Biology subjects

Vales, K.

Publications and source records attributed to Vales, K..

3 recordsLinked to original sources

bioRxiv2024

Dizocilpine derivatives with neuroprotective effect lacking the psychomimetic side effects

We aimed to prepare novel dibenzosuberane derivatives that act on N-methyl-D-aspartate (NMDA) receptors with potential neuroprotective effects. Our approach involved modifying the tropane moiety of MK-801, a potent open-channel blocker known for its psychomimetic side effects, by introducing a seven-membered ring with substituted base moieties specifically to alleviate these undesirable effects. Our in silico analyses showed that these derivatives should have high gastrointestinal absorption and cross the blood-brain barrier (BBB). Our pharmacokinetic studies in rats supported this conclusion and confirmed the ability of leading compounds 3l and 6f to penetrate the BBB. Electrophysiological experiments showed that all compounds exhibited different inhibitory activity towards the two major NMDA receptor subtypes, GluN1/GluN2A and GluN1/GluN2B. Of the selected compounds intentionally differing in the inhibitory efficacy, 6f showed high relative inhibition ([~]90% for GluN1/GluN2A), while 3l showed moderate inhibition ([~]50%). An in vivo toxicity study determined that compounds 3l and 6f were safe at 10 mg/kg doses with no adverse effects. Behavioral studies demonstrated that these compounds did not induce hyperlocomotion or impair prepulse inhibition of startle response in rats. Neuroprotective assays using a model of NMDA-induced hippocampal neurodegeneration showed that compound 3l at a concentration of 30 M significantly reduced hippocampal damage in rats. These results suggest that these novel dibenzosuberane derivatives are promising candidates for developing NMDA receptor-targeted therapies with minimal psychotomimetic side effects.

neuroscience↗

bioRxiv2024

Pro-cognitive Effects of Dual Tacrine Derivatives Acting as Cholinesterase Inhibitors and NMDA Receptor Antagonists

Therapeutic options for Alzheimers disease are limited. Dual compounds targeting two pathophysiological pathways concurrently may enable enhanced effect. The study focuses on tacrine derivatives acting as acetylcholinesterase (AChE) inhibitors and simultaneously as subunit-dependent N-methyl-D-aspartate (NMDA) receptor antagonists. Compounds with balanced inhibitory potencies for target proteins (K1578 and K1599) or with increased inhibitory potency for AChE (K1592 and K1594) were studied. We aimed to identify the most promising pro-cognitive compound. The pro-cognitive effects of the compounds were studied in cholinergic (scopolamine-induced) and glutamatergic (MK-801-induced) rat models of cognitive deficits in the Morris water maze. Moreover, the effect on locomotion in open field and on AChE activity in relevant brain structures were investigated. The effect of the most promising compound on NMDA receptors was explored by in vitro electrophysiology. The cholinergic antagonist scopolamine induced a deficit of memory acquisition, however was unaffected by the compounds, and a deficit of reversal learning, that was alleviated by K1578 and K1599. K1578 and K1599 significantly inhibited AChE in striatum, potentially explaining the behavioral observations. Glutamatergic antagonist dizocilpine (MK-801) induced a deficit of memory acquisition, which was alleviated by K1599. K1599 also mitigated the MK-801-induced hyperlocomotion in the open field. The electrophysiology study corroborated the K1599-associated NMDA receptor inhibitory effect. K1599 emerged as the most promising compound, demonstrating pro-cognitive efficacy in both models, consistently with intended dual effect. Our findings contributed to elucidation of structural and functional properties of tacrine derivatives associated with optimal in vivo pro-cognitive effects, which further research may benefit from.

pharmacology and toxicology↗

bioRxiv2024

Genetic Modulation of Protein Expression in Rat Brain

Genetic variations in protein expression are implicated in a broad spectrum of common diseases and complex traits. However, the fundamental genetic architecture and variation of protein expression have received comparatively less attention than either mRNA or classical phenotypes. In this study, we systematically quantified proteins in the brains of a large family of rats using tandem mass tag (TMT)-based quantitative mass-spectrometry (MS) technology. We identified and quantified a comprehensive proteome of 8,119 proteins from Spontaneously Hypertensive (SHR/Olalpcv), Brown Norway with polydactyly-luxate (BN-Lx/Cub), and 29 of their fully inbred HXB/BXH progeny. Differential expression (DE) analysis identified 597 proteins with significant differences in expression between the parental strains (fold change > 2 and FDR < 0.01). We characterized 95 variant peptides by proteogenomics approach and discovered 464 proteins linked to strong cis-acting quantitative trait loci (pQTLs, FDR < 0.05). We also explored the linkage of pQTLs with behavioral phenotypes in rats and examined the sex-specific pQTLs to reveal both distinct and shared cis-pQTLs between sexes. Furthermore, by creating a novel view of the rat pangenome, we improved the ability to pinpoint candidate genes underlying pQTL. Finally, we explored the connection between the pQTLs in rat and human disorders, underscoring the translational potential of our findings. Collectively, this work demonstrates the value of large and systematic proteo-genetic datasets in understanding protein modulation in the brain and its functional linkage to complex central nervous system (CNS) traits.

genetics↗