Parkinson's disease (PD) is a common
neurodegenerative disease characterized by the progressive loss of dopaminergic (DAergic) neurons in the ventral brain. A
disaccharide trehalose has demonstrated the potential to mitigate the DAergic loss in disease models for PD. However,
trehalose is rapidly hydrolyzed into
glucose by
trehalase in the intestine, limiting its potential for clinical practice. Here, we investigated the neuroprotective potential of two
trehalase-indigestible analogs,
lactulose and
melibiose, in sub-chronic
1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (
MPTP)-induced mouse model of PD. Treatment with
MPTP generated significant motor deficits, inhibited
dopamine levels, and down-regulated
dopamine transporter (DAT) in the striatum. Expression levels of genes involved in anti-oxidative stress pathways, including
superoxide dismutase 2 (SOD2), nuclear factor erythroid 2-related factor 2 (NRF2), and
NAD(P)H
dehydrogenase (NQO1) were also down-regulated. Meanwhile, expression of the oxidative stress marker
4-hydroxynonenal (4-HNE) was up-regulated along with increased microglia and astrocyte reactivity in the ventral midbrain following
MPTP treatment.
MPTP also reduced the activity of autophagy, evaluated by the autophagosomal marker
microtubule-associated protein 1 light chain 3 (LC3)-II.
Lactulose and
melibiose significantly rescued motor deficits, increased
dopamine in the striatum, reduced microglia and astrocyte reactivity as well as decreased levels of 4-HNE. Furthermore,
lactulose and
melibiose up-regulated SOD2, NRF2, and NQO1 levels, as well as enhanced the LC3-II/LC3-I ratio in the ventral midbrain with
MPTP treatment. Our findings indicate the potential of
lactulose and
melibiose to protect DAergic neurons in PD.