• MeSH
• Alzheimerova nemoc metabolismus   MeSH
• cholinergní vlákna metabolismus   MeSH
• lidé MeSH
• mozek metabolismus   MeSH
• receptory cholinergní metabolismus   MeSH
• Check Tag
• lidé MeSH
• Publikační typ
• časopisecké články MeSH
• Názvy látek
• receptory cholinergní MeSH

Organophosphorus nerve agents inhibit acetylcholinesterase (AChE) which causes the breakdown of the transmitter acetylcholine (ACh) in the synaptic cleft. Overstimulation of cholinergic receptors (muscarinic and nicotinic) by excessive amounts of ACh causes several health problems and may even cause death. Reversible AChE inhibitors play an important role in prophylaxis against nerve agents. The presented study investigated whether 7-methoxytacrine (7-MEOTA) and 7-MEOTA-donepezil derivatives can act as central and peripheral reversible AChE inhibitors and simultaneously antagonize muscarinic and nicotinic receptors. The possible mechanism of action was studied on cell cultures (patch clamp technique, calcium mobilization assay) and on isolated smooth muscle tissue (contraction study). Furthermore, the kinetics of the compounds were also examined. CNS availability was predicted by determining the passive blood-brain barrier penetration estimated via a modified PAMPA assay. In conclusion, this study provides promising evidence that the new synthesized 7-MEOTA-donepezil derivatives have the desired anticholinergic effect; they can inhibit AChE, and nicotinic and muscarinic receptors in the micromolar range. Furthermore, they seem to penetrate readily into the CNS. However, their real potency and benefit must be verified by in vivo experiments.

• MeSH
• antagonisté muskarinových receptorů aplikace a dávkování   MeSH
• cholinergní antagonisté aplikace a dávkování   MeSH
• donepezil MeSH
• indany aplikace a dávkování   MeSH
• kosterní svalová vlákna účinky léků   metabolismus   MeSH
• krysa rodu Rattus MeSH
• kultivované buňky MeSH
• nikotinoví antagonisté aplikace a dávkování   MeSH
• piperidiny aplikace a dávkování   MeSH
• potkani Wistar MeSH
• takrin aplikace a dávkování   analogy a deriváty   MeSH
• vztah mezi dávkou a účinkem léčiva MeSH
• zvířata MeSH
• Check Tag
• krysa rodu Rattus MeSH
• mužské pohlaví MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH
• Názvy látek
• 7-methoxytacrine MeSH Prohlížeč
• antagonisté muskarinových receptorů MeSH
• cholinergní antagonisté MeSH
• donepezil MeSH
• indany MeSH
• nikotinoví antagonisté MeSH
• piperidiny MeSH
• takrin MeSH

BACKGROUND: Stroke is devastating cerebrovascular event which is responsible for 6.7 million deaths each year worldwide. Inflammation plays an important role in the pathophysiology of stroke. Targeting inflammation after stroke is highly actual topic for both experimental and clinical research. METHODS: Research articles related to cholinergic anti-inflammatory pathway (CHAIP) and stroke were reviewed. The first part of review describes the basic characteristics of inflammatory response after stroke, main components and function of CHAIP. The second part reviews studies focused on CHAIP as a therapeutic target for ischemic and hemorrhagic stroke. Both pharmacological stimulation of α7 nAChR and vagus nerve stimulation after stroke are reviewed. RESULTS: Cholinergic anti-inflammatory pathway (CHAIP) is a physiological mechanism by which central nervous system regulates immune response and controls inflammation. Vagus nerve, spleen and α7 nicotinic acetylcholine receptor (α7 nAChR) are the main components of CHAIP. CONCLUSION: Targeting cholinergic anti-inflammatory pathway is a promising way of immunomodulation which attenuates inflammation in a complex manner without causing immunosuppression.

• Klíčová slova
• Cerebral ischemia, Vagus nerve stimulation, cholinergic anti-inflammatory pathway, inflammation, intracerebral hemorrhage, stroke, subarachnoid hemorrhage, α7 nicotinic acetylcholine receptor (α7 nAChR),
• MeSH
• alfa7 nikotinové acetylcholinové receptory fyziologie   MeSH
• centrální nervový systém fyziologie   MeSH
• cévní mozková příhoda imunologie   patofyziologie   MeSH
• lidé MeSH
• nervus vagus fyziologie   MeSH
• slezina fyziologie   MeSH
• zánět patofyziologie   MeSH
• Check Tag
• lidé MeSH
• Publikační typ
• časopisecké články MeSH
• přehledy MeSH
• Názvy látek
• alfa7 nikotinové acetylcholinové receptory MeSH

