Reduced postischemic apoptosis in the hippocampus of mice deficient in interleukin‐1

Abstract

The cytokine interleukin-1 (IL-1) has been implicated in ischemic brain damage, because the IL-1 receptor antagonist markedly inhibits experimentally induced neuronal loss. However, to date, no studies have demonstrated the involvement of endogenous IL-1alpha and IL- 1beta in neurodegeneration. We report here, for the first time, that mice lacking IL-1alpha/beta (double knockout) exhibit markedly reduced neuronal loss and apoptotic cell death when exposed to transient cardiac arrest. Furthermore, we show that, despite the reduced neuronal loss, phosphorylation of JNK/SAPK (c-Jun NH2- terminal protein kinase/stress activated protein kinase) and p38 enzymes remain elevated in IL-1 knockout mice. In contrast, the inducible nitric oxide (iNOS) immunoreactivity after global ischemia was reduced in IL-1 knockout mice as compared with wild-type mice. The levels of nitrite (NO(2) (-)) and nitrate (NO(3) (-)) in the hippocampus of wild-type mice were increased with time after ischemia-reperfusion, whereas the increase was significantly inhibited in IL-1 knockout mice. These observations strongly suggest that endogenous IL-1 contributes to ischemic brain damage, and this influence may act through the release of nitric oxide by iNOS.

CD40 Mediates Retinal Inflammation and Neurovascular Degeneration

“…The rapid expression of IL-1 after ischemia and the role of this cytokine in chemokine secretion and tissue injury (44,45,58) provided rationale for exploring whether CD40 and IL-1 cooperate to produce KC/CXCL1 by retinal cells. We report that CD40 stimulation of retinal endothelial cells in the presence of IL-1␤ results in a marked increase in production of KC/CXCL1.…”

Vasoconstriction Caused by Cocaine is Enhanced by Sodium Salicylate: Is Inducible Nitric Oxide Synthase mRNA Related?

“…An increase in leukotriene production, as mentioned earlier, may also induce inflammatory changes (Henderson, 1994). The inflammatory processes may stimulate microglial cells to produce inflammatory cytokines, like interleukin-1-beta (Il-1b), which can lead to iNOS mRNA expression (Mizushima et al, 2002;del Zoppo et al, 2000).…”

Evaluation of Brain Ischemia in Mice

“…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.…”

“…The CA total ischemia model in mice has been extensively used and developed by our group [13,34] as a superior pathophysiological model mimicking human cardiac arrest and cardiac infarction. We carry out compression for 5 min by inserting the shaped device shown in Fig.…”