Major depressive disorder, particularly its treatment-resistant form (TRD), poses significant treatment challenges. Ketamine, an N-methyl-d-aspartate receptor antagonist, has shown promise in rapidly alleviating depressive symptoms by influencing neuroplasticity and glutamatergic modulation, which are thought to influence brain activity complexity. In this placebo-controlled study, we examined the effects of subanesthetic doses of intravenous ketamine on EEG signal complexity in 24 MDD patients, 21 of whom had TRD. Treatment response was defined by a ≥ 33 % reduction in Montgomery-Åsberg Depression Rating Scale (MADRS) after ketamine administration. Patients underwent eyes-closed resting state EEG recording pre-, start-, end- and 24 h post-infusion, analyzed for temporospatial and spatiotemporal Lempel-Ziv complexity (LZCT and LZCS). Results indicated that ketamine significantly increased whole-brain LZCT during infusion compared to placebo (sodium chloride 0.9 %) (16.90 % vs. -4.84 %, 95 % CI 4.29 to 39.18, p = 0.017). Elevated LZCT at end-pre was associated with less short-term symptom improvement the following day. Conversely, lower pretreatment occipital LZCT (0.33 vs. 0.46, 95 % CI 0.007 to 0.26, p = 0.040) predicted a favorable response to ketamine, supported by a logistic regression model with an ROC area of 0.75. No significant changes were observed in LZCS, suggesting limited utility as a biomarker. In conclusion, occipital LZCT could serve as an effective predictive biomarker for ketamine's therapeutic effects in MDD, with implications for patients with TRD. This underscores the potential of EEG complexity measures in stratifying treatment and enhancing our understanding of the neural impacts of ketamine in depressive disorders.

• Klíčová slova
• Biomarker, EEG, Ketamine, Lempel-Ziv complexity, MDD, Treatment response,
• MeSH
• antagonisté excitačních aminokyselin * aplikace a dávkování   farmakologie   MeSH
• deprese nereagující na léčbu * farmakoterapie   patofyziologie   MeSH
• depresivní porucha unipolární * farmakoterapie   patofyziologie   MeSH
• dospělí MeSH
• dvojitá slepá metoda MeSH
• elektroencefalografie * účinky léků   MeSH
• ketamin * aplikace a dávkování   farmakologie   terapeutické užití   MeSH
• lidé středního věku MeSH
• lidé MeSH
• mozek * účinky léků   patofyziologie   MeSH
• výsledek terapie MeSH
• Check Tag
• dospělí MeSH
• lidé středního věku MeSH
• lidé MeSH
• mužské pohlaví MeSH
• ženské pohlaví MeSH
• Publikační typ
• časopisecké články MeSH
• randomizované kontrolované studie MeSH
• Názvy látek
• antagonisté excitačních aminokyselin * MeSH
• ketamin * MeSH

Alzheimer's disease (AD) is a multifaceted neurodegenerative disorder for which current treatments provide only symptomatic relief, primarily through cholinesterase (ChE) inhibition and N-methyl-d-aspartate receptor (NMDAR) antagonism. To improve therapeutic efficacy and safety, we designed and synthesized 16 novel tacrine derivatives modified at position 7 with various (hetero)aryl groups or deuterium substitution. Initially, in silico screening predicted favorable CNS permeability and oral bioavailability. Subsequent in vitro evaluations demonstrated significant inhibitory potency against acetylcholinesterase (AChE) and butyrylcholinesterase (BChE), with derivatives 5i and 5m displaying particularly promising profiles. Metabolic stability assessed using human liver microsomes revealed enhanced stability for compound 5e, whereas 5i and 5m underwent rapid metabolism. Notably, compound 7 showed improved metabolic stability attributed to deuterium incorporation. The newly synthesized compounds were further tested for antagonistic activity on the GluN1/GluN2B subtype of NMDAR, with compound 5m exhibiting the most potent and voltage-independent inhibition. The ability of these compounds to permeate the blood-brain barrier (BBB) was confirmed through in vitro PAMPA assays. In preliminary hepatotoxicity screening (HepG2 cells), most derivatives exhibited higher cytotoxicity than tacrine, emphasizing the ongoing challenge in hepatotoxicity management. Based on its overall favorable profile, compound 5m advanced to in vivo pharmacokinetic studies in mice, demonstrating efficient CNS penetration, with brain concentrations exceeding plasma levels (brain-to-plasma ratio 2.36), indicating active transport across the BBB. These findings highlight compound 5m as a promising tacrine-based multi-target-directed ligand, supporting further preclinical development as a potential therapeutic candidate for AD.

