Endogenous brain activity
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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.
- 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
Electroencephalography (EEG) has been instrumental in epilepsy research for the past century, both for basic and translational studies. Its contributions have advanced our understanding of epilepsy, shedding light on the pathophysiology and functional organization of epileptic networks, and the mechanisms underlying seizures. Here we re-examine the historical significance, ongoing relevance, and future trajectories of EEG in epilepsy research. We describe traditional approaches to record brain electrical activity and discuss novel cutting-edge, large-scale techniques using micro-electrode arrays. Contemporary EEG studies explore brain potentials beyond the traditional Berger frequencies to uncover underexplored mechanisms operating at ultra-slow and high frequencies, which have proven valuable in understanding the principles of ictogenesis, epileptogenesis, and endogenous epileptogenicity. Integrating EEG with modern techniques such as optogenetics, chemogenetics, and imaging provides a more comprehensive understanding of epilepsy. EEG has become an integral element in a powerful suite of tools for capturing epileptic network dynamics across various temporal and spatial scales, ranging from rapid pathological synchronization to the long-term processes of epileptogenesis or seizure cycles. Advancements in EEG recording techniques parallel the application of sophisticated mathematical analyses and algorithms, significantly augmenting the information yield of EEG recordings. Beyond seizures and interictal activity, EEG has been instrumental in elucidating the mechanisms underlying epilepsy-related cognitive deficits and other comorbidities. Although EEG remains a cornerstone in epilepsy research, persistent challenges such as limited spatial resolution, artifacts, and the difficulty of long-term recording highlight the ongoing need for refinement. Despite these challenges, EEG continues to be a fundamental research tool, playing a central role in unraveling disease mechanisms and drug discovery.
- MeSH
- elektroencefalografie * metody MeSH
- epilepsie * patofyziologie diagnóza epidemiologie MeSH
- komorbidita MeSH
- lidé MeSH
- mozek * patofyziologie MeSH
- záchvaty * patofyziologie diagnóza MeSH
- zvířata MeSH
- Check Tag
- lidé MeSH
- zvířata MeSH
- Publikační typ
- časopisecké články MeSH
- přehledy MeSH
The human body gets exposed to a variety of toxins intentionally or unintentionally on a regular basis from sources such as air, water, food, and soil. Certain toxins can be synthetic, while some are biological. The toxins affect the various parts of the body by activating numerous pro-inflammatory markers, like oxidative stresses, that tend to disturb the normal function of the organs ultimately. Nowadays, people use different types of herbal treatments, viz., herbal drinks that contain different spices for detoxification of their bodies. One such example is turmeric, the most commonly available spice in the kitchen and used across all kinds of households. Turmeric contains curcumin, which is a natural polyphenol. Curcumin is a medicinal compound with different biological activities, such as antioxidant, antineoplastic, anti-inflammatory, and antibacterial. Hence, this review gives a comprehensive insight into the promising potential of curcumin in the detoxification of heavy metals, carbon tetrachloride, drugs, alcohol, acrylamide, mycotoxins, nicotine, and plastics. The review encompasses diverse animal-based studies portraying curcumin's role in nullifying the different toxic effects in various organs of the body (especially the liver, kidney, testicles, and brain) by enhancing defensive signaling pathways, improving antioxidant enzyme levels, inhibiting pro-inflammatory markers activities and so on. Furthermore, this review also argues over curcumin's safety assessment for its utilization as a detoxifying agent.
- MeSH
- akrylamid toxicita MeSH
- antioxidancia farmakologie MeSH
- Curcuma chemie MeSH
- kurkumin * farmakologie chemie MeSH
- lidé MeSH
- metabolická inaktivace MeSH
- mykotoxiny toxicita MeSH
- nikotin MeSH
- oxidační stres účinky léků MeSH
- těžké kovy toxicita MeSH
- zvířata MeSH
- Check Tag
- lidé MeSH
- zvířata MeSH
- Publikační typ
- časopisecké články MeSH
- přehledy MeSH
The central nervous system is a well-known steroidogenic tissue producing, among others, cholesterol metabolites such as neuroactive steroids, oxysterols and steroid hormones. It is well known that these endogenous molecules affect several receptor classes, including ionotropic GABAergic and NMDA glutamatergic receptors in neurons. It has been shown that also ionotropic purinergic (P2X) receptors are cholesterol metabolites' targets. Among P2X receptors, purinergic P2X4 and P2X7 receptors are expressed in microglia, the innate immune cells involved in the brain inflammatory response. In this study, we explore the ionotropic purinergic receptors modulation by cholesterol metabolites in microglia. Patch-clamp experiments were performed in BV2 cells, a murine microglia cell line, to evaluate effects of cholesterol metabolites using micro- and nanomolar concentrations. About P2X4 receptor, we found that testosterone butyrate (20 μM and 200 nM) and allopregnanolone (10 μM and 100 nM) both potentiated its current, while neither 25-hydroxycholesterol (10 μM and 100 nM) nor 17β-estradiol (1 μM) showed any effects. On the other hand, P2X7 receptor current was potentiated by allopregnanolone (10 μM) and 25-hydroxycholesterol (10 μM and 100 nM). Taken together, our data show that modulation of either P2X4 and P2X7 current is affected differently by cholesterol metabolites, suggesting a structure-activity relationship among these players. Identifying the possible link between purinergic transmission, microglia and cholesterol metabolites will allow to define new targets for drug development to treat neuroinflammation.
