Retrieval deficit of long-term memory is a cardinal symptom of dementia and has been proposed to associate with abnormalities in the central cholinergic system. Difficulty in the retrieval of memory is experienced by healthy individuals and not limited to patients with neurological disorders that result in forgetfulness. The difficulty of retrieving memories is associated with various factors, such as how often the event was experienced or remembered, but it is unclear how the cholinergic system plays a role in the retrieval of memory formed by a daily routine (accumulated experience). To investigate this point, we trained rats moderately (for a week) or extensively (for a month) to detect a visual cue in a two-alternative forced-choice task. First, we confirmed the well-established memory in the extensively trained group was more resistant to the retrieval problem than recently acquired memory in the moderately trained group. Next, we tested the effect of a cholinesterase inhibitor, donepezil, on the retrieval of memory after a long no-task period in extensively trained rats. Pre-administration of donepezil improved performance and reduced the latency of task initiation compared to the saline-treated group. Finally, we lesioned cholinergic neurons of the nucleus basalis magnocellularis (NBM), which project to the entire neocortex, by injecting the cholinergic toxin 192 IgG-saporin. NBM-lesioned rats showed severely impaired task initiation and performance. These abilities recovered as the trials progressed, though they never reached the level observed in rats with intact NBM. These results suggest that acetylcholine released from the NBM contributes to the retrieval of well-established memory developed by a daily routine.Previous data indicate that the diabetogenic substance streptozotocin might act in nociceptive neurons changing the sensory signal, regardless of hyperglycemia. In the present article the effects of streptozotocin were compared with another diabetogenic drug, alloxan, for diabetes induction in rats. A possible direct effect of these drugs was tested by means of in vivo experiments and in vitro assays using cultured primary nociceptive neurons. Streptozotocin (17.5 and 35 mg/kg), alloxan (15 and 30 mg/kg) or vehicle were injected in adult male rats and the animal groups were separated according to glycemic levels. Body mass, glycemia and paw mechanical sensitivity were evaluated for 5 weeks. Streptozotocin caused an increase in mechanical sensitivity in both hyperglycemic and normoglycemic rats, while alloxan induced mechanical sensitization only in hyperglycemic animals. Injection of both substances induced local inflammation at rat paws; however, only streptozotocin caused significant mechanical sensitization when injected near to sensory neurons at the dorsal root ganglia. Also, streptozotocin treatment induced a reduction in intracellular calcium levels and inhibited capsaicin induced calcium transients and membrane depolarization. Alloxan did not affect calcium levels or membrane potential in primary nociceptive neurons. These findings suggest that alloxan might be a better option for animal studies regarding painful diabetic neuropathy as streptozotocin directly affects nociceptive neurons, probably by modulating TRPV1 channel activation.Often, the time evolution of a biochemical reaction network is crucial for determining the effects of combining multiple pharmaceuticals. Here we illustrate a mathematical framework for modeling the dominant temporal behaviour of a complicated molecular pathway or biochemical reaction network in response to an arbitrary perturbation, such as resulting from the administration of a therapeutic agent. The method enables the determination of the temporal evolution of a target protein as the perturbation propagates through its regulatory network. The mathematical approach is particularly useful when the experimental data that is available for characterizing or parameterizing the regulatory network is limited or incomplete. To illustrate the method, we consider the examples of the regulatory networks for the target proteins c-Myc and Chop, which play an important role in venetoclax resistance in acute myeloid leukemia. First we show how the networks that regulate each target protein can be reduced to a mean-field masily extended to sets of target proteins to model components of a larger systems biology model, and provides an approach for partially integrating RNA sequencing data and protein expression data. Moreover, it is a general approach that can be used to study drug effects on specific protein(s) in any disease or condition.ZCY-15, N-(3,5-dimethyladamatan-1-yl)-N-(3-methylphenyl) urea, is a candidate compound synthesized from the memantine structure and has been shown to be remarkably effective in treating Alzheimer's disease. To elucidate the pharmacokinetics and tissue distribution of ZCY-15 in rats after oral and intravenous administration, a rapid and selective LC-MS/MS method was established for the determination of ZCY-15 in rat plasma and tissues.  https://www.selleckchem.com/products/nms-p937-nms1286937.html  According to the dissolution characteristics, the plasma samples were prepared by acetonitrile protein precipitation and carbamazepine was selected as the internal standard (IS). After separation by gradient elution using Aqela Venusil ASB C8 (2.1 × 50 mm, 3 µm), the pretreated samples were analyzed in MRM mode in positive ESI mode. The effective detection limit of this method was 1.95-1000 ng·mL-1. Tissue samples were collected from the heart, liver, spleen, lung, kidney, fat, muscle, brain, hippocampus, testicles or ovaries, large intestine, small intestine and stomach. The proposed method demonstrated fine precision and accuracy for analyzing ZCY-15 in selected tissues within the concentration range of standard liquid chromatography-tandem mass spectrometry. The whole analysis time was 3.6 min per sample. After oral administration, the blood and tissue concentrations of ZCY-15 in female rats were significantly higher than those in male rats. The clearance rate of ZCY-15 in female rats was lower than that in male rats. The results confirmed that there were gender differences. It has been shown that ZCY-15 could pass through the blood-brain barrier and was highly concentrated in the hippocampus. We established the first bioanalytical method to quantify ZCY-15 in rodent bio-samples for ongoing pharmacokinetic and tissue distribution studies, and the results were expected to lay foundation for the subsequent studies.