Pharmacological reports : PR最新文献

{"title":"Neuroendocrine microRNAs linked to energy homeostasis: future therapeutic potential.","authors":"Kimberly W Y Mak,&nbsp;Aws F Mustafa,&nbsp;Denise D Belsham","doi":"10.1007/s43440-022-00409-5","DOIUrl":"https://doi.org/10.1007/s43440-022-00409-5","url":null,"abstract":"<p><p>The brain orchestrates whole-body metabolism through an intricate system involving interneuronal crosstalk and communication. Specifically, a key player in this complex circuitry is the hypothalamus that controls feeding behaviour, energy expenditure, body weight and metabolism, whereby hypothalamic neurons sense and respond to circulating hormones, nutrients, and chemicals. Dysregulation of these neurons contributes to the development of metabolic disorders, such as obesity and type 2 diabetes. The involvement of hypothalamic microRNAs, post-transcriptional regulators of gene expression, in the central regulation of energy homeostasis has become increasingly apparent, although not completely delineated. This review summarizes current evidence demonstrating the regulation of feeding-related neuropeptides by brain-derived microRNAs as well as the regulation of specific miRNAs by nutrients and other peripheral signals. Moreover, the involvement of microRNAs in the central nervous system control of insulin, leptin, and estrogen signal transduction is examined. Finally, the therapeutic and diagnostic potential of microRNAs for metabolic disorders will be discussed and the regulation of brain-derived microRNAs by nutrients and other peripheral signals is considered. Demonstrating a critical role of microRNAs in hypothalamic regulation of energy homeostasis is an innovative route to uncover novel biomarkers and therapeutic candidates for metabolic disorders.</p>","PeriodicalId":166986,"journal":{"name":"Pharmacological reports : PR","volume":" ","pages":"774-789"},"PeriodicalIF":4.4,"publicationDate":"2022-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"33455984","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Changes in regulators of lipid metabolism in the brain: a study of animal models of depression and hypothyroidism.","authors":"Katarzyna Głombik,&nbsp;Jan Detka,&nbsp;Magdalena Kukla-Bartoszek,&nbsp;Alicja Maciejska,&nbsp;Bogusława Budziszewska","doi":"10.1007/s43440-022-00395-8","DOIUrl":"https://doi.org/10.1007/s43440-022-00395-8","url":null,"abstract":"<p><p>Metabolic disturbances in the brain are assumed to be early changes involved in the pathogenesis of depression, and these alterations may be intensified by a deficiency of thyroid hormones. In contrast to glucose metabolism, the link between altered brain lipids and the pathogenesis of depression is poorly understood, therefore in the present study, we determine transcription factors and enzymes regulating cholesterol and fatty acid biosynthesis in the brain structures in an animal model of depression, hypothyroidism and the coexistence of these diseases.In used model of depression, a decrease in the active form of the transcription factor SREBP-2 in the hippocampus was demonstrated, thus suggesting a reduction in cholesterol biosynthesis. In turn, in the hypothyroidism model, the reduction of cholesterol biosynthesis in the frontal cortex was demonstrated by both the reduction of mature SREBP-2 and the concentration of enzymes involved in cholesterol biosynthesis. The lower expression of LDL receptors in the frontal cortex indicates the restriction of cholesterol uptake into the cells in the model of coexistence of depression and hypothyroidism. Moreover, the identified changes in the levels of SNAP-25, GLP-1R and GLP-2R pointed to disturbances in synaptic plasticity and neuroprotection mechanisms in the examined brain structures.In conclusion, a reduction in cholesterol synthesis in the hippocampus in the model of depression may be the reason for the reduction of synaptic plasticity, whereas a lower level of LDL-R occurring in the frontal cortex in rats from the model of depression and hypothyroidism coexistence could be the reason of anxiogenic and depression-like behaviors.