- MeSH
- buněčné linie MeSH
- mikroglie * metabolismus MeSH
- pregnanolon * metabolismus MeSH
- purinergní receptory P2X4 * metabolismus MeSH
- testosteron * metabolismus MeSH
- zvířata MeSH
- Check Tag
- zvířata MeSH
- Publikační typ
- časopisecké články MeSH
Huntington's disease (HD) is a debilitating neurodegenerative disorder characterized by severe motor deficits, cognitive decline and psychiatric disturbances. An early and significant morphological hallmark of HD is the activation of astrocytes triggered by mutant huntingtin, leading to the release of inflammatory mediators. Fingolimod (FTY), an FDA-approved sphingosine-1-phosphate (S1P) receptor agonist is used to treat multiple sclerosis (MS), a neuroinflammatory disease, and has shown therapeutic promise in other neurological conditions. Our study aimed to investigate the therapeutic potential of FTY for treating HD by utilizing a well-characterized mouse model of HD (zQ175dn) and wild-type littermates. The study design included a crossover, long-term oral treatment with 1 mg/kg to 2 mg/kg FTY from the age of 15-46 weeks (n = 128). Different motor behavior and physiological parameters were assessed throughout the study. The findings revealed that FTY rescued disease-related body weight loss in a sex-dependent manner, indicating its potential to regulate metabolic disturbances and to counteract neurodegenerative processes in HD. FTY intervention also rescued testicular atrophy, restored testis tissue structure in male mice suggesting a broader impact on peripheral tissues affected by huntingtin pathology. Histological analyses of the brain revealed delayed accumulation of activated astrocytes contributing to the preservation of the neural microenvironment by reducing neuroinflammation. The extent of FTY-related disease improvement was sex-dependent. Motor functions and body weight improved mostly in female mice with sustained estrogen levels, whereas males had to compensate for the ongoing, disease-related testis atrophy and the loss of androgen production. Our study underscores the beneficial therapeutic effects of FTY on HD involving endogenous steroid hormones and their important anabolic effects. It positions FTY as a promising candidate for therapeutic interventions targeting various aspects of HD pathology. Further studies are needed to fully evaluate its therapeutic potential in patients.
- MeSH
- fingolimod hydrochlorid * terapeutické užití farmakologie MeSH
- Huntingtonova nemoc * farmakoterapie metabolismus MeSH
- modely nemocí na zvířatech MeSH
- modulátory receptorů sfingosin-1-fosfátu * farmakologie terapeutické užití MeSH
- myši inbrední C57BL MeSH
- myši MeSH
- pohybová aktivita účinky léků MeSH
- receptory sfingosin-1-fosfátu agonisté metabolismus MeSH
- testis účinky léků patologie metabolismus MeSH
- zvířata MeSH
- Check Tag
- mužské pohlaví MeSH
- myši MeSH
- ženské pohlaví MeSH
- zvířata MeSH
- Publikační typ
- časopisecké články MeSH
Chemogenetics is a newly developed set of tools that allow for selective manipulation of cell activity. They consist of a receptor mutated irresponsive to endogenous ligands and a synthetic ligand that does not interact with the wild-type receptors. Many different types of these receptors and their respective ligands for inhibiting or excitating neuronal subpopulations were designed in the past few decades. It has been mainly the G-protein coupled receptors (GPCRs) selectively responding to clozapine-N-oxide (CNO), namely Designer Receptors Exclusively Activated by Designer Drugs (DREADDs), that have been employed in research. Chemogenetics offers great possibilities since the activity of the receptors is reversible, inducible on demand by the ligand, and non-invasive. Also, specific groups or types of neurons can be selectively manipulated thanks to the delivery by viral vectors. The effect of the chemogenetic receptors on neurons lasts longer, and even chronic activation can be achieved. That can be useful for behavioral testing. The great advantage of chemogenetic tools is especially apparent in research on brain diseases since they can manipulate whole neuronal circuits and connections between different brain areas. Many psychiatric or other brain diseases revolve around the dysfunction of specific brain networks. Therefore, chemogenetics presents a powerful tool for investigating the underlying mechanisms causing the disease and revealing the link between the circuit dysfunction and the behavioral or cognitive symptoms observed in patients. It could also contribute to the development of more effective treatments.
