One of the consequences of cytokine-orchestrated inflammation after CNS trauma is apoptosis. Our hypothesis is that cell death in the spinal cord after injury results in part from increased synthesis and release of IL-1beta. Using a ribonuclease protection assay, we demonstrated that there is increased transient expression of IL-1beta mRNA and, by using IL-1beta protein ELISA assay, that there are increased IL-1beta protein levels in the contused rat spinal cord, initially localized to the impact region of the spinal cord (segment T8). Using an ELISA cell death assay, we showed that there is apoptosis in the spinal cord 72 h after injury, a finding that was confirmed by measuring caspase-3 activity, which also significantly increased at the site of injury 72 h after trauma. Treatment of the contused spinal cord at the site of injury with the IL-1 receptor antagonist (rmIL-lra, 750 ng/mL) for 72 h using an osmotic minipump completely abolished the increases in contusion-induced apoptosis and caspase-3 activity.
Ye Y, Martinez JD, Perez-Polo RJ, Lin Y, Uretsky BF, Birnbaum Y. The role of eNOS, iNOS, and NF-B in upregulation and activation of cyclooxygenase-2 and infarct size reduction by atorvastatin. Am J Physiol Heart Circ Physiol 295: H343-H351, 2008. First published May 9, 2008 doi:10.1152/ajpheart.01350.2007.-Pretreatment with atorvastatin (ATV) reduces infarct size (IS) and increases myocardial expression of phosphorylated endothelial nitric oxide synthase (p-eNOS), inducible NOS (iNOS), and cyclooxygenase-2 (COX2) in the rat. Inhibiting COX2 abolished the ATV-induced IS limitation without affecting p-eNOS and iNOS expression. We investigated 1) whether 3-day ATV pretreatment limits IS in eNOS Ϫ/Ϫ and iNOS Ϫ/Ϫ mice and 2) whether COX2 expression and/or activation by ATV is eNOS, iNOS, and/or NF-B dependent. Male C57BL/6 wild-type (WT), University of North Carolina eNOS Ϫ/Ϫ and iNOS Ϫ/Ϫ mice received ATV (10 mg ⅐ kg Ϫ1 ⅐ day Ϫ1 ; ATV ϩ ) or water alone (ATV Ϫ ) for 3 days. Mice underwent 30 min of coronary artery occlusion and 4 h of reperfusion, or hearts were harvested and subjected to ELISA, immunoblotting, biotin switch, and electrophoretic mobility shift assay. As a result, ATV reduced IS only in the WT mice. ATV increased eNOS, p-eNOS, iNOS, and COX2 levels and activated NF-B in WT mice. It also increased myocardial COX2 activity. In eNOS Ϫ/Ϫ mice, ATV increased COX2 expression but not COX2 activity or iNOS expression. NF-B was not activated by ATV in the eNOS Ϫ/Ϫ mice. In the iNOS Ϫ/Ϫ mice, eNOS and p-eNOS levels were increased but not iNOS and COX2 levels; however, NF-B was activated. In conclusion, both eNOS and iNOS are essential for the IS-limiting effect of ATV. The expression of COX2 by ATV is iNOS, but not eNOS or NF-B, dependent. Activation of COX2 is dependent on iNOS. endothelial nitric oxide synthase; inducible nitric oxide synthase; nuclear factor-B THE 3-HYDROXY-3-METHYLGLUTARYL coenzyme A (HMG-CoA) reductase inhibitors (statins) protect against ischemia-reperfusion injury and, when administered before ischemia (2, 5, 7, 25, 26, 34 -36, 43, 44, 46 -48, 52, 53) or immediately upon reperfusion (4, 17, 47), limit myocardial infarct size (IS) in various animal models. Several investigators have shown that the activation of endothelial nitric oxide synthase (eNOS) is essential for this protective effect, since nonspecific nitric oxide synthase (NOS) inhibitors blunt the IS-limiting effect of statins (5, 48) and since statins do not reduce IS in eNOS Ϫ/Ϫ mice (1, 4, 18, 25, 52). However, most of these studies used a particular eNOS Ϫ/Ϫ line (Harvard). As reported by Sharp et al. (37), there are two distinct lines of eNOS Ϫ/Ϫ mice: the Harvard line lacks compensatory increases in inducible NOS (iNOS) and has an IS bigger than the corresponding wild-type (WT) mice, and the University of North Carolina line, which has compensatory increases in iNOS expression and an IS smaller than the corresponding WT mice. It has been suggested that iNOS can be protective and compensate for the lack in eNOS and that ...
