BACKGROUND: Severe hyperbilirubinemia is toxic during central nervous system development. Prolonged and uncontrolled high levels of unconjugated bilirubin lead to bilirubin-induced neurological damage and eventually death by kernicterus. Bilirubin neurotoxicity is characterized by a wide array of neurological deficits, including irreversible abnormalities in motor, sensitive and cognitive functions, due to bilirubin accumulation in the brain. Despite the abundant literature documenting the in vitro and in vivo toxic effects of bilirubin, it is unclear which molecular and cellular events actually characterize bilirubin-induced neurodegeneration in vivo. METHODS: We used a mouse model of neonatal hyperbilirubinemia to temporally and spatially define the response of the developing cerebellum to the bilirubin insult. RESULTS: We showed that the exposure of developing cerebellum to sustained bilirubin levels induces the activation of oxidative stress, ER stress and inflammatory markers at the early stages of the disease onset. In particular, we identified TNFα and NFKβ as key mediators of bilirubin-induced inflammatory response. Moreover, we reported that M1 type microglia is increasingly activated during disease progression. Failure to counteract this overwhelming stress condition resulted in the induction of the apoptotic pathway and the generation of the glial scar. Finally, bilirubin induced the autophagy pathway in the stages preceding death of the animals. CONCLUSIONS: This study demonstrates that inflammation is a key contributor to bilirubin damage that cooperates with ER stress in the onset of neurotoxicity. Pharmacological modulation of the inflammatory pathway may be a potential intervention target to ameliorate neonatal lethality in Ugt1-/-mice.
- MeSH
- degenerace nervu etiologie metabolismus patologie MeSH
- glukuronosyltransferasa nedostatek MeSH
- modely nemocí na zvířatech MeSH
- mozeček patologie MeSH
- myši knockoutované MeSH
- myši MeSH
- novorozená zvířata MeSH
- novorozenecká hyperbilirubinemie komplikace patologie MeSH
- zánět etiologie metabolismus patologie MeSH
- zvířata MeSH
- Check Tag
- myši MeSH
- zvířata MeSH
- Publikační typ
- časopisecké články MeSH
BACKGROUND AND PURPOSE: The aim of this prospective study is to evaluate post-whole brain radiotherapy (WBRT) changes in hippocampal concentration of N-acetylaspartate (h-tNAA) as a marker of neuronal loss and to correlate those changes to neurocognitive function. MATERIAL AND METHODS: Thirty-five patients with brain metastases underwent baseline single slice multi-voxel MR spectroscopy (MRS) examination for measurement of hippocampal h-tNAA together with baseline battery of neurocognitive tests focused on memory (Auditory Verbal Learning Test and Brief Visuospatial Memory Test - Revised) as well as quality of life questionnaires (EORTC QLQ-C30 a EORTC QLQ-BN20). Eighteen patients completed follow-up evaluation four months after standard WBRT (2 laterolateral fields, 10×3.0Gy, 6MV photons) and were included in this analysis. MRS and cognitive examinations were repeated and compared to baseline measurements. RESULTS: Statistically significant decreases in h-tNAA were observed in the right (8.52-7.42mM; -12.9%, 95%CI: -7.6 to -16.4%) as well as in the left hippocampus (8.64-7.60mM; -12%, 95%CI: -7.9 to -16.2%). Statistically significant decline was observed in all AVLT and BVMT-R subtests with exception of AVLT_Recognition. Quality of life declined after WBRT (mean Δ -14.1±20.3 points in transformed 0-100 point scale; p=0.018) with no correlation to changes in hippocampal metabolite concentrations. Moderate positive correlation was observed between left h-tNAA concentration decrease and AVLT_TR decline (r=+0.32; p=0.24) as well as with AVLT_DR (r=+0.33; p=0.22) decline. Changes in right h-tNAA/Cr negatively correlated with AVLT_DR (r=-0.48; p=0.061). No correlation between right hippocampus h-tNAA and memory decline (AVLT) was observed. CONCLUSIONS: Our results suggest hippocampal NAA concentrations decline after WBRT and MRS may be a useful biomarker for monitoring neuronal loss after radiotherapy.