• Klíčová slova
• Acetylcholinesterase, Alzheimer's disease, Butyrylcholinesterase, Multi-target directed ligands, N-methyl-d-aspartate receptor, Tacrine,
• MeSH
• acetylcholinesterasa metabolismus   MeSH
• Alzheimerova nemoc * farmakoterapie   metabolismus   MeSH
• biologická dostupnost MeSH
• butyrylcholinesterasa metabolismus   MeSH
• cholinesterasové inhibitory * farmakologie   chemie   chemická syntéza   MeSH
• hematoencefalická bariéra metabolismus   MeSH
• jaterní mikrozomy metabolismus   MeSH
• lidé MeSH
• ligandy MeSH
• molekulární struktura MeSH
• myši MeSH
• receptory N-methyl-D-aspartátu * antagonisté a inhibitory   metabolismus   MeSH
• takrin * farmakologie   chemie   chemická syntéza   MeSH
• vztah mezi dávkou a účinkem léčiva MeSH
• vztahy mezi strukturou a aktivitou MeSH
• zvířata MeSH
• Check Tag
• lidé MeSH
• mužské pohlaví MeSH
• myši MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH
• Názvy látek
• acetylcholinesterasa MeSH
• butyrylcholinesterasa MeSH
• cholinesterasové inhibitory * MeSH
• ligandy MeSH
• receptory N-methyl-D-aspartátu * MeSH
• takrin * MeSH

This study aimed to determine the paraoxonase activity and prooxidant-antioxidant balance in the brain tissue of Wistar rats following subacute treatment with selected K-oximes. Each K-oxime was administered intramuscularly (0.1 LD50/kg) twice per week for four weeks, and 7 days after the last treatment, the paraoxonase activity (PON1), the prooxidant-antioxidant balance (PAB), the levels of superoxide anion radical (O2•-), the concentration of nitrite (NO2-) and the content of free protein thiol groups in the brain homogenates were evaluated. The PON1 and PAB activity were significantly reduced in almost all oxime-treated groups (p < 0.01 and p < 0.001, respectively). The concentrations of O2•- were significantly increased in the obidoxime-, K048-, K074- and K075-treated groups (p < 0.001), while the levels of NO2- was significantly decreased in asoxime-, obidoxime-, K074 and K075-treated rats (p < 0.01, p < 0.001, respectively). The content of Thiol groups was significantly elevated in all oxime-treated groups (p < 0.001). Continuing our previously published data, these results confirmed that applied K-oximes improved the oxidative status and further harmful systemic effects of rats after subacute administration.

• Klíčová slova
• Brain tissue, Oximes, Paraoxonase activity, Rats, Subacute toxicity,
• MeSH
• antioxidancia * metabolismus   MeSH
• aryldialkylfosfatasa * metabolismus   MeSH
• dusitany metabolismus   MeSH
• krysa rodu Rattus MeSH
• mozek * účinky léků   metabolismus   enzymologie   MeSH
• oximy * farmakologie   aplikace a dávkování   MeSH
• potkani Wistar MeSH
• sulfhydrylové sloučeniny metabolismus   MeSH
• superoxidy metabolismus   MeSH
• zvířata MeSH
• Check Tag
• krysa rodu Rattus MeSH
• mužské pohlaví MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH
• Názvy látek
• antioxidancia * MeSH
• aryldialkylfosfatasa * MeSH
• dusitany MeSH
• oximy * MeSH
• sulfhydrylové sloučeniny MeSH
• superoxidy MeSH