- MeSH
- duševní poruchy * genetika metabolismus MeSH
- klozapin analogy a deriváty farmakologie terapeutické užití MeSH
- lidé MeSH
- neurony metabolismus účinky léků MeSH
- nové syntetické drogy farmakologie MeSH
- receptory spřažené s G-proteiny metabolismus genetika MeSH
- zvířata MeSH
- Check Tag
- lidé MeSH
- zvířata MeSH
- Publikační typ
- časopisecké články MeSH
- přehledy MeSH
BACKGROUND: Elevated brain levels of kynurenic acid (KYNA), a metabolite in the kynurenine pathway, are associated with cognitive dysfunctions, which are nowadays often considered as fundamental characteristics of several psychopathologies; however, the role of KYNA in mental illnesses, such as schizophrenia, is not fully elucidated. This study aimed to assess KYNA levels in the prefrontal cortex (PFC) of rats prenatally treated with methylazoxymethanol (MAM) acetate, i.e., a well-validated neurodevelopmental animal model of schizophrenia. The effects of an early pharmacological modulation of the endogenous cannabinoid system were also evaluated. METHODS: Pregnant Sprague-Dawley rats were treated with MAM (22 mg/kg, ip) or its vehicle at gestational day 17. Male offspring were treated with the cannabinoid CB1 receptor antagonist/inverse agonist AM251 (0.5 mg/kg/day, ip) or with the typical antipsychotic haloperidol (0.6 mg/kg/day, ip) from postnatal day (PND) 19 to PND39. The locomotor activity and cognitive performance were assessed in the novel object recognition test and the open field test in adulthood. KYNA levels in the PFC of prenatally MAM-treated rats were also assessed. RESULTS: A significant cognitive impairment was observed in prenatally MAM-treated rats (p < 0.01), which was associated with enhanced PFC KYNA levels (p < 0.05). The peripubertal AM251, but not haloperidol, treatment ameliorated the cognitive deficit (p < 0.05), by normalizing the PFC KYNA content in MAM rats. CONCLUSIONS: The present findings suggest that the cognitive deficit observed in MAM rats may be related to enhanced PFC KYNA levels which could be, in turn, mediated by the activation of cannabinoid CB1 receptor. These results further support the modulation of brain KYNA levels as a potential therapeutic strategy to ameliorate the cognitive dysfunctions in schizophrenia.
- MeSH
- antipsychotika farmakologie MeSH
- haloperidol farmakologie MeSH
- kognitivní dysfunkce metabolismus farmakoterapie MeSH
- krysa rodu rattus MeSH
- kyselina kynurenová * metabolismus MeSH
- methylazoxymethanolacetát * analogy a deriváty MeSH
- modely nemocí na zvířatech MeSH
- piperidiny farmakologie MeSH
- potkani Sprague-Dawley * MeSH
- prefrontální mozková kůra * metabolismus účinky léků MeSH
- pyrazoly farmakologie MeSH
- receptor kanabinoidní CB1 metabolismus MeSH
- schizofrenie * metabolismus farmakoterapie MeSH
- těhotenství MeSH
- zpožděný efekt prenatální expozice * metabolismus MeSH
- zvířata MeSH
- Check Tag
- krysa rodu rattus MeSH
- mužské pohlaví MeSH
- těhotenství MeSH
- ženské pohlaví MeSH
- zvířata MeSH
- Publikační typ
- časopisecké články MeSH
OBJECTIVE: Anxiety and depression in patients following cerebrovascular accidents are among frequently occurring complications of the medical condition. The consequences affect personal, family, professional, and social life. They cause severe functional and cognitive impairments, limit the ability to perform normal daily activities, which can result in complete disability. The aim of the study was to monitor the occurrence of anxiety and depression in patients following cerebrovascular accidents hospitalized in neurological departments in the region of eastern Slovakia. METHODS: A total of 101 patients following cerebrovascular accidents, aged from 48-86 years, were included in the descriptive study. Demographic and clinical data were obtained from patients and from medical records. We determined the occurrence of anxiety disorders, depression and emotional distress in patients following cerebrovascular accidents using a standardized Hospital Anxiety and Depression Scale (HADS) questionnaire. RESULTS: Data analysis confirms a high incidence of anxiety in the HADS-A subscale (9.23 ± 4.13) and depression in the HADS-D subscale (9.09 ± 4.43) during the hospitalization phase of the disease. It demonstrates the pathological occurrence of anxiety states in 37%, depression in 36%, emotional distress in 36%, and a serious degree of combination of pathological values of the anxiety subscale and the depression subscale in 27% of patients. The existence of a strong positive correlation between anxiety and depression indicators was confirmed. CONCLUSION: The results confirm a high prevalence of anxiety and depression in the acute phase of the disease. The findings indicate that patients recovering from cerebrovascular accidents not only face physical difficulties and loss of independence but also struggle with anxiety and depression, which can negatively impact and slow their recovery. Given the high frequency of these psychological conditions, further research is needed to enhance the quality and effectiveness of care provided to patients with cerebrovascular accidents.
