The identification and quantification of mitochondrial effects of novel antipsychotics (brexpiprazole, cariprazine, loxapine, and lurasidone) were studied in vitro in pig brain mitochondria. Selected parameters of mitochondrial metabolism, electron transport chain (ETC) complexes, citrate synthase (CS), malate dehydrogenase (MDH), monoamine oxidase (MAO), mitochondrial respiration, and total ATP and reactive oxygen species (ROS) production were evaluated and associated with possible adverse effects of drugs. All tested antipsychotics decreased the ETC activities (except for complex IV, which increased in activity after brexpiprazole and loxapine addition). Both complex I- and complex II-linked respiration were dose-dependently inhibited, and significant correlations were found between complex I-linked respiration and both complex I activity (positive correlation) and complex IV activity (negative correlation). All drugs significantly decreased mitochondrial ATP production at higher concentrations. Hydrogen peroxide production was significantly increased at 10 μM brexpiprazole and lurasidone and at 100 μM cariprazine and loxapine. All antipsychotics acted as partial inhibitors of MAO-A, brexpiprazole and loxapine partially inhibited MAO-B. Based on our results, novel antipsychotics probably lacked oxygen uncoupling properties. The mitochondrial effects of novel antipsychotics might contribute on their adverse effects, which are mostly related to decreased ATP production and increased ROS production, while MAO-A inhibition might contribute to their antidepressant effect, and brexpiprazole- and loxapine-induced MAO-B inhibition might likely promote neuroplasticity and neuroprotection. The assessment of drug-induced mitochondrial dysfunctions is important in development of new drugs as well as in the understanding of molecular mechanism of adverse or side drug effects.

• MeSH
• adenosintrifosfát biosyntéza   MeSH
• antipsychotika klasifikace   farmakologie   MeSH
• chinolony farmakologie   MeSH
• elektronový transportní řetězec účinky léků   MeSH
• energetický metabolismus účinky léků   MeSH
• inhibitory MAO farmakologie   MeSH
• loxapin farmakologie   MeSH
• lurasidon hydrochlorid farmakologie   MeSH
• mitochondrie účinky léků   metabolismus   MeSH
• peroxid vodíku metabolismus   MeSH
• piperaziny farmakologie   MeSH
• prasata MeSH
• reaktivní formy kyslíku metabolismus   MeSH
• receptory neurotransmiterů účinky léků   MeSH
• spotřeba kyslíku účinky léků   MeSH
• thiofeny farmakologie   MeSH
• zvířata MeSH
• Check Tag
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH

Alzheimer's disease (AD) and sporadic Creutzfeldt-Jakob disease (sCJD) are both characterized by extracellular pathologically conformed aggregates of amyloid proteins-amyloid β-protein (Aβ) and prion protein (PrPSc), respectively. To investigate the potential morphological colocalization of Aβ and PrPSc aggregates, we examined the hippocampal regions (archicortex and neocortex) of 20 subjects with confirmed comorbid AD and sCJD using neurohistopathological analyses, immunohistochemical methods, and confocal fluorescent microscopy. Our data showed that extracellular Aβ and PrPSc aggregates tended to be, in most cases, located separately, and "compound" plaques were relatively rare. We observed PrPSc plaque-like structures in the periphery of the non-compact parts of Aβ plaques, as well as in tau protein-positive dystrophic structures. The AD ABC score according to the NIA-Alzheimer's association guidelines, and prion protein subtype with codon 129 methionine-valine (M/V) polymorphisms in sCJD, while representing key characteristics of these diseases, did not correlate with the morphology of the Aβ/PrPSc co-aggregates. However, our data showed that PrPSc aggregation could dominate during co-aggregation with non-compact Aβ in the periphery of Aβ plaques.

