Suppression of oxidative neuronal damage after transient middle cerebral artery occlusion in mice lacking interleukin-1

Abstract

Interleukin-1 (IL-1) contributes to ischemic neurodegeneration. However, the mechanisms regulating action of IL-1 are still poorly understood. In order to clear this central issue, mice that were gene deficient in IL-1a and b (IL-1 KO) and wild-type mice were subjected to 1-h transient middle cerebral artery occlusion (tMCAO). Expression levels of IL-1b and IL-1 receptor I (IL-1RI) were then examined. Generation of peroxynitrite and the expression of mRNAs for nitric oxide synthase (NOS) subtypes were also determined. Immunostaining for IL-1b was increased from 6 h and peaked at 24 h after tMCAO in the microglia and macrophage. The immunoreactivities of IL-1RI were increased progressively in the microvasculature and neuron-like cells of the ipsilateral hemisphere. Infarct volumes were significantly lower in IL-1 KO mice compared with wild-type mice 48 h after tMCAO (P B/0.01). The immunoreactivities of 3-nitro-L-tyrosine were determined in the neurons and microvasculature 24 h after tMCAO and were significantly decreased in the IL-1 KO mice compared to wild-type mice. In addition, expression levels of NOS mRNA in IL-1 KO mice were lower than that measured in wild-type mice. These results indicate that IL-1 is up-regulated and may play a role in neurodegeneration by peroxynitrite production during ischemia. #

System xc−Activity and Astrocytes Are Necessary for Interleukin-1β-Mediated Hypoxic Neuronal Injury

“…Moreover, numerous studies indicate that IL-1␤ plays an active role in the brain damage that accompanies ischemia in mice Yang et al, 1997Yang et al, , 1998Yang et al, , 1999Schielke et al, 1998;Liu et al, 1999;Ohtaki et al, 2003), in rats (Relton and Rothwell, 1992;Martin et al, 1994;Betz et al, 1995;Loddick and Rothwell, 1996;Mulcahy et al, 2003), and in humans (Emsley et al, 2005). Despite this, the cellular and biochemical pathway(s) by which this cytokine contributes to neuronal cell death after cerebral ischemia are still unknown.…”

Evaluation of Brain Ischemia in Mice

“…For the last decade, several models of ischemia have been developed using several transgenic and gene deficient mice aimed to examine the functional roles of the many factors involved in ischemic neuronal cell death [19,32,34,35,39,43]. Unfortunately, because the infarction and neuronal cell death after cerebral ischemia in humans is so pathologically heterogeneous, the limited and somewhat inappropriate animal models have not been able to assist in the development of new medicines [10,11,14,44].…”

“…The cytokines and NOS, directly or indirectly, lead to the generation of reactive oxygen species (ROS) and the formation of excessive amounts of free radicals, including NO, superoxide anion (O 2 -), hydrogen peroxide (H 2 O 2 ) and peroxynitrite (ONOO -) [5,34,39]. Elevated Ca 2+ in the mitochondria uncouples oxidative phosphorylation, leading to a further decrease in energy supply and an increase in free radicals [36,46].…”

“…Another component that contributes to cell damage is inflammation. In the ischemic zone, endothelial adhesion receptors are upregulated and leukocytes migrate through the walls of blood vessels, invade the parenchyma and release their cytotoxic cytokines, NOS, and ROS [20,34,38,39,41,42,47,54,55]. In conclusion, ischemic brain damage is multidimensional in origin and offers a broad range of targets for neuroprotective intervention.…”

“…In previous studies, the suture used was between 5-0 and 8-0 and the edge of the suture treated in different ways, such as coating with glue or with poly-L-lysine and heating [9,17]. We usually use size 7-0 monofilament suture, which is then processed to the round form by heating without coating, when performing transient MCAO [39]. When permanent ischemia is performed, however, we coat the suture with poly-L-lysine.…”