BACKGROUND: Age-related neurodegenerative diseases (NDs) pose a formidable challenge to healthcare systems worldwide due to their complex pathogenesis, significant morbidity, and mortality. Scope and Approach: This comprehensive review aims to elucidate the central role of the microbiotagut- brain axis (MGBA) in ND pathogenesis. Specifically, it delves into the perturbations within the gut microbiota and its metabolomic landscape, as well as the structural and functional transformations of the gastrointestinal and blood-brain barrier interfaces in ND patients. Additionally, it provides a comprehensive overview of the recent advancements in medicinal and dietary interventions tailored to modulate the MGBA for ND therapy. CONCLUSION: Accumulating evidence underscores the pivotal role of the gut microbiota in ND pathogenesis through the MGBA. Dysbiosis of the gut microbiota and associated metabolites instigate structural modifications and augmented permeability of both the gastrointestinal barrier and the blood-brain barrier (BBB). These alterations facilitate the transit of microbial molecules from the gut to the brain via neural, endocrine, and immune pathways, potentially contributing to the etiology of NDs. Numerous investigational strategies, encompassing prebiotic and probiotic interventions, pharmaceutical trials, and dietary adaptations, are actively explored to harness the microbiota for ND treatment. This work endeavors to enhance our comprehension of the intricate mechanisms underpinning ND pathogenesis, offering valuable insights for the development of innovative therapeutic modalities targeting these debilitating disorders.

• Klíčová slova
• Neurodegenerative diseases, blood-brain barrier, dietary adaptations., gut microbiota, microbiota-gut-brain axis, therapy,
• MeSH
• dysbióza metabolismus   MeSH
• hematoencefalická bariéra metabolismus   MeSH
• lidé MeSH
• mozek * metabolismus   MeSH
• neurodegenerativní nemoci * mikrobiologie   metabolismus   MeSH
• osa mozek-střevo * fyziologie   MeSH
• probiotika MeSH
• stárnutí * MeSH
• střevní mikroflóra * fyziologie   MeSH
• zvířata MeSH
• Check Tag
• lidé MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH
• přehledy MeSH

L-Aspartate (aspartic acid; C4H7NO4; 2-aminobutanedoic acid) is a non-essential α-amino acid found ubiquitously throughout the body, including in the brain. Aspartate is one of the protein-forming amino acids and the formation of tRNA-aspartate complex is catalysed by aspartyl tRNA synthetase. Free aspartate, which is the main subject of this review, plays key roles in metabolism, as an amino donor and acceptor. It contributes to the synthesis of protein, arginine and nitric oxide, asparagine, N-acetylaspartate and N-methyl-D-aspartate. Its major metabolic role in the brain is recycling reducing equivalents (protons) between the cytoplasm and mitochondrial matrix as part of the malate-aspartate shuttle. L-Aspartate's actions on synaptic receptors, as well as its possible presence in nerve terminals and synaptic vesicles, are, in principle, consistent with a role as an excitatory neurotransmitter. The evidence is far from conclusive and at times controversial. The role of D-aspartate in brain function is even less certain but, it appears that, rather than being a minor neurotransmitter, D-aspartate is more likely to be involved in fine regulation of endocrine and homeostatic processes. Much research remains to be done in this area. The diversity of its functions and chemistry make aspartate a complex molecule to investigate and measure in vivo. Perturbations of aspartate metabolism have been described in a range of neurological deficits, particularly those of white matter. Here, we examine what is known about the various roles of aspartate in brain, its metabolism, transport and compartmentation, its role as a neurotransmitter or a more general signalling molecule, and what is currently known about its role(s) in disease processes.

