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N-Propargyl Caffeamide (PACA) Ameliorates Dopaminergic Neuronal Loss and Motor Dysfunctions in MPTP Mouse Model of Parkinson’s Disease and in MPP+-Induced Neurons via Promoting the Conversion of proNGF to NGF

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Abstract

Insufficient production of nerve growth factor (NGF) is implicated in Parkinson’s disease (PD). We recently discovered that caffeic acid derivative N-propargyl caffeamide (PACA) not only potentiated NGF-induced neurite outgrowth but also attenuated 6-hydroxydopamine neurotoxicity in neuronal culture. The aim of the present study was to investigate whether PACA could increase NGF levels against 1-methyl-4-phenyl-1, 2, 3, 6-tetrahydropyridine (MPTP) neurotoxicity in a mouse PD model. We induced parkinsonism in mice by intraperitoneal injection of MPTP for seven consecutive days. Animal motor functions were assessed by rotarod test and pole test. Our results showed that PACA ameliorated motor impairments in MPTP-challenged mice. Based on Western blot analysis and/or immunofluorescence staining of NGF and tyrosine hydroxylase (TH), PACA preserved TH levels in the midbrain substantia nigra pars compacta. PACA also increased NGF expression while it decreased proNGF accumulation. Interestingly, NGF was widely induced in the midbrains including astrocytes. To elucidate the mechanisms by which PACA induces NGF, we focused on the effects of PACA on two neurotrophic signaling pathways, the PI3K and MEK pathways. We found that PACA induced the phosphorylation of Akt, ERK, and CREB against MPTP-mediated alterations. Importantly, PACA increased NGF levels and subsequently induced TrkA activation in MPTP-treated mice. Consistently, PACA also increased NGF levels in dopaminergic PC12 cells and primary rat midbrain neurons against N-methyl-4-phenylpyridinium iodide (MPP+) toxicity. ERK and PI3K inhibitors attenuated the effects of PACA on NGF levels. Collectively, our results suggest that PACA may rescue NGF insufficiency via sequential activation of PI3K/Akt, ERK1/2, and CREB signaling pathways.

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Abbreviations

PACA:

N-propargyl caffeamide

NGF:

nerve growth factor

PD:

Parkinson’s disease

TH:

Tyrosine hydroxylase

MPTP:

1-methyl-4-phenyl-1, 2, 3, 6-tetrahydropyridine

6-OHDA:

6-hydroxydopamine

SNpc:

Substantia nigra pars compacta

TrkA:

Tropomyosin receptor kinase A

PI3K:

Phosphoinositide 3-kinase

ERK:

Extracellular Signal-regulated Kinase-1

MPP+ :

N-methyl-4-phenylpyridinium iodide

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Acknowledgements

This work was supported by General Research Fund (GRF) grants (775812M and 17120915) from the Research Grants Council of Hong Kong and the Seed Funding for Basic Research Program from University of Hong Kong.

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Authors and Affiliations

  1. School of Chinese Medicine, Li Ka Shing Faculty of Medicine, The University of Hong Kong, 10 Sassoon Road, Pokfulam, Hong Kong, China

    Dan Luo, Jia Zhao, Yuanyuan Cheng & Jianhui Rong

  2. State Key Laboratory of Quality Research in Chinese Medicine, Institute of Chinese Medical Sciences, University of Macau, Macau, SAR, China

    Simon Ming-Yuen Lee

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  1. Dan Luo
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Luo, D., Zhao, J., Cheng, Y. et al. N-Propargyl Caffeamide (PACA) Ameliorates Dopaminergic Neuronal Loss and Motor Dysfunctions in MPTP Mouse Model of Parkinson’s Disease and in MPP+-Induced Neurons via Promoting the Conversion of proNGF to NGF. Mol Neurobiol 55, 2258–2267 (2018). https://doi.org/10.1007/s12035-017-0486-6

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