Protective effects of octacosanol on 6-hydroxydopamine-induced Parkinsonism in rats via regulation of ProNGF and NGF signaling

Wang, Tao; Liu, Y; Wang, Xin; Yang, Nan; Zhu, Haibo; Zuo, Pingping

doi:10.1038/aps.2010.69

Cited by 60 publications

(33 citation statements)

References 55 publications

(63 reference statements)

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“…6-OHDA is a neurotoxin that induces the specific degeneration of DA neurons and is usually used to prepare PD animal models [35] . It has been reported that 6-OHDA produces reactive oxygen species (ROS) and impairs mitochondrial function [36] .…”

Section: Discussionmentioning

confidence: 99%

Parkin represses 6-hydroxydopamine-induced apoptosis via stabilizing scaffold protein p62 in PC12 cells

Hou

Ren

et al. 2015

Acta Pharmacol Sin

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Aim: Parkin has been shown to exert protective effects against 6-hydroxydopamine (6-OHDA)-induced neurotoxicity in different models of Parkinson disease. In the present study we investigated the molecular mechanisms underlying the neuroprotective action of parkin in vitro. Methods: HEK293, HeLa and PC12 cells were transfected with parkin, parkin mutants, p62 or si-p62. Protein expression and ubiquitination were assessed using immunoblot analysis. Immunoprecipitation assay was performed to identify the interaction between parkin and scaffold protein p62. PC12 and SH-SY5Y cells were treated with 6-OHDA (200 μmol/L), and cell apoptosis was detected using PI and Hoechst staining. Results: In HEK293 cells co-transfected with parkin and p62, parkin was co-immunoprecipitated with p62, and parkin overexpression increased p62 protein levels. In parkin-deficient HeLa cells, transfection with wild-type pakin, but not with ligase activity-deficient pakin mutants, significantly increased p62 levels, suggesting that parkin stabilized p62 through its E3 ligase activity. Transfection with parkin or p62 significantly repressed ERK1/2 phosphorylation in HeLa cells, but transfection with parkin did not repress ERK1/2 phosphorylation in p62-knockdown HeLa cells, suggesting that p62 was involved in parkin-induced inhibition on ERK1/2 phosphorylation. Overexpression of parkin or p62 significantly repressed 6-OHDA-induced ERK1/2 phosphorylation in PC12 cells, and parkin overexpression inhibited 6-OHDA-induced apoptosis in PC12 and SH-SY5Y cells. Conclusion: Parkin protects PC12 cells against 6-OHDA-induced apoptosis via ubiquitinating and stabilizing scaffold protein p62, and repressing ERK1/2 activation.

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Section: Discussionmentioning

confidence: 99%

Parkin represses 6-hydroxydopamine-induced apoptosis via stabilizing scaffold protein p62 in PC12 cells

Hou

Ren

et al. 2015

Acta Pharmacol Sin

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“…Previous researchers have shown that octacosanol possessed cholesterol-lowering, antiaggregatory, cytoprotective, ergogenic, neurological, antioxidant properties and protective effects on parkinsonism (Oliaro-Bosso et al, 2009;Taylor et al, 2003;Wang et al, 2010). Long-term clinical studies have demonstrated that, octacosanol was welltolerated and safe (Irmak, Dunford, & Milligan, 2006), and a number of dietary supplements containing octacosanol are commercially available in the US market (Irmak et al, 2006).…”

Section: Introductionmentioning

confidence: 99%

Preparation of octacosanol from filter mud produced after sugarcane juice clarification

Zhao

Wang

et al. 2012

LWT - Food Science and Technology

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“…NGF regulates the survival, growth, and differentiation of neurons through multiple mechanisms, especially via activating PI3K/Akt and Raf/MEK/ERK pathways [40]. It is possible that natural or synthetic small molecules elicit the neuroprotective and neurotrophic activities by targeting NGF signals [12,41]. For example, these compounds induce the activation of the prosurvival PI3K/Akt and ERK1/2 signaling pathways [14].…”

Section: Discussionmentioning

confidence: 99%

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

et al. 2017

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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. Graphical Abstract ᅟ.

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Protective effects of octacosanol on 6-hydroxydopamine-induced Parkinsonism in rats via regulation of ProNGF and NGF signaling

Cited by 60 publications

References 55 publications

Parkin represses 6-hydroxydopamine-induced apoptosis via stabilizing scaffold protein p62 in PC12 cells

Parkin represses 6-hydroxydopamine-induced apoptosis via stabilizing scaffold protein p62 in PC12 cells

Preparation of octacosanol from filter mud produced after sugarcane juice clarification

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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