up-regulation of compensatory inflammatory signals due to the lifetime blockade of IL-1 receptors.
Oprica
Mircea
M
Neurotec Department, Division of Experimental Geriatrics, Karolinska Institutet, Novum, Karolinska University Hospital Huddinge, 141 86, Stockholm, Sweden. Mircea.Oprica@neurotec.ki.se
Van Dam
Anne-Marie
AM
Lundkvist
Johan
J
Iverfeldt
Kerstin
K
Winblad
Bengt
B
Bartfai
Tamas
T
Schultzberg
Marianne
M
D000818:Animals; D001929:Brain Edema / Q000209:etiology / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D020520:Brain Infarction / Q000209:etiology / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D002545:Brain Ischemia / Q000209:etiology / Q000235:genetics / Q000378:metabolism*; D020170:Caspase 1 / Q000378:metabolism; D004195:Disease Models, Animal; D005455:Fluorescent Antibody Technique / Q000379:methods; D005786:Gene Expression Regulation / Q000235:genetics*; D005904:Glial Fibrillary Acidic Protein / Q000235:genetics / Q000378:metabolism; D020244:Infarction, Middle Cerebral Artery / Q000150:complications / Q000188:drug therapy / Q000235:genetics; D053590:Interleukin 1 Receptor Antagonist Protein; D007375:Interleukin-1 / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D009457:Neuroglia / Q000378:metabolism*; D009460:Neurologic Examination; D012039:Regional Blood Flow / Q000502:physiology; D012795:Sialoglycoproteins / Q000378:metabolism*
D005904:Glial Fibrillary Acidic Protein; C507763:IL1RN protein, human; C507764:Il1rn protein, mouse; D053590:Interleukin 1 Receptor Antagonist Protein; D007375:Interleukin-1; D012795:Sialoglycoproteins; D020170:Caspase 1