cytochrome-c-t and Encephalitis

Topics: 8-Hydroxy-2'-Deoxyguanosine; Acute Disease; Biomarkers; Child; Cytochromes c; Deoxyguanosine; Electroencephalography; Encephalitis; Humans; Interleukin-6; Monitoring, Physiologic; Mutation; NAV1.2 Voltage-Gated Sodium Channel; Nerve Growth Factors; Phosphopyruvate Hydratase; Prognosis; Research; S100 Calcium Binding Protein beta Subunit; Voltage-Gated Sodium Channel beta-1 Subunit

Alzheimer's disease (AD) is a neurodegenerative disorder featured by deposition of beta-amyloid (Aβ) plaques in the hippocampus and associated cortices and progressive cognitive decline. Tropisetron, a selective 5-HT3 receptor antagonist, is conventionally used to counteract chemotherapy-induced emesis. Recent investigations describe antiphlogistic properties for tropisetron. It has been shown that tropisetron protects against rat embolic stroke. We investigated protective properties of tropisetron in a beta-amyloid (Aβ) rat model of AD and possible involvement of 5-HT3 receptors.. Aβ (1-42) was injected into the hippocampus of male rats. Animals were treated intracerebroventricularly with tropisetron, mCPBG (selective 5-HT3 receptor agonist) or mCPBG plus tropisetron on days 1, 3, 5 and 7. Seven days following Aβ administration, inflammatory markers (TNF-α, COX-2, iNOS and NF-κB), apoptotic markers (caspase 3 cytochrome c release) and calcineurin phosphatase activity were assessed in hippocampus.. Seven days following Aβ inoculation, control animals displayed dramatic increase in TNF-α, COX-2, iNOS, NF-κB, active caspase 3, cytochrome c release and calcineurin phosphatase activity in the hippocampus. Tropisetron significantly diminished the elevated levels of these markers and reversed the cognitive deficit. Interestingly, tropisetron was also found to be a potent inhibitor of calcineurin phosphatase activity. The selective 5-HT3 receptor agonist mCPBG, when co-administered with tropisetron, completely reversed the procognitive and anti-apoptotic properties of tropisetron while it could only partially counteract the anti-inflammatory effects. mCPBG alone significantly aggravated Aβ-induced injury.. Our findings indicate that tropisetron protects against Aβ-induced neurotoxicity in vivo through both 5-HT3 receptor-dependent and independent pathways.

Topics: Alzheimer Disease; Amyloid beta-Peptides; Animals; Apoptosis; Calcineurin; Cyclooxygenase 2; Cytochromes c; Encephalitis; Hippocampus; Indoles; Male; Maze Learning; NF-kappa B; Nitric Oxide Synthase Type II; Nitrites; Rats; Rats, Wistar; Serotonin 5-HT3 Receptor Antagonists; Tropisetron; Tumor Necrosis Factor-alpha

Traumatic brain injury (TBI) causes massive brain damage. However, the secondary injury and temporal sequence of events with multiple mechanisms after the insult has not been elucidated. Here, we examined the occurrence of apoptosis and a causal relationship between inflammation and apoptosis in the TBI brain. Following a lateral moderate fluid percussion injury model of TBI in adult rats, microarray analyses detected apparent changes in the expression levels of apoptosis-related genes which revealed time-dependent expression patterns for 23 genes in the lateral cortex. The upregulated 23 genes included inflammatory cytokines such as interleukin 1 (IL-1) α, IL-1β, and tumor necrotic factor (TNF) which immediately increased at 3 h following the injury. Time-dependent gene expression profile analyses showed that apoptosis was subsequently induced following inflammation. These results taken together suggested changes in expression of apoptosis-related genes may be associated with inflammatory response. Accompanying this surge of cell death genes after TBI was a neurostructural pathologic hallmark of apoptosis characterized by leakage of cytochrome c into cytoplasm, DNA fragmentation and apoptotic cells in the lateral cortex of the impacted hemisphere. Caspase-3 positive cells in the TBI brain were initially sporadic after 3 h, but these apoptotic cells subsequently increased and populated the cerebral cortex at 6 and 12 h, and gradually reached a plateau by 48 h. Interestingly, the expression profile of CD68 macrophage labeled cells closely resembled that of apoptotic cells after TBI, including the role of inflammatory signaling pathway in the progression of apoptotic cell death. These results taken together suggest that TBI induced upregulation of apoptosis-related genes, concomitant with the detection of apoptotic brain pathology during the 3-48 h post-injury period, which may be likely mediated by inflammation. Therapies designed at abrogating apoptosis and/or inflammation may prove effective when initiated at this subacute TBI phase.

Topics: Animals; Antigens, CD; Antigens, Differentiation, Myelomonocytic; Apoptosis; Brain Injuries; Caspase 3; Cerebral Cortex; Cytochromes c; Cytokines; Disease Models, Animal; Encephalitis; Gene Expression Profiling; Gene Expression Regulation; In Situ Nick-End Labeling; Male; Oligonucleotide Array Sequence Analysis; Percussion; Phosphopyruvate Hydratase; Rats; Rats, Wistar; Time Factors