• MeSH
• Alzheimerova nemoc patologie   MeSH
• amyloidní beta-protein genetika   metabolismus   MeSH
• amyloidní plaky patologie   MeSH
• Creutzfeldtova-Jakobova nemoc patologie   MeSH
• extracelulární prostor chemie   MeSH
• jednonukleotidový polymorfismus genetika   MeSH
• kodon genetika   MeSH
• komorbidita MeSH
• lidé středního věku MeSH
• lidé MeSH
• mozek patologie   MeSH
• neurony patologie   MeSH
• pilotní projekty MeSH
• proteinové agregáty * MeSH
• proteiny tau metabolismus   MeSH
• PrPSc proteiny genetika   metabolismus   MeSH
• senioři nad 80 let MeSH
• senioři MeSH
• Check Tag
• lidé středního věku MeSH
• lidé MeSH
• mužské pohlaví MeSH
• senioři nad 80 let MeSH
• senioři MeSH
• ženské pohlaví MeSH
• Publikační typ
• časopisecké články MeSH

Flavonoids are common plant natural products able to suppress ROS-related damage and alleviate oxidative stress. One of key mechanisms, involved in this phenomenon is chelation of transition metal ions. From a physiological perspective, iron is the most significant transition metal, because of its abundance in living organisms and ubiquitous involvement in redox processes. The chemical, pharmaceutical, and biological properties of flavonoids can be significantly affected by their interaction with transition metal ions, mainly iron. In this review, we explain the interaction of various flavonoid structures with Fe(II) and Fe(III) ions and critically discuss the influence of chelated ions on the flavonoid biochemical properties. In addition, specific biological effects of their iron metallocomplexes, such as the inhibition of iron-containing enzymes, have been included in this review.

• MeSH
• antioxidancia chemie   farmakologie   MeSH
• chelátory chemie   farmakologie   MeSH
• flavonoidy chemie   MeSH
• hem chemie   MeSH
• ionty chemie   metabolismus   MeSH
• komplexní sloučeniny chemie   MeSH
• lidé MeSH
• molekulární struktura MeSH
• vazba proteinů MeSH
• vztahy mezi strukturou a aktivitou MeSH
• železo chemie   MeSH
• zvířata MeSH
• Check Tag
• lidé MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH
• přehledy MeSH

Neurodegenerative diseases are characterized by the deposition of specific protein aggregates, both intracellularly and/or extracellularly, depending on the type of disease. The extracellular occurrence of tridimensional structures formed by amyloidogenic proteins defines Alzheimer's disease, in which plaques are composed of amyloid β-protein, while in prionoses, the same term "amyloid" refers to the amyloid prion protein. In this review, we focused on providing a detailed didactic description and differentiation of diffuse, neuritic, and burnt-out plaques found in Alzheimer's disease and kuru-like, florid, multicentric, and neuritic plaques in human transmissible spongiform encephalopathies, followed by a systematic classification of the morphological similarities and differences between the extracellular amyloid deposits in these disorders. Both conditions are accompanied by the extracellular deposits that share certain signs, including neuritic degeneration, suggesting a particular role for amyloid protein toxicity.

• MeSH
• Alzheimerova nemoc metabolismus   MeSH
• amyloid metabolismus   MeSH
• amyloidní beta-protein metabolismus   MeSH
• amyloidní plaky metabolismus   MeSH
• amyloidogenní proteiny metabolismus   MeSH
• amyloidóza metabolismus   MeSH
• Creutzfeldtova-Jakobova nemoc metabolismus   MeSH
• lidé MeSH
• mozek metabolismus   patologie   MeSH
• neurity metabolismus   patologie   MeSH
• Check Tag
• lidé MeSH
• Publikační typ
• časopisecké články MeSH
• přehledy MeSH

