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N-Methyl-4-phenylpyridinium Scaffold-Containing Lipophilic Compounds Are Potent Complex I Inhibitors and Selective Dopaminergic Toxins.

ABSTRACT: Although the exact cause or causes of Parkinson's disease (PD) are not fully understood, it is believed that environmental factors play a major role. The discovery that a synthetic chemical, 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine-derived N-methyl-4-phenylpyridinium (MPP+), recapitulates major pathophysiological characteristics of PD in humans has provided the strongest support for this possibility. While the mechanism of the selective dopaminergic toxicity of MPP+ has been extensively studied and is, in most respects, well accepted, several key aspects of the mechanism are still debatable. In the present study, we use a series of structurally related, novel, and lipophilic MPP+ derivatives [ N-(2-phenyl-1-propene)-4-phenylpyridinium] to probe the mechanism of action of MPP+ using dopaminergic MN9D and non-neuronal HepG2 cells in vitro. Here we show that effective mitochondrial complex I inhibition is necessary and that the specific uptake through plasma membrane dopamine transporter is not essential for dopaminergic toxicity of MPP+ and related toxins. We also provide strong evidence to support our previous proposal that the selective vulnerability of dopaminergic cells to MPP+ and similar toxins is likely due to the high inherent propensity of these cells to produce excessive reactive oxygen species as a downstream effect of complex I inhibition. Based on the current and previous findings, we propose that MPP+ is the simplest of a larger group of unidentified environmental dopaminergic toxins, a possibility that may have major public health implications.

SUBMITTER: Lickteig B

PROVIDER: S-EPMC7063993 | biostudies-literature | 2019 Jun

REPOSITORIES: biostudies-literature

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N-Methyl-4-phenylpyridinium Scaffold-Containing Lipophilic Compounds Are Potent Complex I Inhibitors and Selective Dopaminergic Toxins.

Lickteig Bryan B Wimalasena Virangika K VK Wimalasena Kandatege K

ACS chemical neuroscience 20190410 6

Although the exact cause or causes of Parkinson's disease (PD) are not fully understood, it is believed that environmental factors play a major role. The discovery that a synthetic chemical, 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine-derived N-methyl-4-phenylpyridinium (MPP<sup>+</sup>), recapitulates major pathophysiological characteristics of PD in humans has provided the strongest support for this possibility. While the mechanism of the selective dopaminergic toxicity of MPP<sup>+</sup> has ...[more]

PMID: 30929447

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Project description:BackgroundReactive oxygen species (ROS), superoxide and hydrogen peroxide (H2O2), are necessary for appropriate responses to immune challenges. In the brain, excess superoxide production predicts neuronal cell loss, suggesting that Parkinson's disease (PD) with its wholesale death of dopaminergic neurons in substantia nigra pars compacta (nigra) may be a case in point. Although microglial NADPH oxidase-produced superoxide contributes to dopaminergic neuron death in an MPTP mouse model of PD, this is secondary to an initial die off of such neurons, suggesting that the initial MPTP-induced death of neurons may be via activation of NADPH oxidase in neurons themselves, thus providing an early therapeutic target.MethodsNADPH oxidase subunits were visualized in adult mouse nigra neurons and in N27 rat dopaminergic cells by immunofluorescence. NADPH oxidase subunits in N27 cell cultures were detected by immunoblots and RT-PCR. Superoxide was measured by flow cytometric detection of H2O2-induced carboxy-H2-DCFDA fluorescence. Cells were treated with MPP+ (MPTP metabolite) following siRNA silencing of the Nox2-stabilizing subunit p22phox, or simultaneously with NADPH oxidase pharmacological inhibitors or with losartan to antagonize angiotensin II type 1 receptor-induced NADPH oxidase activation.ResultsNigral dopaminergic neurons in situ expressed three subunits necessary for NADPH oxidase activation, and these as well as several other NADPH oxidase subunits and their encoding mRNAs were detected in unstimulated N27 cells. Overnight MPP+ treatment of N27 cells induced Nox2 protein and superoxide generation, which was counteracted by NADPH oxidase inhibitors, by siRNA silencing of p22phox, or losartan. A two-wave ROS cascade was identified: 1) as a first wave, mitochondrial H2O2 production was first noted at three hours of MPP+ treatment; and 2) as a second wave, H2O2 levels were further increased by 24 hours. This second wave was eliminated by pharmacological inhibitors and a blocker of protein synthesis.ConclusionsA two-wave cascade of ROS production is active in nigral dopaminergic neurons in response to neurotoxicity-induced superoxide. Our findings allow us to conclude that superoxide generated by NADPH oxidase present in nigral neurons contributes to the loss of such neurons in PD. Losartan suppression of nigral-cell superoxide production suggests that angiotensin receptor blockers have potential as PD preventatives.

Dataset Information

N-Methyl-4-phenylpyridinium Scaffold-Containing Lipophilic Compounds Are Potent Complex I Inhibitors and Selective Dopaminergic Toxins.

Publications

N-Methyl-4-phenylpyridinium Scaffold-Containing Lipophilic Compounds Are Potent Complex I Inhibitors and Selective Dopaminergic Toxins.

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