Brain research
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The present study aimed to evaluate the therapeutic potential of apocynin, an NADPH oxidase assembly inhibitor, on traumatic brain injury. Rat traumatic brain injury (TBI) was performed using a weight drop model. Apocynin (100mg/kg) was injected into the intraperitoneal space 15 min before TBI. ⋯ This pre-treatment with apocynin decreased the blood-brain barrier disruption, the number of degenerating neurons in the hippocampal CA3 region and microglial activation after TBI. The present study indicates that apocynin pre-treatment prevents TBI-induced ROS production, thus decreasing BBB disruption, neuronal death and microglial activation. Therefore, the present study suggests that inhibition of NADPH oxidase by apocynin may have a high therapeutic potential to reduce traumatic brain injury-induced neuronal death.
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Cocaine and amphetamine regulated transcript (CART) mRNA and peptides are highly expressed in the paraventricular (PVN), dorsomedial (DMH) and arcuate (ARC) nuclei of the hypothalamus. It has been suggested that these nuclei regulate the hypothalamic-pituitary-adrenal (HPA) axis, autonomic nervous system activity, and feeding behavior. Our previous studies showed that forced swim stress augmented CART peptide expression significantly in whole hypothalamus of male rats. ⋯ In male rats, forced swim stress upregulated CART mRNA expression in DMH and downregulated it in the ARC. In female rats, forced swim stress increased CART mRNA expression in PVN and DMH, whereas a decrease was observed in the ARC nucleus. Our results show that forced swim stress elicits region- and sex-specific changes in CART mRNA expression in rat hypothalamus that may help in explaining some of the effects of stress.
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Previous studies using animal models of cognitive aging showed that hypothalamic-pituitary-adrenal (HPA) responses to stress are impaired and glucocorticoid receptor (GR) mRNA is decreased in cognitively impaired aged rats, compared with those in young rats and cognitively unimpaired aged rats. Increased HPA activity is associated with the loss of hippocampal corticosteroid receptors. In the current investigation, GR expressions in the hippocampus were examined in young and aged male Long-Evans rats whose spatial memory was initially assessed on the Morris water maze task. ⋯ In the hippocampus of aged rats with spatial memory impairments, GR protein level was decreased in the nucleus but not in the cytosol, and levels of glucocorticoid response elements binding activity was decreased. These results suggest that GR signaling is impaired in the hippocampus of rats with cognitive impairment. Impaired GR signaling may contribute to HPA axis dysfunction in aged rats and aged humans with cognitive impairment.
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Ketamine, an N-methyl-d-aspartate (NMDA) receptor antagonist, is widely used as a general pediatric anesthetic. Recent studies suggest that ketamine enhances neuronal apoptosis in developing rodents and nonhuman primates. The main goal of this study is to determine whether ketamine causes hippocampal neurodegeneration and behavioral deficits in adulthood, and if so, whether the effects of ketamine are associated with protein kinase C-gamma (PKCγ), extracellular signal regulated kinase (ERK)1/2 and Bcl-2 expression. ⋯ Ketamine administered to the developing brains of P7 rats at a dose of 75mg/kg caused learning and memory impairments in adulthood. Therefore, these data demonstrate that ketamine at a dose of 75mg/kg in the developing brain results in hippocampal neurodegeneration and persistent learning and memory impairment, which is associated with the PKCγ-ERK signaling pathway. This article is part of a Special Issue entitled: Brain Integration.
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Although the risk factor for harboring the apolipoprotein E4 (apoE4) allele in late-onset Alzheimer's disease (AD) is well known, the mechanism by which apoE4 contributes to AD pathogenesis has yet to be clarified. Preferential cleavage of the ApoE4 isoform relative to other polymorphic forms appears to be significant, as the resulting fragments are associated with hallmarks of AD. To examine the possible role of apoE4 proteolysis in AD, we designed a site-directed antibody directed at position D172, which would yield a predicted amino-terminal fragment previously identified in AD brain extracts. ⋯ Mass spectrometry confirmed the identity of this 18kDa fragment as being an amino-terminal fragment of apoE4. Immunohistochemical experiments indicated the nApoE4CF Ab specifically labeled neurofibrillary tangles (NFTs) in AD frontal cortex sections that colocalized with the mature tangle marker PHF-1. Taken together, these results suggest a novel cleavage event of apoE4, generating an amino-terminal fragment that localizes within NFTs of the AD brain.