- MeSH
- biologické markery metabolismus MeSH
- degenerace nervu etiologie metabolismus MeSH
- hipokampus diagnostické zobrazování metabolismus účinky záření MeSH
- kognitivní dysfunkce etiologie metabolismus MeSH
- kraniální ozáření škodlivé účinky MeSH
- kvalita života MeSH
- kyselina aspartová analogy a deriváty metabolismus MeSH
- lidé středního věku MeSH
- lidé MeSH
- magnetická rezonanční spektroskopie metody MeSH
- nádory mozku radioterapie sekundární MeSH
- následné studie MeSH
- neuropsychologické testy MeSH
- paměť účinky záření MeSH
- prospektivní studie MeSH
- průzkumy a dotazníky MeSH
- Check Tag
- lidé středního věku MeSH
- lidé MeSH
- mužské pohlaví MeSH
- ženské pohlaví MeSH
- Publikační typ
- časopisecké články MeSH
- práce podpořená grantem MeSH
Excessive stimulation of NMDA receptors with glutamate or other potent agonists such as NMDA leads to excitotoxicity and neural injury. In this study, we aimed to provide insight into an animal model of brain excitotoxic damage; single unilateral infusion of NMDA at mild dose into the hippocampal formation. NMDA infusion induced chronic, focal neurodegeneration in the proximity of the injection site. The lesion was accompanied by severe and progressive neuroinflammation and affected preferentially principal neurons while sparing GABAergic interneurons. Furthermore, the unilateral lesion did not cause significant impairment of spatial learning abilities. Finally, GluN1 and GluN2B subunits of NMDA receptor were significantly upregulated up to 3 days after the NMDA infusion, while GABAA α5 subunit was downregulated at 30 days after the lesion. Taken together, a single infusion of NMDA into the hippocampal formation represents an animal model of excitotoxicity-induced chronic neurodegeneration of principal neurons accompanied by severe neuroinflammation and subunit specific changes in NMDA and GABAA receptors.
- MeSH
- bludiště - učení účinky léků fyziologie MeSH
- degenerace nervu diagnostické zobrazování metabolismus patologie MeSH
- funkční lateralita MeSH
- hipokampus diagnostické zobrazování účinky léků metabolismus patologie MeSH
- modely nemocí na zvířatech MeSH
- N-methylaspartát aplikace a dávkování toxicita MeSH
- neurodegenerativní nemoci diagnostické zobrazování metabolismus patologie MeSH
- neuroimunomodulace fyziologie MeSH
- neurony účinky léků metabolismus patologie MeSH
- potkani Long-Evans MeSH
- receptory GABA-A metabolismus MeSH
- receptory N-methyl-D-aspartátu metabolismus MeSH
- zvířata MeSH
- Check Tag
- mužské pohlaví MeSH
- zvířata MeSH
- Publikační typ
- časopisecké články MeSH
Magnetic resonance imaging (MRI) enables a noninvasive in vivo quantification of iron in various organs. Several techniques have been developed that detect signal alterations derived mainly from the magnetic properties of ferritin and hemosiderin, the major iron storage compounds. High magnetic susceptibility of ferritin shortens the transversal relaxation time of nearby water protons and thus induces a focal signal extinction of iron-rich areas in T2-weighted (T2w) MRI. T2w tissue contrast is additionally influenced by other factors such as water content, myelin density, and the presence of other metals. Therefore, more specific methods are needed with higher specificity to iron. These in vivo techniques can be divided into three groups: relaxometry, magnetic field correlation imaging and phase-based contrast covering susceptibility-weighted imaging, and quantitative susceptibility mapping. The differential diagnosis of various neurological disorders is aided by characteristic patterns of iron depositions. Reliable estimates of cerebral tissue iron concentration are equally important in studying physiological age-related as well as pathological conditions in neurodegenerative, neuroinflammatory, and vascular diseases. In the future, monitoring changes in iron storage and content may serve as sensitive biomarker for diagnosis as well as treatment monitoring.