</p>","PeriodicalId":166986,"journal":{"name":"Pharmacological reports : PR","volume":" ","pages":"859-870"},"PeriodicalIF":4.4,"publicationDate":"2022-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9584974/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"40698518","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Vortioxetine liposomes as a novel alternative to improve drug stability under stress conditions: toxicity studies and evaluation of antidepressant-like effect.","authors":"Caroline Hermann Nodari,&nbsp;Natália Dalanhol De Quadros,&nbsp;Raquel Chiarentin,&nbsp;Francini Pereira Da Silva,&nbsp;Fernando Dal Pont Morisso,&nbsp;Mariele Feiffer Charão,&nbsp;Juliane Deise Fleck,&nbsp;Cristiane Bastos De Mattos,&nbsp;Andresa Heemann Betti,&nbsp;Simone Gasparin Verza","doi":"10.1007/s43440-022-00412-w","DOIUrl":"https://doi.org/10.1007/s43440-022-00412-w","url":null,"abstract":"<p><strong>Background: </strong>Vortioxetine hydrobromide (VXT), a new therapeutic option in the treatment of major depressive disorder, is a poorly soluble drug, and instability under stress conditions has been reported. The aim of the present study was to prepare VXT liposomes (VXT-Ls) with an antidepressant-like effect, to improve drug stability and reduce toxicity of the free drug.</p><p><strong>Methods: </strong>Liposomes were prepared using the thin lipid film hydration method and properly characterized. Forced degradation studies were conducted in photolytic and oxidative conditions. The cytotoxicity was evaluated in VERO cells through MTT assay and in vivo toxicity was assessed in mice. The antidepressant-like effect in mice was confirmed using the open-field test paradigm and tail suspension test.</p><p><strong>Results: </strong>The optimized VXT-Ls have multilamellar vesicles with an average size of 176.74 nm ± 2.43. The liposomal formulation increased the stability of VXT. VERO cell viability was maintained at around 40% when the VXT-Ls were tested at higher concentrations and no signs of acute toxicity were observed in mice. The antidepressant-like effect was effective, for VXT-Ls, at doses ranging from 2.5 mg/kg to 10 mg/kg, measured by the tail suspension test in mice. The non-liposomal formulation was effective at a dose of 10 mg/kg. The open field test was performed and any unspecific changes in locomotor activity were revealed.</p><p><strong>Conclusions: </strong>Liposomes seem to be a promising alternative for an oral VXT formulation at lower doses (2.5 mg/kg).</p>","PeriodicalId":166986,"journal":{"name":"Pharmacological reports : PR","volume":" ","pages":"969-981"},"PeriodicalIF":4.4,"publicationDate":"2022-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"33450788","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Luteolin alleviates vascular dysfunctions in CLP-induced polymicrobial sepsis in mice.","authors":"Soya Rungsung,&nbsp;Thakur Uttam Singh,&nbsp;Kirthika Perumalraja,&nbsp;Archana Mahobiya,&nbsp;Meemansha Sharma,&nbsp;Madhu Cholenahalli Lingaraju,&nbsp;Subhashree Parida,&nbsp;Monalisa Sahoo,&nbsp;Dinesh Kumar","doi":"10.1007/s43440-022-00399-4","DOIUrl":"https://doi.org/10.1007/s43440-022-00399-4","url":null,"abstract":"<p><strong>Background: </strong>Luteolin, a naturally occurring flavonoid, is thought to have health-promoting properties as a part of human diet and has been reported to possess a wide range of pharmacological activities. Therefore, the present study was undertaken to evaluate the effect of luteolin pre-treatment on vascular dysfunctions in sepsis induced by caecal ligation and puncture (CLP) in the mouse model.</p><p><strong>Methods: </strong>Mice were divided into four groups: sham, luteolin plus sham, CLP, and luteolin plus CLP. Luteolin was administered (0.2 mg/kg body weight) intraperitoneally one hour (h) before CLP surgery in mice. 20 ± 2 h post CLP surgery, the isolated thoracic aorta of mice was assessed for its vascular reactivity to noradrenaline (NA) and acetylcholine (ACh). To explore the underlying mechanism, aortic mRNA expressions of α_1D adrenoceptors, eNOS and iNOS were investigated.