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Phytanic Acid-Induced Neurotoxicological Manifestations and Apoptosis Ameliorated by Mitochondria-Mediated Actions of Melatonin

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Abstract

Phytanic acid, a saturated branched chain fatty acid and a major constituent of human diet, is predominantly found in dairy products, meat, and fish. It is a degradation product from the phytol side chain of chlorophyll. Degradation of PA is known to occur mainly in peroxisomes via α-oxidation and in mitochondria via β-oxidation. Due to its β-methyl group present at the 3-position of the carbon atoms, PA cannot be β-oxidized. Although alteration in the metabolism of PA may play an important role in neurodegeneration, the exact mechanism behind it remains to be evaluated. In this study, we have described the potential of PA to induce neurotoxicity as an in vitro model (neuronal cell line, SH-SY5Y cells). Cells were pretreated with melatonin (10 μM) for 1 h followed by with and without PA (100 μM) for 24 h. In the present study, our data has confirmed that PA markedly increased both intracellular reactive oxygen species and reactive nitrogen species levels. Our results have shown that PA treatment did not induce cell death by cleavage of caspase-3/PARP-1 mediated by mitochondria through intrinsic pathways; however, PA induced nitric oxide-dependent apoptosis in SH-SY5Y cells. Additionally, melatonin pretreatment reduced the cell death in SH-SY5Y cells. Melatonin also effectively exerted an antiapoptotic and anti-inflammatory action by regulating Bax, Bcl-2, p-NFκB, and iNOS expressions in SH-SY5Y cells. These results suggested that melatonin acted as an antioxidative and antiapoptotic agent by modulating ROS, apoptotic proteins, and inflammatory responses under BCFA-induced neurotoxic conditions. The protective effects of melatonin depend on direct scavenging activity of free radicals and indirect antioxidant effects. Further deciphering of the cellular and molecular mechanism associated with neuroprotection by melatonin is warranted in BCFA-induced neurotoxicity.

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Acknowledgments

The authors would like to thank the funding agencies involved in supporting SP (SERB-EMR Grant 2016/001070/HS) and SC (ICMR-Senior Research Fellowship 45/47/2013-PHA/BMS).

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Authors and Affiliations

  1. Department of Medical Elementology and Toxicology, Jamia Hamdard (Hamdard University), New Delhi, 110062, India

    Shaista Chaudhary, Upasana Sahu & Suhel Parvez

  2. Jamia Hamdard Institute of Molecular Medicine, Jamia Hamdard (Hamdard University), New Delhi, 110062, India

    Upasana Sahu & Sudeshna Kar

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  1. Shaista Chaudhary
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  2. Upasana Sahu
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  3. Sudeshna Kar
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Correspondence to Suhel Parvez.

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Shaista Chaudhary and Upasana Sahu contributed equally to the study

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Chaudhary, S., Sahu, U., Kar, S. et al. Phytanic Acid-Induced Neurotoxicological Manifestations and Apoptosis Ameliorated by Mitochondria-Mediated Actions of Melatonin. Mol Neurobiol 54, 6960–6969 (2017). https://doi.org/10.1007/s12035-016-0209-4

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