OBJECTIVES: Tacrine was the first acetylcholinesterase inhibitor approved for the treatment of Alzheimer disease. The compound is not available for therapeutic purposes as it was withdrawn due to hepatotoxicity of its metabolites. The hepatotoxicity can be decreased by alternative ways of drug administration avoiding thus the first pass effect. The present study is aimed to investigate the influence of intramuscularly administrated tacrine on oxidative stress. METHODS: Laboratory guinea pigs were exposed to tacrine at doses of 0-800 μg/kg. The animals were euthanized 1 and 24 hours after the exposure. Parameters such as ferric reducing antioxidant power (FRAP), thiobarbituric acid reactive substances (TBARS), carbonylated proteins, caspase 3 activity, superoxide dismutase activity and glutathione reductase activity were assessed in the frontal, temporal and occipital lobe, cerebellum, liver, spleen, heart, and kidney. Moreover, levels of glucose, total and HDL cholesterol forms, triglycerides, blood urea nitrogen, creatinine, total bilirubin, total protein, albumin and activities of aspartate aminotransferase, alanine aminotransferase, alkaline phosphatase and lactate dehydrogenase were assessed in plasma samples. RESULTS: Activities of the enzymatic markers, level of carbonylated proteins in organs and levels of biochemical markers in plasma were only slightly influenced by tacrine. Dose-dependent elevation of the FRAP value was recognized in the brain tissues and the liver. The TBARS value was increased in the kidney and heart 1 and 24 hours, respectively, after exposure. CONCLUSION: In the study, the effect of tacrine on markers of oxidative stress was proved. Possible positive effects of tacrine on the antioxidant defence in the brain tissue were discussed.
- MeSH
- Alzheimerova nemoc chemicky indukované metabolismus MeSH
- antioxidancia metabolismus MeSH
- cholinesterasové inhibitory toxicita MeSH
- degenerace nervu chemicky indukované metabolismus MeSH
- kaspasa 3 metabolismus MeSH
- látky reagující s kyselinou thiobarbiturovou metabolismus MeSH
- ledviny účinky léků metabolismus MeSH
- lékové postižení jater metabolismus MeSH
- modely nemocí na zvířatech MeSH
- morčata MeSH
- mozek účinky léků metabolismus MeSH
- myokard metabolismus MeSH
- oxidační stres účinky léků fyziologie MeSH
- srdce účinky léků MeSH
- takrin toxicita MeSH
- zvířata MeSH
- Check Tag
- morčata MeSH
- ženské pohlaví MeSH
- zvířata MeSH
- Publikační typ
- časopisecké články MeSH
We investigated the functional characteristics of pre- and postsynaptic cholinergic transmission in APPswe/PS1dE9 double transgenic mice at a young age (7-10 weeks) before the onset of amyloid plaque formation and at adult age (5-6 months) at its onset. We compared brain slices from cerebral cortex and hippocampus with amyloid deposits to slices from striatum with no amyloid plaques by 6 months of age. In young transgenic mice we found no impairments of preformed and newly synthesized [(3)H]-ACh release, indicating intact releasing machinery and release turnover, respectively. Adult transgenic mice displayed a significant increase in preformed [(3)H]-ACh release in cortex but a decrease in hippocampus and striatum. The extent of presynaptic muscarinic autoregulation was unchanged. Evoked release of newly synthesized [(3)H]-ACh was significantly reduced in the cortex and hippocampus but unchanged in the striatum. Carbachol-induced G-protein activation in cortical membranes displayed decreased potency but normal efficacy in adult animals and no changes in young animals. These results indicate that functional pre- and postsynaptic cholinergic deficits are not present in APPswe/PS1dE9 transgenic mice before 10 weeks of age, but develop along with beta-amyloid accumulation in the brain.
- MeSH
- acetylcholin nedostatek MeSH
- Alzheimerova nemoc genetika metabolismus patofyziologie MeSH
- amyloid metabolismus MeSH
- amyloidový prekurzorový protein beta genetika MeSH
- cholinergní agonisté farmakologie MeSH
- cholinergní vlákna metabolismus patologie MeSH
- degenerace nervu metabolismus patologie MeSH
- down regulace genetika MeSH
- hipokampus metabolismus patologie patofyziologie MeSH
- modely nemocí na zvířatech MeSH
- mozek - chemie genetika MeSH
- mozek růst a vývoj metabolismus patofyziologie MeSH
- mozková kůra růst a vývoj metabolismus patofyziologie MeSH
- myši transgenní MeSH
- myši MeSH
- orgánové kultury - kultivační techniky MeSH
- presenilin-1 genetika MeSH
- proteiny vázající GTP účinky léků genetika metabolismus MeSH
- receptory muskarinové metabolismus MeSH
- stárnutí metabolismus MeSH
- věkové faktory MeSH
- zvířata MeSH
- Check Tag
- myši MeSH
- ženské pohlaví MeSH
- zvířata MeSH
- Publikační typ
- časopisecké články MeSH
- práce podpořená grantem MeSH
Neuroprotective effects of estrogens and progesterone have been widely studied in various experimental models. The present study was designed to compare possible neuroprotective effects of 17alpha-estradiol, 17beta-estradiol, and progesterone on oxidative stress in rats subjected to global cerebral ischemia. Global cerebral ischemia was induced in ovariectomized female rats by four vessel occlusion for 10 min. Following 72 h of reperfusion, levels of malondialdehyde (MDA, oxidative stress marker), and reduced glutathione (GSH, major endogenous antioxidant) were assessed in hippocampus, striatum and cortex of rats treated with either 17alpha-estradiol, 17beta-estradiol, progesterone or estradiol + progesterone beforehand. Steroid administration ameliorated ischemia-induced decrease in GSH and increase in MDA levels. Our data offers additional evidence that estrogens and progesterone or combination of two exert a remarkable neuroprotective effect reducing oxidative stress.
