A series of tacrine - benzothiazole hybrids incorporate inhibitors of acetylcholinesterase (AChE), amyloid β (Aβ) aggregation and mitochondrial enzyme ABAD, whose interaction with Aβ leads to mitochondrial dysfunction, into a single molecule. In vitro, several of 25 final compounds exerted excellent anti-AChE properties and interesting capabilities to block Aβ aggregation. The best derivative of the series could be considered 10w that was found to be highly potent and selective towards AChE with the IC50 value in nanomolar range. Moreover, the same drug candidate exerted absolutely the best results of the series against ABAD, decreasing its activity by 23% at 100 μM concentration. Regarding the cytotoxicity profile of highlighted compound, it roughly matched that of its parent compound - 6-chlorotacrine. Finally, 10w was forwarded for in vivo scopolamine-induced amnesia experiment consisting of Morris Water Maze test, where it demonstrated mild procognitive effect. Taking into account all in vitro and in vivo data, highlighted derivative 10w could be considered as the lead structure worthy of further investigation.
- MeSH
- 3-hydroxyacyl-CoA-dehydrogenasy antagonisté a inhibitory metabolismus MeSH
- acetylcholinesterasa metabolismus MeSH
- Alzheimerova nemoc farmakoterapie metabolismus MeSH
- amyloidní beta-protein antagonisté a inhibitory metabolismus MeSH
- benzothiazoly chemie farmakologie MeSH
- cholinergní látky chemická syntéza chemie farmakologie MeSH
- inhibitory enzymů chemická syntéza chemie farmakologie MeSH
- lidé MeSH
- mitochondrie účinky léků metabolismus MeSH
- molekulární struktura MeSH
- neuroprotektivní látky chemická syntéza chemie farmakologie MeSH
- proteinové agregáty účinky léků MeSH
- takrin chemie farmakologie MeSH
- vztah mezi dávkou a účinkem léčiva MeSH
- vztahy mezi strukturou a aktivitou MeSH
- Check Tag
- lidé MeSH
- Publikační typ
- časopisecké články MeSH
- práce podpořená grantem MeSH
Macrophages play an important role in the immune system. They also participate in multiple processes including angiogenesis and triggering of inflammation. The present study summarizes pieces of knowledge on the importance of macrophages in disease, especially the inflammation. Special attention is paid to the cholinergic anti-inflammatory pathway (CAP) associated with the nicotinic acetylcholine receptor (nAChR) and the parasympathetic nervous system. The current pharmacological effectiveness in suppressing the inflammation in general and the septic shock in particular, is limited. CAP was discovered recently and it seems to be a suitable target for the development of new drugs. Moreover, available drugs binding to either nAChR or acetylcholinesterase (AChE) are candidates for either an inhibition or enhancement of CAP. Though the current scientific databases do not include all necessary data on the association of CAP with body functions and the research is quite intensive, the objective of the present review is to introduce the current trends and to critically evaluate CAP and macrophage-associated pathways.
- MeSH
- acetylcholinesterasa metabolismus MeSH
- antiflogistika nesteroidní chemie terapeutické užití MeSH
- cholinergní látky chemie terapeutické užití MeSH
- HIV infekce imunologie patologie MeSH
- hormony kůry nadledvin terapeutické užití MeSH
- lidé MeSH
- makrofágy imunologie MeSH
- nikotinové receptory metabolismus MeSH
- reaktivní formy kyslíku metabolismus MeSH
- zánět farmakoterapie imunologie MeSH
- zvířata MeSH
- Check Tag
- lidé MeSH
- zvířata MeSH
- Publikační typ
- časopisecké články MeSH
- práce podpořená grantem MeSH
- přehledy MeSH
A variety of current studies is concentrated on the effect of short-term or long-term administration of nicotine in humans and in animals. The aim of this study was to investigate the effect of nicotine after a single administration in two different doses on the brain bioelectrical activity and on behaviour and motor activity in young, immature rats. Male Wistar albino rats, 12-day-old, were used in the experiment. Two groups were administrated by one intraperitoneal (i.p.) injection of nicotine in two various doses. The last (the third) group, which was given one i.p. saline injection, served as a control group. The group with lower dose of nicotine (0.75 mg/kg body weight) showed only mild alteration of the electrocorticogram (ECoG), and no behavioural or motor changes. In the second group (with higher dose of nicotine – 1.00 mg/kg), epileptiform discharges manifested in about 50% of animals. Those animals showed also changes in motor activity (tremor of hindlimbs), but only slightly expressed within the time when epileptiform changes occurred in the ECoG. Routine behaviour and locomotion was observed only in a part of animals. In the third group (control group) no changes in bioelectrical activity, in behaviour or in motor activity were observed. We conclude that even a single dose of nicotine can evoke alteration in the ECoG, in behaviour and in motor activity of immature rats. On the other hand, the quantity, quality and length of ECoG abnormalities as well as parameters of behaviour were closely related to the dose of nicotine.
- MeSH
- centrální nervový systém patofyziologie účinky léků MeSH
- cholinergní látky chemie metabolismus MeSH
- chování zvířat fyziologie účinky léků MeSH
- elektroencefalografie metody přístrojové vybavení využití MeSH
- elektrofyziologie metody přístrojové vybavení MeSH
- experimenty na zvířatech MeSH
- financování organizované MeSH
- mozek patofyziologie patologie účinky léků MeSH
- neurotransmiterové látky chemie metabolismus MeSH
- nikotin aplikace a dávkování škodlivé účinky MeSH
- pohybová aktivita fyziologie účinky léků MeSH
- potkani Wistar MeSH
- statistika jako téma MeSH
- věkové faktory MeSH
- zvířata MeSH
- Check Tag
- zvířata MeSH
- MeSH
- barvení a značení metody MeSH
- cholinergní látky chemie MeSH
- finanční podpora výzkumu jako téma MeSH
- mikroskopie elektronová rastrovací MeSH
- platýs parazitologie MeSH
- ploštěnci anatomie a histologie růst a vývoj ultrastruktura MeSH
- stadia vývoje MeSH
- žábry parazitologie MeSH
- zvířata MeSH
- Check Tag
- zvířata MeSH
