Metabolic Profiling of Rat Brain and Cognitive Behavioral Tasks: Potential Complementary Strategies in Preclinical Cognition Enhancement Research

Abstract

In this study, the correlation between the metabolic profiles of rats undergoing cognition enhancement drug therapy and their associated cognitive behavioral outcomes were investigated. Male Lister Hooded rats were administered either with donepezil, galantamine, or vehicle and subjected to Atlantis watermaze training and novel object recognition tests. An UPLC/MS/MS method was developed to profile 21 neurologically related metabolites in the rat brains. Pharmacologically induced behavioral changes were compared subsequently with the metabolic fluctuations of neurologically related metabolites from multiple neurotransmitter pathways using multivariate and univariate statistical analyses. Significant improvements in cognitive behavioral outcomes were demonstrated in the rats administered with donepezil and galantamine using both AWM training (P < 0.05) and NOR (P < 0.05) tests as compared to those dosed with the vehicle. This corroborated with the significant elevation of eight prominent biomarkers after the cognitive enhancement therapy. An orthogonal partial least-squares discriminant analysis model generated using only the 8 metabolites identified as discriminating the drug-dosed rats from the vehicle-dosed rats gave a Q(2) = 0.566, receiver operator characteristic (ROC) AUC = 1.000, using 7-fold cross validation. Our study suggests that metabolic profiling of rat brain is a potential complementary strategy to the cognitive behavioral tasks for characterizing neurobiological responses to cognition enhancement drug testing.

Metabolome and microbiome profiling of a stress-sensitive rat model of gut-brain axis dysfunction

“…Whole brain was used to obtain a broad picture of whether brain chemistry was altered, which has been useful in initial studies 40,41 . This allowed us to examine the overall macro-physiological changes in brain lipids and polar metabolites in response to stress and whether these differ broadly between rat strains.…”

Liquid Chromatography-Mass Spectrometric Multiple Reaction Monitoring-based Strategies for Expanding Targeted Profiling towards Quantitative Metabolomics

“…and the Science Research sampling time and gender differences [190] Mercapturic acids human urine LC-NLS PCA, PLS-DA, OSC negative control vs acetaminophentreated group [186] Neurotransmitter metabolites rat brain UPLC-MRM PCA, OPLS-DA, ROC, PLS-DA vehicle-dosed vs drug-dosed rats [191] Endo-metabolites human plasma LC-MRM PCA normal vs liver failure patient [192] Hydrophilic metabolites in mouse tissues mouse urine, liver, duodenum, kidney, plasma, heart, skeletal muscle…”

Neural Basis of Object Recognition

“…Specifically, a lot of laboratory studies have shown that the object recognition task in rodents is highly sensitive to psychoactive drug. For example, this is the case of drugs such as acetylcholinesterase inhibitors (AChEIs) which can improve object memory performance in rats [Prickaerts et al, 2002;Hornick et al, 2008;Goh et al, 2009]. In fact, in rats these ACh enhancers can reverse drug-induced memory impairments [Bejar et al, 1999;van der Staay and Bouger, 2005;Yamada et al, 2005].…”