</p><p><strong>Results: </strong>In mice with CLP-induced sepsis luteolin pre-treatment markedly increased the survival time and attenuated serum lactate level. The CLP group manifested the reduced vascular reactivity to NA and this deficit was restored by luteolin pre-treatment. However, luteolin pre-treatment did not improve α_1D adrenoceptors down-regulation observed in septic mice aorta. In the presence of 1400 W, the NA contractile response was significantly restored in CLP mice aortic tissue in comparison with the respective control of septic mice and further enhanced in the presence of luteolin. Luteolin reduced the iNOS mRNA expression and iNOS-derived nitrite production. Pre-treatment with luteolin restored the endothelial dysfunction in septic mice aorta by improving eNOS mRNA expression and enhanced eNOS-derived nitric oxide (NO) production in septic mice aorta and aortic iNOS gene expression and inducible NO production.</p><p><strong>Conclusion: </strong>The present study suggests that the vasoplegic state to NA in aorta was restored through the iNOS pathway and endothelial dysfunction was reversed via eNOS and NO production pathway.</p>","PeriodicalId":166986,"journal":{"name":"Pharmacological reports : PR","volume":" ","pages":"1054-1068"},"PeriodicalIF":4.4,"publicationDate":"2022-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"40609640","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Cannabidiol effect in pentylenetetrazole-induced seizures depends on PI3K.","authors":"Isabel Vieira de Assis Lima,&nbsp;Hyorrana Priscila Pereira Pinto,&nbsp;Paula Maria Quaglio Bellozi,&nbsp;Maria Carolina Machado da Silva,&nbsp;Luciano R Vilela,&nbsp;Fabrício A Moreira,&nbsp;Márcio Flávio Dutra Moraes,&nbsp;Antônio Carlos Pinheiro de Oliveira","doi":"10.1007/s43440-022-00391-y","DOIUrl":"https://doi.org/10.1007/s43440-022-00391-y","url":null,"abstract":"<p><strong>Background: </strong>The phytocannabinoid cannabidiol (CBD) has previously shown to have anticonvulsant effects in preclinical and clinical studies. Recently, CBD has been approved to treat certain types of drug-resistant epileptic syndromes. However, the underlying mechanism of action remains unclear. The phosphatidylinositol 3-kinase (PI3K) signaling pathway has been proposed to modulate seizures and might be recruited by CBD. Thus, we tested the hypothesis that the anticonvulsant effect of CBD involves PI3K in a seizure model induced by pentylenetetrazole (PTZ).</p><p><strong>Methods: </strong>We employed pharmacological and genetic approaches to inhibit PI3K and quantified its effects on seizure duration, latency, and number.</p><p><strong>Results: </strong>PI3K genetic ablation increased the duration and number of seizures. CBD inhibited PTZ-induced seizures in mice. Genetic deletion of PI3K or pretreatment with the selective inhibitor LY294002 prevented CBD effects.</p><p><strong>Conclusion: </strong>Our data strengthen the hypothesis that the CBD anticonvulsant effect requires the PI3K signaling pathway.</p>","PeriodicalId":166986,"journal":{"name":"Pharmacological reports : PR","volume":" ","pages":"1099-1106"},"PeriodicalIF":4.4,"publicationDate":"2022-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"40364174","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"The ixabepilone and vandetanib combination shows synergistic activity in docetaxel-resistant MDA-MB-231 breast cancer cells.","authors":"Stanton Tam,&nbsp;Yassir Al-Zubaidi,&nbsp;Md Khalilur Rahman,&nbsp;Kirsi Bourget,&nbsp;Fanfan Zhou,&nbsp;Michael Murray","doi":"10.1007/s43440-022-00396-7","DOIUrl":"https://doi.org/10.1007/s43440-022-00396-7","url":null,"abstract":"<p><strong>Background: </strong>The lack of drug targets is an obstacle to the treatment of patients with triple-negative breast cancer (TNBC). At present, non-specific cytotoxic drugs are first-line agents, but the development of resistance is a major problem with these agents. The epidermal growth factor receptor (EGFR) is a potential target in some TNBCs, because its tyrosine kinase activity drives tumorigenesis. Thus, small molecule inhibitors of the EGFR in combination with cytotoxic agents could be important for the treatment of TNBCs.