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The neuroprotective effect of nicotine in Parkinson's disease models is associated with inhibiting PARP-1 and caspase-3 cleavage.

ABSTRACT: Clinical evidence points to neuroprotective effects of smoking in Parkinson's disease (PD), but the molecular mechanisms remain unclear. We investigated the pharmacological pathways involved in these neuroprotective effects, which could provide novel ideas for developing targeted neuroprotective treatments for PD. We used the ETC complex I inhibitor methylpyridinium ion (MPP⁺) to induce cell death in SH-SY5Y cells as a cellular model for PD and found that nicotine inhibits cell death. Using choline as a nicotinic acetylcholine receptor (nAChR) agonist, we found that nAChR stimulation was sufficient to protect SH-SY5Y cells against cell death from MPP⁺. Blocking ?7 nAChR with methyllycaconitine (MLA) prevented the protective effects of nicotine, demonstrating that these receptors are necessary for the neuroprotective effects of nicotine. The neuroprotective effect of nicotine involves other pathways relevant to PD. Cleaved Poly (ADP-ribose) polymerase-1 (PARP-1) and cleaved caspase-3 were decreased by nicotine in 6-hydroxydopamine (6-OHDA) lesioned mice and in MPP⁺-treated SH-SY5Y cells. In conclusion, our data indicate that nicotine likely exerts neuroprotective effects in PD through the ?7 nAChR and downstream pathways including PARP-1 and caspase-3. This knowledge could be pursued in future research to develop neuroprotective treatments for PD.

SUBMITTER: Lu JYD

PROVIDER: S-EPMC5651169 | biostudies-literature | 2017

REPOSITORIES: biostudies-literature

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The neuroprotective effect of nicotine in Parkinson's disease models is associated with inhibiting PARP-1 and caspase-3 cleavage.

Lu Justin Y D JYD Su Ping P Barber James E M JEM Nash Joanne E JE Le Anh D AD Liu Fang F Wong Albert H C AHC

PeerJ 20171019

Clinical evidence points to neuroprotective effects of smoking in Parkinson's disease (PD), but the molecular mechanisms remain unclear. We investigated the pharmacological pathways involved in these neuroprotective effects, which could provide novel ideas for developing targeted neuroprotective treatments for PD. We used the ETC complex I inhibitor methylpyridinium ion (MPP<sup>+</sup>) to induce cell death in SH-SY5Y cells as a cellular model for PD and found that nicotine inhibits cell death. ...[more]

PMID: 29062606

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Project description:Moutan cortex, Angelica Dahurica root, and Bupleurum root are traditional herbal medicines used in Asian countries to treat various diseases caused by oxidative stress or inflammation. Parkinson's disease (PD) has been associated with mitochondrial dysfunction, but no effective treatment for mitochondrial dysfunction has yet been identified. In this study we investigated the neuroprotective effects of the triple herbal extract DA-9805 in experimental models of PD. DA-9805 was prepared by extracting three dried plant materials (Moutan cortex, Angelica Dahurica root, and Bupleurum root in a 1:1:1 mixture) with 90% ethanol on a stirring plate for 24 h at room temperature and fingerprinted using high-performance liquid chromatography. 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) and its active metabolite 1-methyl-4-phenylpyridinium (MPP+), which both exert neurotoxic effects on dopaminergic neurons by inhibiting mitochondrial oxidative phosphorylation (OXPHOS) complex I, were used to make experimental models of PD. In MPP+-treated SH-SY5Y cells, DA-9805 ameliorated the suppression of tyrosine hydroxylase expression and mitochondrial damage on OXPHOS complex 1 activity, mitochondrial membrane potential, reactive oxygen species (ROS) generation, and oxygen consumption rate. In the MPTP-induced subacute PD model mice, oral administration of DA-9805 recovered dopamine content as well as bradykinesia, as determined by the rotarod test. DA-9805 protected against neuronal damage in the substantia nigra pars compacta (SNpc) and striatum. In both in vitro and in vivo models of PD, DA-9805 normalized the phosphorylation of AKT at S473 and T308 on the insulin signaling pathway and the expression of mitochondria-related genes. These results demonstrate that the triple herbal extract DA-9805 showed neuroprotective effects via alleviating mitochondria damage in experimental models of PD. We propose that DA-9805 may be a suitable candidate for disease-modifying therapeutics for PD.

Dataset Information

The neuroprotective effect of nicotine in Parkinson's disease models is associated with inhibiting PARP-1 and caspase-3 cleavage.

Publications

The neuroprotective effect of nicotine in Parkinson's disease models is associated with inhibiting PARP-1 and caspase-3 cleavage.

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