The histone deacetylase inhibitor, sodium butyrate, alleviates cognitive deficits in pre-motor stage PD

Abstract

Parkinson's disease (PD) patients often times experience impairment in their cognitive abilities early on in the progression of the disease. The reported deficits appear to mainly involve functions that are associated with frontal lobe and frontal-striatal pathways subserving attentional set-shifting, working memory and executive function.The current study explored executive function deficits in a rat model of PD in the pre-motor deficit stage. The rats were lesioned with 12 μg of 6-hydroxydonpamine (6-OHDA) in the striatum in a two step process (10 μg/μl followed by 2 μg/μl) 48 hours apart. Executive function was tested at 3 weeks post-surgery using a rat analogue of Wisconsin card sorting test called the Extra Dimensional/Intra Dimensional (ED/ID) set-shifting task. The results demonstrated that performance by the pre-motor rat model of PD was equivalent to that of the control groups in the simple and the compound discriminations as well as the intra-dimensional set-shifting. However the PD group exhibited attentional set-shifting deficits similar to those observed in PD patients.Additionally, sodium butyrate, a short chain fatty acid derivative and inhibitor of class I and II histone deacetylase (HDACi), was tested as a potential therapeutic agent to mitigate the pre-motor cognitive deficits in PD. The results indicated that the sodium butyrate treatment not only effectively alleviated the set-shifting deficits, but also improved the attentional set formation in the treated rats.