</p><p><strong>Methods: </strong>The present study evaluated the efficacies of clinically approved EGFR inhibitors in combination with the cytotoxic agent ixabepilone in parental and docetaxel-resistant MDA-MB-231 cells (231C and TXT cells, respectively). Cell viability was assessed using MTT reduction assays, cell death pathways were evaluated using annexin V/7-aminoactinomycin D staining and flow cytometry and Western immunoblotting was used to assess the expression of pro- and anti-apoptotic proteins in cells.</p><p><strong>Results: </strong>Ixabepilone and the EGFR inhibitors gefitinib and vandetanib inhibited 231C and TXT cell proliferation, but the alternate EGFR inhibitors erlotinib and lapatinib were poorly active. Using combination analysis, ixabepilone/vandetanib was synergistic in both cell types, whereas the ixabepilone/gefitinib combination exhibited antagonism. By flow cytometry, ixabepilone/vandetanib enhanced 231C and TXT cell death over that produced by the single agents and also enhanced caspase-3 cleavage and the pro/anti-apoptotic Bcl-2 protein ratios over ixabepilone alone.</p><p><strong>Conclusions: </strong>These findings suggest that the ixabepilone/vandetanib combination may have promise for the treatment of patients with drug-resistant TNBC.</p>","PeriodicalId":166986,"journal":{"name":"Pharmacological reports : PR","volume":" ","pages":"998-1010"},"PeriodicalIF":4.4,"publicationDate":"2022-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9584993/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"40655053","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Repetitive transcranial direct current stimulation modulates the brain-gut-microbiome axis in obese rodents.","authors":"Agata Ziomber-Lisiak,&nbsp;Katarzyna Talaga-Ćwiertnia,&nbsp;Agnieszka Sroka-Oleksiak,&nbsp;Artur D Surówka,&nbsp;Kajetan Juszczak,&nbsp;Magdalena Szczerbowska-Boruchowska","doi":"10.1007/s43440-022-00401-z","DOIUrl":"https://doi.org/10.1007/s43440-022-00401-z","url":null,"abstract":"<p><strong>Background: </strong>Complex interactions between the brain, gut and adipose tissue allow to recognize obesity as a neurometabolic disorder. The recent data have shown that gut microbiota can play a potential role in obesity development. Transcranial direct current stimulation (tDCS) is a safe and non-invasive technique to modulate the activity of cerebral cortex and other connected brain areas also in context of appetite control. The objective of this study was to evaluate the effects of repetitive anodal tDCS (AtDCS) of prefrontal cortex on feeding behavior, metabolic status and selected phyla of gut microbiota in rats with obesity induced by high-calorie diet (HCD).</p><p><strong>Methods: </strong>32 female Wistar rats were equally divided into 4 subgroups depending on diet effect (lean versus obese) and type of stimulation (active versus sham tDCS versus no stimulation). Feed intake, body weight, blood lipoproteins and leptin levels as well as Firmicutes and Bacteroidetes in intestines and stool were examined.</p><p><strong>Results: </strong>HCD changed feeding behavior and metabolic parameters typically for obesity-related ranges and resulted in an abundance of Firmicutes at the expanse of Bacteroidetes in the large intestine and stool. AtDCS decreased appetite, body weight, and cholesterol levels. In addition, AtDCS reduced ratio of the average number of Firmicutes to average number of Bacteroidetes in all examined tissues.