Umbelliferone Ameliorates Memory Impairment and Enhances Hippocampal Synaptic Plasticity in Scopolamine-Induced Rat Model.

Alzheimer's disease (AD) is a neurodegenerative disorder, characterized by memory loss and cognitive decline. Among the suggested pathogenic mechanisms of AD, the cholinergic hypothesis proposes that AD symptoms are a result of reduced synthesis of acetylcholine (ACh). A non-selective antagonist of the muscarinic ACh receptor, scopolamine (SCOP) induced cognitive impairment in rodents. Umbelliferone (UMB) is a Apiaceae-family-derived 7-hydeoxycoumarin known for its antioxidant, anti-tumor, anticancer, anti-inflammatory, antibacterial, antimicrobial, and antidiabetic properties. However, the effects of UMB on the electrophysiological and ultrastructure morphological aspects of learning and memory are still not well-established. Thus, we investigated the effect of UMB treatment on cognitive behaviors and used organotypic hippocampal slice cultures for long-term potentiation (LTP) and the hippocampal synaptic ultrastructure. A hippocampal tissue analysis revealed that UMB attenuated a SCOP-induced blockade of field excitatory post-synaptic potential (fEPSP) activity and ameliorated the impairment of LTP by the NMDA and AMPA receptor antagonists. UMB also enhanced the hippocampal synaptic vesicle density on the synaptic ultrastructure. Furthermore, behavioral tests on male SD rats (7-8 weeks old) using the Y-maze test, passive avoidance test (PA), and Morris water maze test (MWM) showed that UMB recovered learning and memory deficits by SCOP. These cognitive improvements were in association with the enhanced expression of BDNF, TrkB, and the pCREB/CREB ratio and the suppression of acetylcholinesterase activity. The current findings indicate that UMB may be an effective neuroprotective reagent applicable for improving learning and memory against AD.

Effect of Sinapic Acid on Scopolamine-Induced Learning and Memory Impairment in SD Rats.

The seriousness of the diseases caused by aging have recently gained attention. Alzheimer's disease (AD), a chronic neurodegenerative disease, accounts for 60-80% of senile dementia cases. Continuous research is being conducted on the cause of Alzheimer's disease, and it is believed to include complex factors, such as genetic factors, the accumulation of amyloid beta plaques, a tangle of tau protein, oxidative stress, cholinergic dysfunction, neuroinflammation, and cell death. Sinapic acid is a hydroxycinnamic acid found in plant families, such as oranges, grapefruit, cranberry, mustard seeds, and rapeseeds. It exhibits various biological activities, including anti-inflammatory, anti-oxidant, anti-cancer, and anti-depressant effects. Sinapic acid is an acetylcholine esterase inhibitor that can be applied to the treatment of dementia caused by Alzheimer's disease and Parkinson's disease. However, electrophysiological studies on the effects of sinapic acid on memory and learning must still be conducted. Therefore, it was confirmed that sinapic acid was effective in long-term potentiation (LTP) using organotypic hippocampal segment tissue. In addition, the effect on scopolamine-induced learning and memory impairment was measured by oral administration of sinapic acid 10 mg/kg/day for 14 days, and behavioral experiments related to short-term and long-term spatial memory and avoidance memory were conducted. Sinapic acid increased the activity of the field excitatory postsynaptic potential (fEPSP) in a dose-dependent manner after TBS, and restored fEPSP activity in the CA1 region suppressed by scopolamine. The scopolamine-induced learning and memory impairment group showed lower results than the control group in the Y-maze, Passive avoidance (PA), and Morris water maze (MWM) experiments. Sinapic acid improved avoidance memory, short and long-term spatial recognition learning, and memory. In addition, sinapic acid weakened the inhibition of the brain-derived neurotrophic factor (BDNF), tropomyosin receptor kinase B (TrkB) and the activation of prostaglandin-endoperoxide synthase 2 (COX-2) and interleukin 1 beta (IL-1ß) induced by scopolamine in the hippocampus. These results show that sinapic acid is effective in restoring LTP and cognitive impairment induced by the cholinergic receptor blockade. Moreover, it showed the effect of alleviating the reduction in scopolamine-induced BDNF and TrkB, and alleviated neuroinflammatory effects by inhibiting the increase in COX-2 and IL-1ß. Therefore, we showed that sinapic acid has potential as a treatment for neurodegenerative cognitive impairment.

Novel Cocrystals of Vonoprazan: Machine Learning-Assisted Discovery.

Vonoprazan (VPZ) is the first-in-class potassium-competitive acid blocker (P-CAB), and has many advantages over proton pump inhibitors (PPIs). It is administered as a fumarate salt for the treatment of acid-related diseases, including reflux esophagitis, gastric ulcer, and duodenal ulcer, and for eradication of Helicobacter pylori. To discover novel cocrystals of VPZ, we adopted an artificial neural network (ANN)-based machine learning model as a virtual screening tool that can guide selection of the most promising coformers for VPZ cocrystals. Experimental screening by liquid-assisted grinding (LAG) confirmed that 8 of 19 coformers selected by the ANN model were likely to create new solid forms with VPZ. Structurally similar benzenediols and benzenetriols, i.e., catechol (CAT), resorcinol (RES), hydroquinone (HYQ), and pyrogallol (GAL), were used as coformers to obtain phase pure cocrystals with VPZ by reaction crystallization. We successfully prepared and characterized three novel cocrystals: VPZ-RES, VPZ-CAT, and VPZ-GAL. VPZ-RES had the highest solubility among the novel cocrystals studied here, and was even more soluble than the commercially available fumarate salt of VPZ in solution at pH 6.8. In addition, novel VPZ cocrystals had superior stability in aqueous media than VPZ fumarates, demonstrating their potential for improved pharmaceutical performance.