We have found earlier that the depolarization-induced release of acetylcholine from the brain could be inhibited by tacrine (tetrahydroaminoacridine) but the mechanism of this action of tacrine was not clarified (S. Tucek, V. Dolezal, J. Neurochem. 56 (1991) 1216). We have now investigated whether tacrine has an effect on the changes in the intracellular concentration of calcium ions ([Ca2+]i) induced by depolarization. Experiments were performed on the cholinergic SN56 neuronal cell line with Fura-2 fluorescence technique of calcium imaging. The depolarization by 71 mmol/l K+ evoked minimum increases of [Ca2+]i up to day 5 in culture. Then the response gradually increased and reached a plateau after 7 days in culture. A similar time course was observed for acetylcholinesterase activity. The effect of K+ ions was concentration-dependent and the concentration of 71 mmol/l K+ evoked maximum [Ca2+]i responses. The increases of [Ca2+]i did not occur in the absence of extracellular calcium. They were mediated by high voltage-activated calcium channels of the L-type and the N-type. Nifedipine (2 micromol/l; L-type calcium channel blocker) and omega-conotoxin GVIA (100 nmol/l; N-type calcium channel blocker) diminished the response to 71 mmol/l K+ by 53% and 39%, respectively, and their effects were additive (decrease to 8% of controls). Non-selective inorganic blocker of voltage-activated calcium channels LaCl3 (0.1 mmol/l) decreased the response by 83%. Tacrine attenuated the [Ca2+]i response in a concentration-dependent manner. At a concentration of 10 micromol/l it inhibited the [Ca2+]i response by 55% and its inhibitory effect was additive with that of omega-conotoxin GVIA but not with that of nifedipine. An equimolar concentration of paraoxon, an irreversible inhibitor of cholinesterases, had no influence on [Ca2+]i response. Tacrine exhibited the same inhibitory effect when paraoxon was present. In conclusion, our data indicate that high-voltage-activated calcium channels of the L-type and the N-type are both present in the SN56 cells but that they are fully expressed only after 6-7 days in culture. Tacrine attenuates the influx of calcium by inhibiting the L-type calcium channels. This inhibitory effect is not a consequence of the anticholinesterase activity of tacrine. The finding that low micromolar concentrations of tacrine may interfere with calcium-dependent events is likely to be of importance for the evaluation of the therapeutic potential of the drug.

• MeSH
• acetylcholin metabolismus   MeSH
• agonisté muskarinových receptorů farmakologie   MeSH
• blokátory kalciových kanálů farmakologie   MeSH
• chlorid draselný farmakologie   MeSH
• cholinesterasové inhibitory farmakologie   MeSH
• fúze buněk MeSH
• intracelulární membrány metabolismus   MeSH
• karbachol farmakologie   MeSH
• myši MeSH
• nádorové buňky kultivované MeSH
• neurony účinky léků   metabolismus   MeSH
• nikotinoví agonisté farmakologie   MeSH
• takrin farmakologie   MeSH
• vápník metabolismus   MeSH
• vztah mezi dávkou a účinkem léčiva MeSH
• zvířata MeSH
• Check Tag
• myši MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH
• Názvy látek
• acetylcholin MeSH
• agonisté muskarinových receptorů MeSH
• blokátory kalciových kanálů MeSH
• chlorid draselný MeSH
• cholinesterasové inhibitory MeSH
• karbachol MeSH
• nikotinoví agonisté MeSH
• takrin MeSH
• vápník MeSH

Brain activity during the resting state is widely used to examine brain organization, cognition and alterations in disease states. While it is known that neuromodulation and the state of alertness impact resting-state activity, neural mechanisms behind such modulation of resting-state activity are unknown. In this work, we used a computational model to demonstrate that change in excitability and recurrent connections, due to cholinergic modulation, impacts resting-state activity. The results of such modulation in the model match closely with experimental work on direct cholinergic modulation of Default Mode Network (DMN) in rodents. We further extended our study to the human connectome derived from diffusion-weighted MRI. In human resting-state simulations, an increase in cholinergic input resulted in a brain-wide reduction of functional connectivity. Furthermore, selective cholinergic modulation of DMN closely captured experimentally observed transitions between the baseline resting state and states with suppressed DMN fluctuations associated with attention to external tasks. Our study thus provides insight into potential neural mechanisms for the effects of cholinergic neuromodulation on resting-state activity and its dynamics.