</p><p><strong>Conclusions: </strong>Repetitive AtDCS is not only effective for appetite restriction but can also modulate gut microbiome composition which demonstrates the existence of the brain-gut-microbiome axis and points at this technique as a promising complementary treatment for obesity. However, the effects should be further replicated in human studies.</p>","PeriodicalId":166986,"journal":{"name":"Pharmacological reports : PR","volume":" ","pages":"871-889"},"PeriodicalIF":4.4,"publicationDate":"2022-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9585011/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"40682221","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Evaluation of analgesic and anti-inflammatory activity of purine-2,6-dione-based TRPA1 antagonists with PDE4/7 inhibitory activity.","authors":"Małgorzata Zygmunt,&nbsp;Marietta Ślusarczyk,&nbsp;Agnieszka Jankowska,&nbsp;Artur Świerczek,&nbsp;Adrian Bryła,&nbsp;Szczepan Mogilski,&nbsp;Grzegorz Kazek,&nbsp;Jacek Sapa,&nbsp;Elżbieta Wyska,&nbsp;Grażyna Chłoń-Rzepa","doi":"10.1007/s43440-022-00397-6","DOIUrl":"https://doi.org/10.1007/s43440-022-00397-6","url":null,"abstract":"<p><strong>Background: </strong>To verify the validity of the proposed pain treatment approach, which is based on concomitant blocking of the Transient Receptor Potential Ankyrin 1 (TRPA1) channel and phosphodiesterases (PDEs) 4B/7A activity, we continued our pharmacological studies on 8-alkoxypurine-2,6-diones selected based on previous in vitro screening.</p><p><strong>Methods: </strong>Derivatives 17, 31, and 36 were pharmacologically evaluated in vivo using the formalin test and oxaliplatin-induced neuropathic pain: the von Frey and the cold plate tests, and in the carrageenan-induced edema model. Compound 36, which turned out to be the most promising, was further evaluated in the collagen-induced arthritis model. The pharmacokinetic parameters of this compound were also estimated.</p><p><strong>Results: </strong>All the tested compounds exhibited significant analgesic and anti-inflammatory activities. Compound 36 was additionally characterized by an antiarthritic effect and showed a favorable pharmacokinetic profile in rats.</p><p><strong>Conclusion: </strong>The compounds evaluated in this study represent a new class of derivatives with analgesic and anti-inflammatory activities that involve TRPA1 antagonism and PDE4/7 inhibition.</p>","PeriodicalId":166986,"journal":{"name":"Pharmacological reports : PR","volume":" ","pages":"982-997"},"PeriodicalIF":4.4,"publicationDate":"2022-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9584878/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"40695851","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Contribution of hyperglycemia-induced changes in microglia to Alzheimer's disease pathology.","authors":"Maricarmen Hernández-Rodríguez,&nbsp;Cecilia Flores Clemente,&nbsp;Martha Edith Macías-Pérez,&nbsp;Rolando Alberto Rodríguez-Fonseca,&nbsp;M Inés Nicolás Vázquez,&nbsp;Joel Martínez,&nbsp;Rene Miranda Ruvalcaba,&nbsp;Martín Martínez Rosas,&nbsp;Elvia Mera Jiménez","doi":"10.1007/s43440-022-00405-9","DOIUrl":"https://doi.org/10.1007/s43440-022-00405-9","url":null,"abstract":"<p><p>Alzheimer's disease (AD) is a neurodegenerative condition characterized by cognitive and functional impairments. The investigation of AD has focused on the formation of senile plaques, composed mainly by amyloid β (Aβ) peptide, and neurofibrillary tangles (NFTs) in the brain. Senile plaques and NFTs cause the excessive recruitment and activation of microglia, thus generating neuroinflammation and neuronal damage. Among the risk factors for the development of AD, diabetes has increasingly attracted attention. Hyperglycemia, the fundamental characteristic of diabetes, is involved in several mechanisms that give rise to microglial overactivation, resulting in neuronal damage and cognitive impairment. Indeed, various studies have identified the correlation between diabetes and AD. The aim of this review is to describe various