New tritarget small molecules combining Ca2+ channels blockade, cholinesterase, and H3 receptor inhibition were obtained by multicomponent synthesis. Compound 3p has been identified as a very promising lead, showing good Ca2+ channels blockade activity (IC50 = 21 ± 1 μM), potent affinity against hH3R (Ki = 565 ± 62 nM), a moderate but selective hBuChE inhibition (IC50 = 7.83 ± 0.10 μM), strong antioxidant power (3.6 TE), and ability to restore cognitive impairment induced by lipopolysaccharide.
- MeSH
- Alzheimerova nemoc farmakoterapie metabolismus MeSH
- blokátory kalciových kanálů chemie farmakologie MeSH
- cholinesterasové inhibitory chemie farmakologie MeSH
- knihovny malých molekul chemie farmakologie MeSH
- lidé MeSH
- myši MeSH
- nádorové buňky kultivované MeSH
- neuroblastom farmakoterapie metabolismus MeSH
- neuroprotektivní látky chemie farmakologie MeSH
- poruchy paměti farmakoterapie metabolismus MeSH
- receptory histaminu H3 chemie MeSH
- vazodilatancia chemie farmakologie MeSH
- zvířata MeSH
- Check Tag
- lidé MeSH
- myši MeSH
- zvířata MeSH
- Publikační typ
- časopisecké články MeSH
- práce podpořená grantem MeSH
Prenatal exposure to caffeine can cause developmental problems. This study determined chronic influence of prenatal caffeine at relatively higher doses on cognitive functions in the rat offspring. Pregnant Sprague-Dawley rats (4-month-old) were exposed to caffeine (20 mg/kg, twice a day) for whole pregnancy from gestational day 4. Fetal and offspring body and brain weight was measured. Learning and memory were tested in adult offspring with Morris water maze. Learning and memory-related receptors were measured. The exposure to prenatal caffeine not only caused fetal growth restriction, but also showed long-term effects on learning and memory in the offspring. The caffeine offspring exhibited longer escape latency and path length in navigation testing. The number of passing the target was significantly reduced in those offspring. The expression of adenosine A(1) and A(2A) receptors, nuclear PKA C(alpha), C(beta) subunits, and pCREB were significantly increased in the fetal and neonatal brain, and suppressed in the hippocampus of the adult offspring. The expression of BDNF and TrkB were reduced regardless of various ages. The results suggest that intrauterine programming dysfunction of adenosine receptors and the down-stream of cAMP/PKA/pCREB system may play an important role in prenatal caffeine induced cognition disorders in the adult offspring.
- MeSH
- bludiště - učení účinky léků fyziologie MeSH
- kofein toxicita MeSH
- krysa rodu rattus MeSH
- mozkový neurotrofický faktor metabolismus MeSH
- paměť účinky léků fyziologie MeSH
- poruchy paměti chemicky indukované diagnóza metabolismus MeSH
- potkani Sprague-Dawley MeSH
- protein vázající cAMP responzivní element metabolismus MeSH
- proteinkinasy závislé na cyklickém AMP metabolismus MeSH
- purinergní receptory P1 metabolismus MeSH
- signální transdukce účinky léků fyziologie MeSH
- těhotenství MeSH
- zpožděný efekt prenatální expozice chemicky indukované diagnóza 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
Obesity and type 2 diabetes mellitus (T2DM) were characterized as risk factors for Alzheimer's disease (AD) development. Subsequently, T2DM drugs, such as liraglutide, were proven to be neuroprotective compounds attenuating levels of amyloid deposits, and tau hyperphosphorylation, both hallmarks of AD. The central anorexigenic effects of liraglutide inspired us to examine the potential neuroprotective effects of palm11-PrRP31, a strong anorexigenic analog with glucose-lowering properties, in THY-Tau22 mice overexpressing mutated human tau, a model of AD-like tau pathology. Seven-month-old THY-Tau22 mice were subcutaneously infused with palm11-PrRP31 for 2 months. Spatial memory was tested before and after the treatment, using a Y-maze. At the end of the treatment, mice were sacrificed by decapitation and hippocampi were dissected and analyzed by immunoblotting with specific antibodies. Treatment with palm11-PrRP31 resulted in significantly improved spatial memory. In the hippocampi of palm11-PrRP31-treated THY-Tau22 mice, tau protein phosphorylation was attenuated at Thr231, Ser396, and Ser404, the epitopes linked to AD progression. The mechanism of this attenuation remains unclear, since the activation of those kinases most implicated in tau hyperphosphorylation, such as GSK-3β, JNK, or MAPK/ERK1/2, remained unchanged by palm11-PrRP31 treatment. Furthermore, we observed a significant increase in the amount of postsynaptic density protein PSD95, and a non-significant increase of synaptophysin, both markers of increased synaptic plasticity, which could also result in improved spatial memory of THY-Tau22 mice treated with palm11-PrRP31. Palm11-PrRP31 seems to be a potential tool for the attenuation of neurodegenerative disorders in the brain. However, the exact mechanism of its action must be elucidated.
- MeSH
- bludiště - učení účinky léků fyziologie MeSH
- fosforylace účinky léků MeSH
- hipokampus účinky léků metabolismus patologie MeSH
- hormon uvolňující prolaktin analogy a deriváty farmakologie terapeutické užití MeSH
- krátkodobá paměť účinky léků fyziologie MeSH
- modely nemocí na zvířatech MeSH
- myši transgenní MeSH
- neuroprotektivní látky farmakologie MeSH
- poruchy paměti farmakoterapie metabolismus patologie MeSH
- prostorová paměť účinky léků fyziologie MeSH
- proteiny tau metabolismus MeSH
- tauopatie farmakoterapie metabolismus patologie psychologie MeSH
- zvířata MeSH
- Check Tag
- ženské pohlaví MeSH
- zvířata MeSH
- Publikační typ
- časopisecké články MeSH
- práce podpořená grantem MeSH
Alzheimer's disease (AD) is a primary cause of dementia in the middle-aged and elderly worldwide. Animal models for AD are widely used to study the disease mechanisms as well as to test potential therapeutic agents for disease modification. Among the non-genetically manipulated neuroinflammation models for AD, lipopolysaccharide (LPS)-induced animal model is commonly used. This review paper aims to discuss the possible factors that influence rats' response following LPS injection. Factors such as dose of LPS, route of administration, nature and duration of exposure as well as age and gender of animal used should be taken into account when designing a study using LPS-induced memory impairment as model for AD.
- MeSH
- Alzheimerova nemoc chemicky indukované metabolismus patologie MeSH
- krysa rodu rattus MeSH
- lidé MeSH
- lipopolysacharidy toxicita MeSH
- mediátory zánětu metabolismus MeSH
- modely nemocí na zvířatech * MeSH
- poruchy paměti chemicky indukované metabolismus patologie MeSH
- zvířata MeSH
- Check Tag
- krysa rodu rattus MeSH
- lidé MeSH
- zvířata MeSH
- Publikační typ
- časopisecké články MeSH
- přehledy MeSH