- MeSH
- antioxidancia farmakologie MeSH
- časové faktory MeSH
- degenerace nervu etiologie metabolismus prevence a kontrola MeSH
- estradiol farmakologie MeSH
- financování organizované MeSH
- glutathion metabolismus MeSH
- ischemie mozku farmakoterapie komplikace metabolismus MeSH
- krysa rodu rattus MeSH
- malondialdehyd metabolismus MeSH
- modely nemocí na zvířatech MeSH
- mozek metabolismus účinky léků MeSH
- neuroprotektivní látky farmakologie MeSH
- ovarektomie MeSH
- oxidační stres účinky léků MeSH
- peroxidace lipidů účinky léků MeSH
- potkani Wistar MeSH
- progesteron farmakologie MeSH
- zvířata MeSH
- Check Tag
- krysa rodu rattus MeSH
- ženské pohlaví MeSH
- zvířata MeSH
OBJECTIVES: In contrast to peripheral nerves, central neurons do not regrow spontaneously after injury. Our previous studies showed that transplantation of degenerating peripheral nerves or their extracts can induce regeneration in the injured central nervous system. Non-predegenerated nerves show much weaker neurotrophic activity. The aim of the present work was to examine quantitatively and qualitatively the protein composition of rat sciatic nerve extracts. MATERIAL AND METHODS: The experiments were carried out on male Wistar C rats. Distal fragments were collected immediately after transection or after 7 day-long predegeneration. The nerves were homogenized, centrifuged and ultracetrifuged. Extracts were analyzed by means of two-dimensional electrophoresis. RESULTS: The two-dimensional electrophoresis showed 69 protein subfractions with isoelectric points ranging from 4.2 to 7.0 pH and molecular weight ranging from 13.5 kDa to 335.4 kDa in extracts obtained from nonpredegenerated nerves. In predegenerated nerve extracts 114 subfractions with isoelectric points ranging from 4.2 to 7.4 pH and molecular weight from 21.1 kDa to 335.4 kDa were found. Fractions: 25.5 kDa, 31.6 kDa, 36 kDa, 38.4 kDa, 42.4 kDa, 46.6 kDa, and 50.5 kDa showed significant increase and two fractions: 68.5 kDa and 335.4 kDa demonstrated significant decrease in the number of subfractions in predegenerated nerves. Fractions 160.8 kDa, 236.1 kDa, and 5 fractions below 21.1 kDa were present only in extracts from non-predegenerated nerves. CONCLUSIONS: In conclusion, the results of our study demonstrate that the most intense changes in protein composition in degenerating nerves take place in low molecular weight fractions.
- MeSH
- degenerace nervu etiologie metabolismus patologie MeSH
- finanční podpora výzkumu jako téma MeSH
- imunohistochemie metody MeSH
- králíci MeSH
- modely nemocí na zvířatech MeSH
- mozková hypoxie a ischemie patologie MeSH
- reperfuze MeSH
- ubichinon farmakologie MeSH
- zvířata MeSH
- Check Tag
- králíci MeSH
- zvířata MeSH
- MeSH
- degenerace nervu metabolismus patologie MeSH
- finanční podpora výzkumu jako téma MeSH
- ischemie mozku metabolismus patofyziologie patologie MeSH
- mozkový infarkt metabolismus patofyziologie patologie MeSH
- přivykání k ischémii MeSH
- pyramidové buňky metabolismus patologie MeSH
- železo metabolismus MeSH
- zvířata MeSH
- Check Tag
- zvířata MeSH