PURPOSE: The quality and precision of post-mortem MRI microscopy may vary depending on the embedding medium used. To investigate this, our study evaluated the impact of 5 widely used media on: (1) image quality, (2) contrast of high spatial resolution gradient-echo (T1 and T2* -weighted) MR images, (3) effective transverse relaxation rate (R2* ), and (4) quantitative susceptibility measurements (QSM) of post-mortem brain specimens. METHODS: Five formaldehyde-fixed brain slices were scanned using 7.0T MRI in: (1) formaldehyde solution (formalin), (2) phosphate-buffered saline (PBS), (3) deuterium oxide (D2 O), (4) perfluoropolyether (Galden), and (5) agarose gel. SNR and contrast-to-noise ratii (SNR/CNR) were calculated for cortex/white matter (WM) and basal ganglia/WM regions. In addition, median R2* and QSM values were extracted from caudate nucleus, putamen, globus pallidus, WM, and cortical regions. RESULTS: PBS, Galden, and agarose returned higher SNR/CNR compared to formalin and D2 O. Formalin fixation, and its use as embedding medium for scanning, increased tissue R2* . Imaging with agarose, D2 O, and Galden returned lower R2* values than PBS (and formalin). No major QSM offsets were observed, although spatial variance was increased (with respect to R2* behaviors) for formalin and agarose. CONCLUSIONS: Embedding media affect gradient-echo image quality, R2* , and QSM in differing ways. In this study, PBS embedding was identified as the most stable experimental setup, although by a small margin. Agarose and Galden were preferred to formalin or D2 O embedding. Formalin significantly increased R2* causing noisier data and increased QSM variance.

• MeSH
• ethery MeSH
• fluorokarbony MeSH
• formaldehyd MeSH
• fosfáty MeSH
• kontrastní látky MeSH
• lidé středního věku MeSH
• lidé MeSH
• magnetická rezonanční tomografie přístrojové vybavení   metody   MeSH
• mapování mozku metody   MeSH
• mozek diagnostické zobrazování   patologie   MeSH
• odběr biologického vzorku MeSH
• oxid deuteria MeSH
• pitva přístrojové vybavení   metody   MeSH
• počítačové zpracování obrazu MeSH
• poměr signál - šum MeSH
• sefarosa chemie   MeSH
• senioři MeSH
• zalévání tkání přístrojové vybavení   MeSH
• Check Tag
• lidé středního věku MeSH
• lidé MeSH
• mužské pohlaví MeSH
• senioři MeSH
• ženské pohlaví MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH

BACKGROUND: We aimed to produce a detailed neuropathological analysis of pyramidal motor system pathology and provide its clinical pathological correlation in cases with definite progressive supranuclear palsy (PSP). METHODS: Pyramidal motor system pathologies were analyzed in 18 cases with neuropathologically confirmed PSP. Based on a retrospective clinical analysis, cases were subtyped according to Movement Disorder Society criteria for clinical diagnosis of PSP as probable, possible or suggestive of PSP with Richardson's syndrome (n = 10), PSP with predominant corticobasal syndrome (n = 3), PSP with predominant parkinsonism (n = 3), PSP with predominant speech/language disorder (n = 1), and PSP with progressive gait freezing (n = 1). Clinical manifestations of motor neuron involvement (pseudobulbar or bulbar signs and spasticity) were retrospectively assessed semiquantitatively. Neuropathologically, hyperphosphorylated tau-related pyramidal motor system neuronal, neuritic, and glial pathology using anti-tau AT8 clone immunohistochemistry, was also evaluated. RESULTS: Clinical manifestations of pyramidal motor system involvement were found in patients with different PSP subtypes. A statistically significant higher load of tau pathology was found in the pyramidal system in PSP-Richardson's syndrome compared to other PSP subtypes (p = 0.016); however, there was no significant correlation between pyramidal system tau pathology and related motor clinical symptoms. CONCLUSIONS: Tau pathology in the spinal cord and pyramidal motor system structures is very common in progressive supranuclear palsy and may neuropathologically supplement the distinction between classic Richardson's syndrome from other progressive supranuclear palsy subtypes.

• MeSH
• imunohistochemie MeSH
• lidé středního věku MeSH
• lidé MeSH
• mozková kůra patologie   MeSH
• parkinsonské poruchy diagnóza   patologie   MeSH
• pohybové poruchy diagnóza   patologie   MeSH
• progresivní supranukleární obrna diagnóza   patologie   MeSH
• proteiny tau metabolismus   MeSH
• pyramidové dráhy patologie   MeSH
• retrospektivní studie MeSH
• senioři nad 80 let MeSH
• senioři MeSH
• Check Tag
• lidé středního věku MeSH
• lidé MeSH
• mužské pohlaví MeSH
• senioři nad 80 let MeSH
• senioři MeSH
• ženské pohlaví MeSH
• Publikační typ
• časopisecké články MeSH