Abstract
Current therapies for Parkinson’s disease (PD) only offer limited symptomatic alleviation but fail to hamper the progress of the disease. Thus, it is imperative to establish new approaches aiming at protecting or reversing neurodegeneration in PD. Recent work elucidates whether smilagenin (abbreviated SMI), a steroidal sapogenin from traditional Chinese medicinal herbs, can take neuroprotective effect on dopaminergic neurons in a chronic model of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) conjuncted with probenecid mice. We reported for the first time that SMI significantly improved the locomotor ability of chronic MPTP/probenecid–lesioned mice. SMI increased the tyrosine hydroxylase (TH) positive and Nissl positive neuron number in the substantia nigra pars compacta (SNpc), augmented striatal DA and its metabolites concentration and elevated striatal dopamine transporter density (DAT). In addition, dopamine receptor D2R not D1R was down-regulated by MPTP/probenecid and slightly raised by SMI prevention. What’s more, we discovered that SMI markedly elevated striatal glial cell line-derived neurotrophic factor (GDNF) and brain-derived neurotrophic factor (BDNF) protein levels in SMI prevented mice. And we found that SMI increased GDNF and BDNF mRNA level by promoting CREB phosphorylation in 1-methyl-4-phenylpyridimium (MPP+) treated SH-SY5Y cells. The results illustrated that SMI could prevent the impairment of dopaminergic neurons in chronic MPTP/probenecid-induced mouse model.
Highlights
Parkinson’s disease (PD) is an age-related debilitating neurodegenerative disorder, characterized pathologically by selective loss of dopaminergic neurons in the substantia nigra pars compacta (SNpc) accompanied by a decrease in striatal dopamine level, and intracytoplasmic Lewy bodies aggregated by phosphorylated α-synuclein
What’s more, we discovered that SMI markedly elevated striatal glial cell line-derived neurotrophic factor (GDNF) and brain-derived neurotrophic factor (BDNF) protein levels in SMI prevented mice
We found that SMI increased GDNF and BDNF mRNA level by promoting Cyclic AMP responsive element binding protein (CREB) phosphorylation in 1-methyl-4-phenylpyridimium (MPP+) treated SH-SY5Y cells
Summary
Parkinson’s disease (PD) is an age-related debilitating neurodegenerative disorder, characterized pathologically by selective loss of dopaminergic neurons in the substantia nigra pars compacta (SNpc) accompanied by a decrease in striatal dopamine level, and intracytoplasmic Lewy bodies aggregated by phosphorylated α-synuclein (αSyn). The clinical symptoms such as resting tremor, rigidity, slowness of initial movement do not fully present until there is a loss of Abbreviations: SMI, smilagenin; MPTP, 1-methyl-4-phenyl-1,2,3 6-tetrahydropyridine; DAT, dopamine transporter density; GDNF, glial cell line-derive neurotrophic factor; BDNF, brain-derived neurotrophic factor; SNpc, substantia nigra pars compacta; α-syn, α-synuclein; PD, Parkinson’s disease; TH, tyrosine hydroxylase. 50%–60% SNpc neurons (Przedborski, 2017; Schapira et al, 2017). Current pharmacological therapies for PD, which dopamine replacement is a mainstay of therapeutic strategies, only alleviate symptoms but fail to hamper neurodegeneration process and restore dopaminergic dysfunction. It is greatly imperative to establish neuroprotective therapy available for PD
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