• Klíčová slova
• d-aspartate, Energy metabolism, Malate aspartate shuttle, Neurotransmitter,
• MeSH
• kyselina asparagová * metabolismus   MeSH
• lidé MeSH
• mozek * metabolismus   MeSH
• zvířata MeSH
• Check Tag
• lidé MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH
• přehledy MeSH
• Názvy látek
• kyselina asparagová * MeSH

The perception of a voice in the absence of an external auditory source-an auditory verbal hallucination-is a characteristic symptom of schizophrenia. To better understand this phenomenon requires integration of findings across behavioural, functional, and neurochemical levels. We address this with a locally adapted MEGA-PRESS sequence incorporating interleaved unsuppressed water acquisitions, allowing concurrent assessment of behaviour, blood-oxygenation-level-dependent (BOLD) functional changes, Glutamate + Glutamine (Glx), and GABA, synchronised with a cognitive (flanker) task. We acquired data from the anterior cingulate cortex (ACC) of 51 patients with psychosis (predominantly schizophrenia spectrum disorder) and hallucinations, matched to healthy controls. Consistent with the notion of an excitatory/inhibitory imbalance, we hypothesized differential effects for Glx and GABA between groups, and aberrant dynamics in response to task. Results showed impaired task performance, lower baseline Glx and positive association between Glx and BOLD in patients, contrasting a negative correlation in healthy controls. Task-related increases in Glx were observed in both groups, with no significant difference between groups. No significant effects were observed for GABA. These findings suggest that a putative excitatory/inhibitory imbalance affecting inhibitory control in the ACC is primarily observed as tonic, baseline glutamate differences, rather than GABAergic effects or aberrant dynamics in relation to a task.

• Klíčová slova
• Functional spectroscopy, GABA, Glutamate, Hallucinations, MEGA-PRESS, Psychosis,
• MeSH
• cingulární gyrus metabolismus   patofyziologie   MeSH
• dospělí MeSH
• GABA * metabolismus   MeSH
• glutamin metabolismus   MeSH
• halucinace * metabolismus   patofyziologie   MeSH
• kognice * fyziologie   MeSH
• kyselina glutamová * metabolismus   MeSH
• lidé středního věku MeSH
• lidé MeSH
• magnetická rezonanční tomografie MeSH
• mladý dospělý MeSH
• psychotické poruchy * metabolismus   patofyziologie   MeSH
• studie případů a kontrol MeSH
• Check Tag
• dospělí MeSH
• lidé středního věku MeSH
• lidé MeSH
• mladý dospělý MeSH
• mužské pohlaví MeSH
• ženské pohlaví MeSH
• Publikační typ
• časopisecké články MeSH
• Názvy látek
• GABA * MeSH
• glutamin MeSH
• kyselina glutamová * MeSH

PURPOSE: Focused ultrasound-induced blood-brain barrier (BBB) opening is a promising method for neurotherapeutic delivery. The standard for quantifying induced BBB permeability is the K trans $$ {K}^{\mathrm{trans}} $$ parameter, which reflects both permeability and plasma flow. The influence of plasma flow can be eliminated by estimating the PS parameter. However, this parameter has been largely unexplored in this application. This study aims to compare permeability estimates based on K trans $$ {K}^{\mathrm{trans}} $$ and PS in focused ultrasound-induced BBB opening experiments. METHODS: We used the extended Tofts model (ETM) and the two-compartment exchange model (2CXM) to estimate K trans $$ {K}^{\mathrm{trans}} $$ and PS parameters, respectively. Permeability estimates were compared using simulated concentration curves, simulated DCE-MRI data, and real datasets. We explored the influence of spatially-regularized model fitting on the results. RESULTS: For opened BBB, K trans $$ {K}^{\mathrm{trans}} $$ was minimally influenced by plasma flow under the tested conditions. However, fitting the ETM often introduced outliers in K trans $$ {K}^{\mathrm{trans}} $$ estimates in regions with closed BBB. The 2CXM outperformed the ETM at high signal-to-noise ratios, but its higher complexity led to lower precision at low signal-to-noise ratios. Both these issues were successfully compensated by spatially-regularized model fitting. CONCLUSION: Both K trans $$ {K}^{\mathrm{trans}} $$ and PS seem to be eligible options for the quantification of BBB opening, and the correct choice depends on the specifics of the acquired DCE-MRI data. Additionally, spatial regularization has demonstrated its importance in enhancing the accuracy and reproducibility of results for both models.