• MeSH
• acetylcholin metabolismus   MeSH
• default mode network fyziologie   diagnostické zobrazování   MeSH
• dospělí MeSH
• konektom * MeSH
• lidé MeSH
• magnetická rezonanční tomografie MeSH
• modely neurologické * MeSH
• mozek * fyziologie   diagnostické zobrazování   MeSH
• nervová síť fyziologie   diagnostické zobrazování   MeSH
• odpočinek * fyziologie   MeSH
• počítačová simulace MeSH
• výpočetní biologie MeSH
• Check Tag
• dospělí MeSH
• lidé MeSH
• mužské pohlaví MeSH
• Publikační typ
• časopisecké články MeSH
• Názvy látek
• acetylcholin MeSH

On the basis of our previous investigations concerning the influence of some central nervous system structures on the immune reaction, we have shown the existence of a brain regulatory system for immune response (BRSIR). We have investigated this BRSIR using small electrolytic lesions placed in different brain areas of male rats, followed by two methods to evaluate the effect of the lesions on the immune response, the method of delayed skin hypersensitivity and the method of utilization of 3H-thymidine for synthesis of DNA after injection of muramyl dipeptide, a very potent immunostimulating compound. The experiments were performed on rats of the Wistar strain. Lesions were placed from the spinal cord through the brain stem to the cerebral cortex. The results suggest that the following structures constitute parts of the BRSIR: medial frontal cortex (areas Cg 1-3), subnucleus basomedialis and centralis of the amygdala, subnucleus medialis and dorsolateralis of the nucleus parabrachialis, lateral reticular formation (nucleus parvocellularis--mainly areas corresponding with aminergic groups A1-7), part of the raphe reticular formation (nucleus raphealis dorsalis and nucleus linearis--mainly areas corresponding with serotoninergic groups B6-8), and the spinal cord.

• MeSH
• amygdala fyziologie   MeSH
• buněčné dělení MeSH
• čelní lalok fyziologie   MeSH
• krysa rodu Rattus MeSH
• mapování mozku MeSH
• mícha fyziologie   MeSH
• mozek fyziologie   MeSH
• neuroimunomodulace fyziologie   MeSH
• potkani Wistar MeSH
• serotonin fyziologie   MeSH
• zvířata MeSH
• Check Tag
• krysa rodu Rattus MeSH
• mužské pohlaví MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH
• Názvy látek
• serotonin MeSH

The lipids constitute majority of dry weight of mature human brain. From lipids, 35% is comprised of PUFA with long chain (LC-PUFA), especially docosahexaenoic acid (DHA) of n-3 family and arachidonic acid (AA) of n-6 family. Humans are dependent on dietary intake of both AA and DHA. Interestingly, the dietary n-6/n-3 ratio increased considerably during last century. LC-PUFAs play numerous roles in the brain, including structural (forming the physico-chemical properties in the lipid bilayer of cellular membranes) and signaling ones. Moreover, they influence neurogenesis and neurotransmission within the nervous tissue. The metabolites of PUFA modulate immune and inflammatory processes in the brain, oxidative stress as well as its consequences. Of high importance is also their connection with several metabolic factors involved in the proper function of the brain and/or were discovered to play a role in the pathogenesis of neuropsychiatric diseases - melatonin, homocysteine, leptin, and adiponectin. This review gives short view of the metabolism and possible mechanisms of PUFA n-3 action in the brain, and their role in the pathogenesis of psychiatric diseases.

• MeSH
• duševní poruchy imunologie   metabolismus   MeSH
• lidé MeSH
• mozek imunologie   metabolismus   MeSH
• neuroimunomodulace fyziologie   MeSH
• omega-3 mastné kyseliny metabolismus   MeSH
• oxidační stres fyziologie   MeSH
• zvířata MeSH
• Check Tag
• lidé MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH
• přehledy MeSH
• Názvy látek
• omega-3 mastné kyseliny MeSH