mechanisms of the hyperglycemia-induced overactivation of microglia, which leads to neuroinflammation and neuronal damage and consequently contributes to the pathology of AD. The disruption of the regulation of microglial activity by hyperglycemia occurs through many mechanisms, including a greater production of reactive oxygen species (ROS) and glycation end products (AGEs), and a decrease in the elimination of Aβ. The future direction of research on the relation between hyperglycemia and AD is addressed, such as the importance of determining whether the hyperglycemia-induced harmful effects on microglial activity can be reversed or attenuated if blood glucose returns to a normal level.</p>","PeriodicalId":166986,"journal":{"name":"Pharmacological reports : PR","volume":" ","pages":"832-846"},"PeriodicalIF":4.4,"publicationDate":"2022-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"40331099","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Effect of tricyclic 1,2-thiazine derivatives in neuroinflammation induced by preincubation with lipopolysaccharide or coculturing with microglia-like cells.","authors":"Benita Wiatrak,&nbsp;Edward Krzyżak,&nbsp;Berenika Szczęśniak-Sięga,&nbsp;Marta Szandruk-Bender,&nbsp;Adam Szeląg,&nbsp;Beata Nowak","doi":"10.1007/s43440-022-00414-8","DOIUrl":"https://doi.org/10.1007/s43440-022-00414-8","url":null,"abstract":"<p><strong>Background: </strong>Alzheimer's disease (AD) is considered the most common cause of dementia among the elderly. One of the modifiable causes of AD is neuroinflammation. The current study aimed to investigate the influence of new tricyclic 1,2-thiazine derivatives on in vitro model of neuroinflammation and their ability to cross the blood-brain barrier (BBB).</p><p><strong>Methods: </strong>The potential anti-inflammatory effect of new tricyclic 1,2-thiazine derivatives (TP1, TP4, TP5, TP6, TP7, TP8, TP9, TP10) was assessed in SH-SY5Y cells differentiated to the neuron-like phenotype incubated with bacterial lipopolysaccharide (5 or 50 μg/ml) or THP-1 microglial cell culture supernatant using MTT, DCF-DA, Griess, and fast halo (FHA) assays. Additionally, for cultures preincubated with 50 µg/ml lipopolysaccharide (LPS), a cyclooxygenase (COX) activity assay was performed. Finally, the potential ability of tested compounds to cross the BBB was evaluated by computational studies. Molecular docking was performed with the TLR4/MD-2 complex to assess the possibility of binding the tested compounds in the LPS binding pocket. Prediction of ADMET parameters (absorption, distribution, metabolism, excretion and toxicity) was also conducted.</p><p><strong>Results: </strong>The unfavorable effect of LPS and co-culture with THP-1 cells on neuronal cell viability was counteracted with TP1 and TP4 in all tested concentrations. Tested compounds reduced the oxidative and nitrosative stress induced by both LPS and microglia activation and also reduced DNA damage. Furthermore, new derivatives inhibited total COX activity. Additionally, new compounds would cross the BBB with high probability and reach concentrations in the brain not lower than in the serum. The binding affinity at the TLR4/MD-2 complex binding site of TP4 and TP8 compounds is similar to that of the drug donepezil used in Alzheimer's disease. The ADMET analysis showed that the tested compounds should not be toxic and should show high intestinal absorption.</p><p><strong>Conclusions: </strong>New tricyclic 1,2-thiazine derivatives exert a neuroregenerative effect in the neuroinflammation model, presumably via their inhibitory influence on COX activity and reduction of oxidative and nitrosative stress.</p>","PeriodicalId":166986,"journal":{"name":"Pharmacological reports : PR","volume":" ","pages":"890-908"},"PeriodicalIF":4.4,"publicationDate":"2022-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9584986/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"40374153","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}