Objective: To investigate whether sodium butyrate (NaB) could enhance autophagy and thus exert a neuroprotective effect through the modulation of α-synuclein in animal models of Parkinson’s disease (PD) induced by chronic rotenone administration.

Background: Accumulating evidence suggests a pivotal role for autophagy in the pathogenesis of PD, and dysfunction in the autophagic system could result in a-synuclein aggregation. A number of histone deacetylase (HDAC) inhibitors including NaB have recently become promising therapeutic candidates in many neurological diseases, such as stroke and Huntington’s disease.

Methods: Male C57BL/6 mice aged 12 months were divided into 3 groups: control group, rotenone-only treated group (30 mg/kg/d, p.o.) and group treated with both NaB (0.3 g/kg/d, i.p.) and rotenone (30 mg/kg/d, p.o., 5 times per week for 8 weeks). Histopathological and immunofluorescence analyses, western blots, and TEM were compared among the 3 groups of mice.

Results: NaB administration significantly rescued loss of tyrosine hydroxylase-positive neurons in the substantia nigra in rotenone-treated animals. Importantly, NaB reduced rotenone-induced a-synuclein aggregation in mice, which is widely thought to play a central role in the pathogenesis of PD. Furthermore, compared with animals treated with rotenone only, NaB administration significantly reduced P62 accumulation, increased the number of LC3-II-positive autophagosomes and promoted final maturation of late autophagic vacuoles through fusion with lysosomes. Moreover, NaB protects against rotenone-induced neurotoxicity in mice by regulating autophagy-related signaling pathways including restoring Beclin-1 expression and reducing mTOR expression.

Conclusions: Our findings suggest that NaB exerts neuroprotective effects by enhancing autophagolysosome formation and preventing α-synuclein aggregation in rotenone-treated Parkinsonian models, providing further evidence that HDAC inhibitors may be a promising approach for disease-modifying treatment of PD.

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MDS Abstracts - https://www.mdsabstracts.org/abstract/sodium-butyrate-attenuates-rotenone-induced-neurodegeneration-via-enhancing-autophagy-and-preventing-synuclein-aggregation/