- MeSH
- cévní mozková příhoda * epidemiologie psychologie MeSH
- deprese epidemiologie MeSH
- depresivní poruchy epidemiologie MeSH
- lidé středního věku MeSH
- lidé MeSH
- průzkumy a dotazníky MeSH
- senioři nad 80 let MeSH
- senioři MeSH
- úzkost epidemiologie MeSH
- úzkostné poruchy epidemiologie 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
- Geografické názvy
- Slovenská republika MeSH
Endogenous opioid peptides serve as potent analgesics through the opioid receptor (OR) activation. However, they often suffer from poor metabolic stability, low lipophilicity, and low blood-brain barrier permeability. Researchers have developed many strategies to overcome the drawbacks of current pain medications and unwanted biological effects produced by the interaction with opioid receptors. Here, we tested multifunctional enkephalin analogs LYS739 (MOR/DOR agonist and KOR partial antagonist) and LYS744 (MOR/DOR agonist and KOR full antagonist) under in vivo conditions in comparison with MOR agonist, morphine. We applied 2D electrophoretic resolution to investigate differences in proteome profiles of crude membrane (CM) fractions isolated from the rat brain cortex and hippocampus exposed to the drugs (10 mg/kg, seven days). Our results have shown that treatment with analog LYS739 induced the most protein changes in cortical and hippocampal samples. The identified proteins were mainly associated with energy metabolism, cell shape and movement, apoptosis, protein folding, regulation of redox homeostasis, and signal transduction. Among these, the isoform of mitochondrial ATP synthase subunit beta (ATP5F1B) was the only protein upregulation in the hippocampus but not in the brain cortex. Contrarily, the administration of analog LYS744 caused a small number of protein alterations in both brain parts. Our results indicate that the KOR full antagonism, together with MOR/DOR agonism of multifunctional opioid ligands, can be beneficial in treating chronic pain states by reducing changes in protein expression levels but retaining analgesic efficacy.
- MeSH
- analgetika MeSH
- enkefaliny metabolismus MeSH
- hipokampus metabolismus MeSH
- krysa rodu rattus MeSH
- morfin * farmakologie MeSH
- mozek metabolismus MeSH
- opioidní analgetika farmakologie MeSH
- receptory opiátové mu * metabolismus MeSH
- receptory opiátové metabolismus MeSH
- zvířata MeSH
- Check Tag
- krysa rodu rattus MeSH
- zvířata MeSH
- Publikační typ
- časopisecké články MeSH
The crucial physiological process of heme breakdown yields biliverdin (BV) and bilirubin (BR) as byproducts. BV, BR, and the enzymes involved in their production (the "yellow players-YP") are increasingly documented as endogenous modulators of human health. Mildly elevated serum bilirubin concentration has been correlated with a reduced risk of multiple chronic pro-oxidant and pro-inflammatory diseases, especially in the elderly. BR and BV per se have been demonstrated to protect against neurodegenerative diseases, in which heme oxygenase (HMOX), the main enzyme in the production of pigments, is almost always altered. HMOX upregulation has been interpreted as a tentative defense against the ongoing pathologic mechanisms. With the demonstration that multiple cells possess YP, their propensity to be modulated, and their broad spectrum of activity on multiple signaling pathways, the YP have assumed the role of an adjustable system that can promote health in adults. Based on that, there is an ongoing effort to induce their activity as a therapeutic option, and natural compounds are an attractive alternative to the goal, possibly requiring only minimal changes in the life style. We review the most recent evidence of the potential of natural compounds in targeting the YP in the context of the most common pathologic condition of adult and elderly life.
