title: Sodium butyrate improves locomotor impairment and early mortality in a rotenone-induced Drosophila model of Parkinson's disease.
abstract: Parkinson's disease (PD) is a neurodegenerative disorder primarily affecting the dopaminergic neurons in the nigrastriatal pathway resulting in debilitating motor impairment in both familial and sporadic cases. Histone deacetylase (HDAC) inhibitors have been recently implicated as a therapeutic candidate because of their ability to correct the disrupted HDAC activity in PD and other neurodegenerative diseases. Sodium butyrate (SB), an HDAC inhibitor, reduces degeneration of dopaminergic neurons in a mutant alpha-synuclein Drosophila transgenic model of familial PD. Chronic exposure to the pesticide rotenone also causes selective degeneration of dopaminergic neurons and causes locomotor impairment and early mortality in a Drosophila model of chemically induced PD. This study investigated the effects of sodium butyrate on locomotor impairment and early mortality in a rotenone-induced PD model. We show that treatment with 10mM SB-supplemented food rescued the rotenone-induced locomotor impairment and early mortality in flies. Additionally, flies with the genetic knockdown of HDAC activity through Sin3A loss-of-function mutation (Sin3A(lof)) were resistant to rotenone-induced locomotor impairment and early mortality. Furthermore, SB-supplemented Sin3A(lof) flies had a modest additive effect for improving locomotor impairment. We also show SB-mediated improvement of rotenone-induced locomotor impairment was associated with elevated dopamine levels in the brain. However, the possibility of SB-mediated protective role through mechanisms independent from dopamine system is also discussed. These findings demonstrate that HDAC inhibitors like SB can ameliorate locomotor impairment in a rotenone-induced PD model.
authors.affiliation: Department of Biology, Colby College, Waterville, ME 04901, USA. robyn.stlaurent@nih.gov
authors.forename: R
authors.initials: R
authors.lastname: St Laurent
authors.forename: L M
authors.initials: LM
authors.lastname: O'Brien
authors.forename: S T
authors.initials: ST
authors.lastname: Ahmad
mesh_terms: D000818:Animals; D030801:Animals, Genetically Modified; D020148:Butyric Acid / Q000494:pharmacology / Q000627:therapeutic use*; D004195:Disease Models, Animal; D004330:Drosophila; D056572:Histone Deacetylase Inhibitors / Q000494:pharmacology / Q000627:therapeutic use; D009043:Motor Activity / Q000187:drug effects* / Q000502:physiology; D010302:Parkinson Disease, Secondary / Q000139:chemically induced* / Q000188:drug therapy* / Q000401:mortality; D010575:Pesticides / Q000633:toxicity; D012402:Rotenone / Q000633:toxicity*
chemical_list: D056572:Histone Deacetylase Inhibitors; D010575:Pesticides; D012402:Rotenone; D020148:Butyric Acid