Intracerebral hemorrhage (ICH) remains a major medical problem and currently has no effective treatment. Hemorrhaged blood is highly toxic to the brain, and catabolism of the pro-oxidant heme, mainly released from hemoglobin, is critical for the resolution of hematoma after ICH. The degradation of the pro-oxidant heme is controlled by heme oxygenase (HO). We have previously reported a neuroprotective role for HO2 in early brain injury after ICH; however, in vivo data that specifically address the role of HO2 in brain edema and neuroinflammation after ICH are absent. Here, we tested the hypothesis that HO2 deletion would exacerbate ICH-induced brain edema, neuroinflammation, and oxidative damage. We subjected wild-type (WT) and HO2 knockout ((-/-)) mice to the collagenase-induced ICH model. Interestingly, HO2(-/-) mice had enhanced brain swelling and neuronal death, although HO2 deletion did not increase collagenase-induced bleeding; the exacerbation of brain injury in HO2(-/-) mice was also associated with increases in neutrophil infiltration, microglial/macrophage and astrocyte activation, DNA damage, peroxynitrite production, and cytochrome c immunoreactivity. In addition, we found that hemispheric enlargement was more sensitive than brain water content in the detection of subtle changes in brain edema formation in this model. Combined, these novel findings extend our previous observations and demonstrate that HO2 deficiency increases brain swelling, neuroinflammation, and oxidative damage. The results provide additional evidence that HO2 plays a critical protective role against ICH-induced early brain injury.

Topics: Analysis of Variance; Animals; Brain Edema; Calcium-Binding Proteins; Cerebral Hemorrhage; Cytochromes c; Disease Models, Animal; Encephalitis; Fluoresceins; Functional Laterality; Glial Fibrillary Acidic Protein; Granulocyte Colony-Stimulating Factor; Heme Oxygenase (Decyclizing); Interleukin-3; Mice; Mice, Inbred C57BL; Mice, Knockout; Microfilament Proteins; Nerve Degeneration; Organic Chemicals; Recombinant Fusion Proteins; Recombinant Proteins; Spectrophotometry; Time Factors; Tyrosine

Inhibition of matrix metalloproteinase-9 (MMP-9) protects the adult brain after cerebral ischemia. However, the role of MMP-9 in the immature brain after hypoxia-ischemia (HI) is unknown. We exposed MMP-9(-/-) [MMP-9 knock-out (KO)] and wild-type (WT) mice to HI on postnatal day 9. HI was induced by unilateral ligation of the left carotid artery followed by hypoxia (10% O2; 36 degrees C). Gelatin zymography showed that MMP-9 activity was transiently increased at 24 h after HI in the ipsilateral hemisphere and MMP-9-positive cells were colocalized with activated microglia. Seven days after 50 min of HI, cerebral tissue volume loss was reduced in MMP-9 KO (21.8 +/- 1.7 mm3; n = 22) compared with WT (32.3 +/- 2.1 mm3; n = 22; p < 0.001) pups, and loss of white-matter components was reduced in MMP-9 KO compared with WT pups (neurofilament: WT, 50.9 +/- 5.4%; KO, 18.4 +/- 3.1%; p < 0.0001; myelin basic protein: WT, 57.5 +/- 5.8%; KO, 23.2 +/- 3.5%; p = 0.0001). The neuropathological changes were associated with a delayed and diminished leakage of the blood-brain barrier (BBB) and a decrease in inflammation in MMP-9-deficient animals. In contrast, the neuroprotective effects after HI in MMP-9-deficient animals were not linked to either caspase-dependent (caspase-3 and cytochrome c) or caspase-independent (apoptosis-inducing factor) processes. This study demonstrates that excessive activation of MMP-9 is deleterious to the immature brain, which is associated with the degree of BBB leakage and inflammation. In contrast, apoptosis does not appear to be a major contributing factor.

Topics: Animals; Animals, Newborn; Apoptosis Inducing Factor; Blood-Brain Barrier; Brain; Brain Infarction; Caspase 3; Cell Death; Cytochromes c; Encephalitis; Gene Expression Regulation, Developmental; Hypoxia-Ischemia, Brain; Immunohistochemistry; Indoles; Matrix Metalloproteinase 9; Mice; Mice, Inbred C57BL; Mice, Knockout; Myelin Basic Protein; Neurofilament Proteins; Reverse Transcriptase Polymerase Chain Reaction; RNA, Messenger; Statistics, Nonparametric; Time Factors

To evaluate the prognostic predictive values of cytochrome c, cytokines, and other laboratory measurements in serum collected during neurological onset in acute encephalopathy with multiple organ failure.. In addition to general laboratory examinations, the concentrations of cytochrome c (apoptosis marker) and cytokines (inflammatory markers) were measured in serum samples collected at the initial phase in 29 patients with acute encephalopathy. The obtained values were evaluated as predictors for the development of severe encephalopathy.. Cytochrome c, tumour necrosis factor alpha (TNF-alpha), interleukin 6 (IL-6), soluble TNF-receptor 1 (sTNF-R1), and aspartate aminotransferase (AST) concentrations at the initial phase were high and correlated well with patient outcome. High concentrations of serum cytochrome c (>45 ng/ml), sTNF-R1 (>2000 pg/ml), AST (>58 IU/dl), IL-6 (>60 pg/ml), and TNF-alpha (>15 pg/ml) predicted an unfavourable prognosis (sequelae and death) at 93%, 79%, 82%, 77%, and 60%, respectively. The specificity of those markers was 100%, 89%, 83%, 100%, and 100%, respectively.. Serum cytochrome c is the most sensitive and specific predictor for the development of severe encephalopathy at the initial phase. Results suggest that this marker might be used to guide decisions regarding the start of the initial treatment and further intensive care.

Topics: Acute Disease; Area Under Curve; Aspartate Aminotransferases; Biomarkers; Brain Edema; Child; Child, Preschool; Critical Care; Cytochromes c; Cytokines; Encephalitis; Female; Humans; Infant; Interleukin-6; Male; Multiple Organ Failure; Prognosis; Receptors, Tumor Necrosis Factor; ROC Curve; Sensitivity and Specificity; Tumor Necrosis Factor-alpha