Free radicals and inflammatory mediators are involved in transient focal cerebral ischemia (FCI). Preadministration of N-acetylcysteine (NAC) has been found to attenuate the cerebral ischemia-reperfusion injury in a rat model of experimental stroke. This study was undertaken to investigate the neuroprotective potential of NAC administered after ischemic events in experimental stroke. FCI was induced for 30 min by occluding the middle cerebral artery (MCA). NAC (150 mg/kg) was administered intraperitoneally at the time of reperfusion followed by another dose 6 hr later. Animals were sacrificed after 24 hr of reperfusion. The cerebral infarct consistently involved the cortex and striatum. Infarction was assessed by staining the brain sections with 2,3,5-triphenyltetrazolium chloride. Animals treated with NAC showed a significant reduction in infarct area and infarct volume and an improvement in neurologic scores and glutathione level. Reduction in infarction was significant even when a single dose of NAC was administered at 6 hr of reperfusion. Immunohistochemical and quantitative real-time PCR studies demonstrated a reduction in the expression of proinflammatory cytokines such as tumor necrosis factor alpha (TNFalpha) and interleukin 1beta (IL-1beta) and inducible nitric oxide synthase (iNOS) in NAC compared to that in vehicle-treated animals. The expression of activated macrophage/microglia (ED1) and apoptotic cell death in ischemic brain was also reduced by NAC treatment. These results indicate that in a rat model of experimental stroke, administration of NAC even after ischemia onset protected the brain from free radical injury, apoptosis, and inflammation, with a wide treatment window.
Combination therapy with AICAR and NAC attenuates renal I/R injury and improves the outcome of the transplanted kidney after prolonged cold preservation.
Lipids are essential for signal transduction in response to trauma leading to neurodegeneration. Ceramide is an important mediator of apoptosis and cell proliferation. We studied the involvement of ceramide/sphingomyelin pathway in rat brain (stroke model) after 45 min ischemia followed by 24‐h reperfusion. Ischemia was performed through occlusion of right middle cerebral artery (MCA). The level of ceramide was found increased (70–100% in ischemic side of brain v/s contralateral side of brain). Sphingomyelin levels were also decreased by 20–25% in ischemic brain v/s contralateral side of brain. Increase in ceramide and decrease in sphingomyelin were in good agreement with observed apoptotic cell loss (TUNEL assay) and decrease in the level of cardiolipin (a mitochondrian specific phospholipids) in affected ischemic brain. N‐acetyl cysteine (NAC), a therapeutic agent recognized as potent antioxidant provided protective effect. Pretreatment with NAC before ischemia reduced the infarct volume size, suppressed apoptosis, restored cardiolipin level and decreased the levels of free fatty acids. However, NAC did not normalize the ceramide level. These interesting observations raise a question about the role of ceramide and its relationship with apoptosis and oxidative stress in rat brain ischemia.
Acknowledgements: Supported by NIH grants NS‐40144, NS‐40810, NS‐22576, NS‐34741 and NS‐37766.
Ischemic cerebrovascular disease (stroke) is one of the leading causes of death and long‐term disability worldwide (or developing countries). The purpose of this study is to investigate the therapeutic potential of N‐acetyl cysteine (NAC), a precursor of glutathione, and a potent antioxidant, in tissue protection against transient focal cerebral ischemia model in rats. Our laboratory has already demonstrated the efficacy of NAC against induction of proinflammatory cytokines, iNOS, and production of NO in cultured cells. In this study, 250–300 g male Sprague–Dawley rats were subjected to 45 min of reversible focal cerebral ischemia through middle cerebral artery (MCA) occlusion. The protective effect of NAC is supported by reduced infarct volume as well as the suppression of TNF‐α and iNOS in the treated animals. Pretreatment with NAC reduced the infarct size by 49.6% as compared to the saline treated group along with reducing the neurological evaluation score by more than 50%. Our results suggest that preadministration of NAC attenuates focal cerebral ischemia by protecting cells against free radical damage.
Acknowledgements: Supported by NIH grants NS‐40144, NS‐40810, NS‐22576, NS‐34741 and NS‐37766.
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