Approximately 75% of traumatic brain injuries (TBI) are classified mild (mTBI). Despite the high frequency of mTBI, it is the least well studied. The prevalence of mTBI among service personnel returning from Operations Iraqi Freedom (OIF) and Enduring Freedom (OEF) and the recent reports of an association between repeated mTBI and the early onset of Alzheimer's and other types of dementias in retired athletes has focused much attention on mTBI. The study of mTBI requires the development and validation of experimental models and one of the most basic requirements for an experimental model is that it replicates important features of the injury or disease in humans. mTBI in humans is associated with acute symptoms such as loss of consciousness and pre- and/or posttraumatic amnesia. In addition, many mTBI patients experience long-term effects of mTBI, including deficits in speed of information processing, attention and concentration, memory acquisition, retention and retrieval, and reasoning and decision-making. Although methods for the diagnosis and evaluation of the acute and chronic effects of mTBI in humans are well established, the same is not the case for rodents, the most widely used animal for TBI studies. Despite the magnitude of the difficulties associated with adapting these methods for experimental mTBI research, they must be surmounted. The identification and testing of treatments for mTBI depends of the development, characterization and validation of reproducible, clinically relevant models of mTBI.
The b-site amyloid precursor protein-cleaving enzyme 1 (BACE1) is a prerequisite for the generation of b-amyloid peptides, the principle constituents of senile plaques in the brains of patients with Alzheimer's disease (AD). BACE1 expression and enzymatic activity are increased in the AD brain, but the regulatory mechanisms of BACE1 expression are largely unknown. Here we show that Yin Yang 1 (YY1), a highly conserved and multifunctional transcription factor, binds to its putative recognition sequence within the BACE1 promoter and stimulates BACE1 promoter activity in rat pheochromocytoma 12 (PC12) cells, rat primary neurones and astrocytes. In rat brain YY1 and BACE1 are widely expressed by neurons, but there was only a minor proportion of neurones that co-expressed YY1 and BACE1, suggesting that YY1 is not required for constitutive neuronal BACE1 expression. Resting astrocytes in the untreated rat brain did not display either YY1 or BACE1 immunoreactivity. When chronically activated, however, astrocytes expressed both YY1 and BACE1 proteins, indicating that YY1 is important for the stimulated BACE1 expression by reactive astrocytes. This is further emphasized by the expression of YY1 and BACE1 by reactive astrocytes in proximity to b-amyloid plaques in the AD brain. Our observations suggest that interfering with expression, translocation or binding of YY1 to its BACE1 promoterspecific sequence may have therapeutic potential for treating patients with AD.
Free radicals are generated in the CNS by ongoing oxygen metabolism and biological events associated with injury and inflammation. Increased free radical levels may also persist in some chronic neurological diseases and in the aged. Nerve growth factor (NGF) is a member of the neurotrophin family of proteins that can regulate neuronal development, maintenance, and recovery from injury. NGF protected rat pheochromocytoma PC12 cells, an adrenal chromaffin-like NGF-responsive cell line, from the oxidant stress accompanying hydrogen peroxide treatment by stimulating GSH levels and enzymes in the GSH metabolism cycle and in the GSH/GSH peroxidase antioxidant redox system, a ubiquitous cellular antioxidant system. Specifically, NGF increased gamma-glutamylcysteine synthetase (GCS) activity, the rate-limiting enzyme for GSH synthesis, by 50% after 9 h and GSH levels by 100% after 24 h of treatment. NGF stimulated GSH peroxidase by 30% after 3 days and glucose 6-phosphate dehydrogenase by 50% after 2 days. Treatment with NGF and cycloheximide, or actinomycin D, which inhibit protein and RNA synthesis, respectively, blocked the NGF stimulation of GCS and glucose 6-phosphate dehydrogenase. Increased GSH levels due to NGF treatment were responsible for the significant protection of PC12 cells from hydrogen peroxide-induced stress. Pretreatment of PC12 cells with NGF for 24 h rescued cells from the toxic effects of the extracellular hydrogen peroxide generated by the glucose/glucose oxidase system but did not rescue cells that were subjected to GSH deprivation due to treatment with 10 microM L-buthionine-(S,R)-sulfoximine, an inhibitor of GCS.(ABSTRACT TRUNCATED AT 250 WORDS)
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