• Klíčová slova
• BBB opening, DCE‐MRI, focused ultrasound, perfusion analysis, simulation,
• MeSH
• hematoencefalická bariéra * diagnostické zobrazování   metabolismus   účinky záření   MeSH
• kontrastní látky MeSH
• lidé MeSH
• magnetická rezonanční tomografie * metody   MeSH
• mozek diagnostické zobrazování   MeSH
• permeabilita MeSH
• počítačová simulace MeSH
• počítačové zpracování obrazu metody   MeSH
• zvířata MeSH
• Check Tag
• lidé MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH
• srovnávací studie MeSH
• Názvy látek
• kontrastní látky MeSH

BACKGROUND: Spatial navigation deficits are early symptoms of Alzheimer's disease (AD). The apolipoprotein E (APOE) ε4 allele is the most important genetic risk factor for AD. This study investigated effects of APOE genotype on spatial navigation in biomarker-defined individuals with amnestic mild cognitive impairment (aMCI) and associations of AD biomarkers and atrophy of AD-related brain regions with spatial navigation. METHODS: 107 participants, cognitively normal older adults (CN, n = 48) and aMCI individuals stratified into AD aMCI (n = 28) and non-AD aMCI (n = 31) groups, underwent cognitive assessment, brain MRI, and spatial navigation assessment using the Virtual Supermarket Test with egocentric and allocentric tasks and a self-report questionnaire. Cerebrospinal fluid (CSF) biomarkers (amyloid-β1-42, phosphorylated tau181 and total tau) and amyloid PET imaging were assessed in aMCI participants. RESULTS: AD aMCI participants had the highest prevalence of APOE ε4 carriers and worst allocentric navigation. CSF levels of AD biomarkers and atrophy in AD-related brain regions were associated with worse allocentric navigation. Between-group differences in spatial navigation and associations with AD biomarkers and regional brain atrophy were not influenced by APOE genotype. Self-reported navigation ability was similar across groups and unrelated to spatial navigation performance. CONCLUSIONS: These findings suggest that allocentric navigation deficits in aMCI individuals are predominantly driven by AD pathology, independent of APOE genotype. This highlights the role of AD pathology as measured by biomarkers, rather than genetic status, as a major factor in navigational impairment in aMCI, and emphasizes the assessment of spatial navigation as a valuable tool for early detection of AD.

• Klíčová slova
• Allocentric navigation, Amyloid-β, Egocentric navigation, Entorhinal cortex, Hippocampus, Tau protein,
• MeSH
• Alzheimerova nemoc * genetika   mozkomíšní mok   diagnostické zobrazování   komplikace   patofyziologie   patologie   MeSH
• amyloidní beta-protein mozkomíšní mok   MeSH
• apolipoprotein E4 * genetika   MeSH
• apolipoproteiny E * genetika   MeSH
• atrofie MeSH
• biologické markery mozkomíšní mok   MeSH
• genotyp MeSH
• kognitivní dysfunkce * genetika   mozkomíšní mok   diagnostické zobrazování   patofyziologie   MeSH
• lidé středního věku MeSH
• lidé MeSH
• magnetická rezonanční tomografie MeSH
• mozek patologie   diagnostické zobrazování   MeSH
• neuropsychologické testy MeSH
• peptidové fragmenty mozkomíšní mok   MeSH
• pozitronová emisní tomografie MeSH
• prostorová navigace * fyziologie   MeSH
• proteiny tau mozkomíšní mok   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
• Názvy látek
• amyloid beta-protein (1-42) MeSH Prohlížeč
• amyloidní beta-protein MeSH
• apolipoprotein E4 * MeSH
• apolipoproteiny E * MeSH
• biologické markery MeSH
• peptidové fragmenty MeSH
• proteiny tau MeSH

