ABSTRACT
This study assessed whether creatine could attenuate 3-nitropropionic acid (3NP)-induced neuropathological and behavioral abnormalities that are analogous to those observed in Huntington's disease (HD). Rats were fed diets containing either 1% creatine or normal rat chow for 2 weeks prior to the onset of 3NP administration, and for the duration of the study. 3NP was administered systemically in gradually increasing concentrations over an 8-week testing period. Results show that creatine can attenuate 3NP-induced striatal lesions, striatal atrophy, ventricular enlargement, cognitive deficits, and motor abnormalities on a balance beam task. Collectively, these findings indicate that creatine provides significant protection against 3NP-induced behavioral and neuropathological abnormalities and may have therapeutic potential for HD.
Subject(s)
Cognition Disorders/drug therapy , Creatine/therapeutic use , Movement Disorders/drug therapy , Propionates , Animals , Behavior, Animal/drug effects , Cerebral Ventricles/drug effects , Cerebral Ventricles/pathology , Cognition Disorders/pathology , Corpus Striatum/drug effects , Corpus Striatum/pathology , Male , Movement Disorders/pathology , Nitro Compounds , Rats , Rats, Sprague-DawleyABSTRACT
Quinolinic acid (QA) is an N-methyl-d-aspartate agonist that has been shown to produce neurotoxic effects that mimic certain neurodegenerative diseases when administered to laboratory animals. Intrastriatal injections of QA in rats have been used extensively to produce some of the neuropathological and behavioral deficits that are analogous to Huntington's disease (HD). However, acute intrastriatal injections of QA produce symptoms that are not analogous to the progressive nature of HD. Thus far, models using chronic administration of QA that produce HD-like behavioral and neuroanatomical changes have necessitated the use of a relatively bulky and fragile microdialytic pump apparatus. The present study tested an alternative way of chronically administering QA. Specifically, this study tested whether gradual release of QA from ethylene vinylacetate (EVA) polymers could produce symptoms analogous to HD. Rats received either no implants or bilateral intrastriatal implants of polymers with or without QA. Subsequent tests for spontaneous motor activity (SMA), grip strength, balance, and learning ability in a radial-arm-water-maze task revealed QA-induced impairments in balance and learning ability, but did not affect grip strength or SMA. Histological analysis revealed QA-induced enlargement of lateral ventricles, striatal atrophy, and striatal neuronal loss, with relative sparing of NADPH-diaphorase-positive neurons. These results suggest that QA released from polymers can produce behavioral and neuropathological profiles analogous to early stages of HD and that EVA polymers offer a useful means of chronically delivering QA in rodent models of neurodegeneration.