Alzheimer's disease is the most common neurodegenerative disorder in men and its incidence increases with the prolongation of life expectancy. The late phase of the disease is accompanied by a failure of cognitive and mental functions. Post mortem examination of the brain reveals the presence of neuritic plaques and neurofibrillary tangles, particularly in the cortex and hippocampus, and a reduction of the number of cerebrocortical neurons. Biochemical changes include the affliction of various neurotransmitter systems with the obligatory damage of the basal forebrain cholinergic system. Understanding of the pathogeny of Alzheimer's disease and, consequently, of ways to its therapy is still quite limited, in spite of enormous effort by investigators. Advanced molecular biological and genetical approaches indicate that the primary cause of Alzheimer's disease is the accumulation and toxic action of beta-amyloid peptide, which is formed as a less common breakdown product of the amyloid precursor protein. In this review we briefly outline some recent ideas concerning the origin and progression of the disease, with the main focus on the metabolism of beta-amyloid and on possible mechanisms of its deleterious influence on the neuronal, particularly cholinergic cells. Two basic cytotoxic effects of beta-amyloid on neurons appear to be the disturbance of the homeostasis of intracellular calcium ions and the induction of oxidative stress, and they together bring about necrotic or apoptotic cell death. However, it has been found in experiments that the damage of cholinergic neurons and cholinergic neurotransmission can be induced by beta-amyloid at such low concentrations which do not yet evoke general cytotoxic effects. Weakening of cholinergic neurotransmission is known to result in an increase in the production of beta-amyloid, and the damage of cholinergic neurons thus seems to initiate a vicious circle which speeds up the progression of the disease.

• MeSH
• Alzheimerova nemoc genetika   metabolismus   patologie   patofyziologie   MeSH
• amyloidní beta-protein genetika   metabolismus   fyziologie   MeSH
• cholinergní vlákna metabolismus   fyziologie   MeSH
• homeostáza MeSH
• lidé MeSH
• mozek metabolismus   patologie   MeSH
• nervový přenos fyziologie   MeSH
• oxidační stres MeSH
• rizikové faktory MeSH
• vápník metabolismus   MeSH
• Check Tag
• lidé MeSH
• Publikační typ
• anglický abstrakt MeSH
• časopisecké články MeSH
• práce podpořená grantem MeSH
• přehledy MeSH
• Názvy látek
• amyloidní beta-protein MeSH
• vápník MeSH

Muramyl dipeptide (MDP) has a variety of biological effects including the effect on CNS, such a promotion of sleep, fever, analgesic effect or some behavioural changes and of course a very potent effect on immune system. The latter effect is at least partly mediated through the structure in CNS. With the small electrolytic lesions which were placed in brain from the spinal cord through the brain stem up to the cerebral cortex we have identified a number of structures such as medial frontal cortex (area Cg1-Cg3), subnucleus basomedialis and centralis of amygdala, subnucleus medialis and dorsolateralis of nucleus parabrachialis, lateral part of reticular formation (monoaminergic groups A1-7) and the part of the reticular formation (serotonergic groups B6-B8) which are evidently involved in the immunomodulatory and immunoadjuvant effect of muramyl dipeptide. The results of experiments also suggest that the interaction between neuroendocrine and immune systems might take place on the level of some of above mentioned anatomical structures.

• MeSH
• acetylmuramyl-alanyl-isoglutamin farmakologie   MeSH
• adjuvancia imunologická farmakologie   MeSH
• chování zvířat účinky léků   MeSH
• horečka chemicky indukované   MeSH
• mozek anatomie a histologie   účinky léků   imunologie   MeSH
• myši MeSH
• neuroimunomodulace * účinky léků   MeSH
• práh bolesti účinky léků   MeSH
• receptory serotoninové účinky léků   metabolismus   MeSH
• serotonin metabolismus   MeSH
• spánek účinky léků   MeSH
• zvířata MeSH
• Check Tag
• myši MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH
• Názvy látek
• acetylmuramyl-alanyl-isoglutamin MeSH
• adjuvancia imunologická MeSH
• receptory serotoninové MeSH
• serotonin MeSH

The author presents a review of agents which are presently included in the category of nootropic drugs and comments the relations between the pharmaceutical research of new nootropic and progressing knowledge of the neuropathobiology of Alzheimer's disease, senile dementia and degenerative processes of aging brain in general. In Part I., several hypotheses are discussed which explain the biological substrate of senile cognitive decline by disturbed brain synaptic neurotransmission (cholinergic, monoaminergic, petidergic) and, at the same time, drugs are suggested which may exert regulatory action on these dysfunctions.

• MeSH
• Alzheimerova nemoc farmakoterapie   patofyziologie   MeSH
• demence farmakoterapie   patologie   patofyziologie   MeSH
• lidé MeSH
• mozek patofyziologie   MeSH
• nervový přenos * účinky léků   MeSH
• nootropní látky terapeutické užití   MeSH
• Check Tag
• lidé MeSH
• Publikační typ
• anglický abstrakt MeSH
• časopisecké články MeSH
• přehledy MeSH
• Názvy látek
• nootropní látky MeSH