In the study, we employ an affordable, tissue-saving, and precise simultaneous multiplex immunofluorescence method with heat-induced antibody stripping to identify and structurally analyse nigral Lewy bodies in dopaminergic neurones. Analysis of different alpha-synuclein epitopes and proteoforms reveals an almost uniform, onion-like morphology of the Lewy bodies. The N-terminal and C-terminal domains are predominantly accessible to antibody binding in the peripheral shell of the bodies.

• Klíčová slova
• Lewy body, Lewy pathology, Parkinson's disease, alpha‐synuclein, immunofluorescence,
• MeSH
• alfa-synuklein * metabolismus   analýza   MeSH
• demence s Lewyho tělísky patologie   MeSH
• dopaminergní neurony metabolismus   patologie   MeSH
• fluorescenční protilátková technika metody   MeSH
• Lewyho tělíska * metabolismus   patologie   MeSH
• lidé MeSH
• substantia nigra * metabolismus   patologie   MeSH
• vysoká teplota MeSH
• Check Tag
• lidé MeSH
• Publikační typ
• časopisecké články MeSH
• Názvy látek
• alfa-synuklein * MeSH

Mitochondria are central to cellular energy metabolism, contributing to synaptic transmission and plasticity. The mitochondrial membranes present the cannabinoid type-1 receptor (mito-CB1R), which has been functionally linked to neuronal energy supply and cognitive processing. Prenatal exposure to Δ9-tetrahydrocannabinol (pTHC) has been associated with cognitive impairments associated with molecular cellular and functional abnormalities in several brain regions, including the hippocampus. This study aims at assessing whether, besides the memory impairment, pTHC exposure may result in mitochondrial molecular and functional alterations in the hippocampus of the offspring. Moreover, the assessment of CB1R expression is also carried out as a proxy of CB1 signalling in pTHC-exposed offspring. THC (2 mg/Kg), or vehicle, was administered to the dams from gestational day (GD) 5 to GD20, and the offspring were tested for declarative memory using the Novel Object Recognition test in the L-maze. We also assessed: mitochondrial respiration by high-resolution respirometry; mitochondrial respiratory complex-I subunit NDUFS1 protein levels, and mito-CB1R expression by ELISA. Our results revealed: significant memory impairment in pTHC-exposed offspring; attenuated mitochondrial respiration in the hippocampus alongside a marked reduction in complex-I-subunit NDUFS1; a significant increase in mito-CB1R expression. This is the first evidence of pTHC exposure-induced impairment in memory processing in the offspring that suggests a functional link between an attenuation in mitochondrial bioenergetics and abnormal CB1R signalling in the hippocampus.

• Klíčová slova
• CB1 receptor, Complex-I, Declarative memory, Hippocampus, Mitochondria, Prenatal THC,
• MeSH
• bludiště - učení účinky léků   MeSH
• buněčné dýchání účinky léků   MeSH
• hipokampus * metabolismus   účinky léků   MeSH
• krysa rodu Rattus MeSH
• mitochondrie * metabolismus   účinky léků   MeSH
• paměť účinky léků   MeSH
• poruchy paměti * metabolismus   chemicky indukované   MeSH
• potkani Wistar MeSH
• receptor kanabinoidní CB1 * metabolismus   MeSH
• těhotenství MeSH
• tetrahydrokanabinol * toxicita   MeSH
• zpožděný efekt prenatální expozice * metabolismus   chemicky indukované   MeSH
• zvířata MeSH
• Check Tag
• krysa rodu Rattus MeSH
• mužské pohlaví MeSH
• těhotenství MeSH
• ženské pohlaví MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH
• Názvy látek
• receptor kanabinoidní CB1 * MeSH
• tetrahydrokanabinol * MeSH