Metabolic profiling of rat brain and cognitive behavioral tasks: potential complementary strategies in preclinical cognition enhancement research.
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.
Goh
Dilys P Q
DP
Department of Pharmacy, Faculty of Science, National University of Singapore, Singapore.
Neo
Aveline H
AH
Goh
Catherine W
CW
Aw
Chiu Cheong
CC
New
Lee Sun
LS
Chen
Woei Shin
WS
Atcha
Zeenat
Z
Browne
Edward R
ER
Chan
Eric C Y
EC
D000818:Animals; D001522:Behavior, Animal / Q000187:drug effects; D001923:Brain Chemistry / Q000187:drug effects / Q000502:physiology; D003071:Cognition / Q000187:drug effects; D000077265:Donepezil; D005702:Galantamine / Q000494:pharmacology; D007189:Indans / Q000494:pharmacology; D008297:Male; D055442:Metabolome / Q000502:physiology*; D010880:Piperidines / Q000494:pharmacology; D051381:Rats; D011919:Rats, Inbred Strains; D053719:Tandem Mass Spectrometry
D007189:Indans; D010880:Piperidines; D005702:Galantamine; D000077265:Donepezil