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Published in:

01-12-2012

Catechins protect neurons against mitochondrial toxins and HIV proteins via activation of the BDNF pathway

Authors: Samir Nath, Muznabanu Bachani, Deepti Harshavardhana, Joseph P. Steiner

Published in: Journal of NeuroVirology | Issue 6/2012

Abstract

Currently, there is no effective treatment for neurological complications of infection with the human immunodeficiency virus that persists despite the use of combination antiretroviral therapy. A medium throughput assay was developed for screening neuroprotective compounds using primary mixed neuronal cells and mitochondrial toxin 3-nitropropionic acid. Using this assay, a library of 2,000 compounds was screened. Out of 256 compounds that showed variable degrees of neuroprotection, nine were related to epicatechin, a monomeric flavonoid found in cocoa and green tea leaves that readily crosses the blood–brain barrier. Hence, catechin, epicatechin, and the related compound, epigallocatechin gallate (EGCG) were further screened for their neuroprotective properties against HIV proteins Tat and gp120, and compared to those of resveratrol. Epicatechin and EGCG targets the brain-derived neurotrophic factor (BDNF) and its precursor proBDNF signaling pathways, normalizing both Tat-mediated increases in proapoptotic proBDNF and concomitant Tat-mediated decreases in the mature BDNF protein in hippocampal neurons. Epicatechin and epigallocatechin gallate were more potent than catechin or resveratrol as neuroprotectants. Due to its simpler structure and more efficient blood–brain barrier penetration properties, epicatechin might be the best therapeutic candidate for neurodegenerative diseases including HIV-associated neurocognitive disorders where oxidative stress is an important pathophysiological mechanism.

Abib RT et al (2010) Genoprotective effects of the green tea-derived polyphenol/epicatechin gallate in C6 astroglial cells. J Med Food 13(5):1111–1115PubMedCrossRef

Dani C et al (2009) Antioxidant activity and phenolic and mineral content of rose grape juice. J Med Food 12(1):188–192PubMedCrossRef

Drouin A et al (2011) Catechin treatment improves cerebrovascular flow-mediated dilation and learning abilities in atherosclerotic mice. Am J Physiol Heart Circ Physiol 300(3):H1032–H1043PubMedCrossRef

Engler MB et al (2004) Flavonoid-rich dark chocolate improves endothelial function and increases plasma epicatechin concentrations in healthy adults. J Am Coll Nutr 23(3):197–204PubMed

Faria A et al (2011) Insights into the putative catechin and epicatechin transport across blood–brain barrier. Food Funct 2(1):39–44PubMedCrossRef

Ferruzzi MG et al (2009) Bioavailability of gallic acid and catechins from grape seed polyphenol extract is improved by repeated dosing in rats: implications for treatment in Alzheimer’s disease. J Alzheimers Dis 18(1):113–124PubMed

Fraga CG, Oteiza PI (2011) Dietary flavonoids: role of (−)-epicatechin and related procyanidins in cell signaling. Free Radic Biol Med 51(4):813–823PubMedCrossRef

Haughey NJ et al (2004) Perturbation of sphingolipid metabolism and ceramide production in HIV-dementia. Ann Neurol 55(2):257–267PubMedCrossRef

He Y et al (2011) Prolonged exposure of cortical neurons to oligomeric amyloid-beta impairs NMDA receptor function via NADPH oxidase-mediated ROS production: protective effect of green tea (−)-epigallocatechin-3-gallate. ASN Neuro 3(1):e00050PubMedCrossRef

Henning SM et al (2003) Catechin content of 18 teas and a green tea extract supplement correlates with the antioxidant capacity. Nutr Cancer 45(2):226–235PubMedCrossRef

Kang KS et al (2010) Dual beneficial effects of (−)-epigallocatechin-3-gallate on levodopa methylation and hippocampal neurodegeneration: in vitro and in vivo studies. PLoS One 5(8):e11951PubMedCrossRef

Kells AP, Henry RA, Connor B (2008) AAV-BDNF mediated attenuation of quinolinic acid-induced neuropathology and motor function impairment. Gene Ther 15(13):966–977PubMedCrossRef

Kim CY et al (2009) Neuroprotective effect of epigallocatechin-3-gallate against beta-amyloid-induced oxidative and nitrosative cell death via augmentation of antioxidant defense capacity. Arch Pharm Res 32(6):869–881PubMedCrossRef

Kumar P, Kumar A (2009) Protective effects of epigallocatechin gallate following 3-nitropropionic acid-induced brain damage: possible nitric oxide mechanisms. Psychopharmacology (Berl) 207(2):257–270CrossRef

Leaver KR et al (2009) Oral pre-treatment with epigallocatechin gallate in 6-OHDA lesioned rats produces subtle symptomatic relief but not neuroprotection. Brain Res Bull 80(6):397–402PubMedCrossRef

Lee JS et al (2010) Epicatechin protects the auditory organ by attenuating cisplatin-induced ototoxicity through inhibition of ERK. Toxicol Lett 199(3):308–316PubMedCrossRef

Li W et al (2008) Nitrosative stress with HIV dementia causes decreased L-prostaglandin D synthase activity. Neurology 70(19 Pt 2):1753–1762PubMed

Li Q et al (2010) Chronic green tea catechins administration prevents oxidative stress-related brain aging in C57BL/6 J mice. Brain Res 1353:28–35PubMedCrossRef

Lu B, Pang PT, Woo NH (2005) The yin and yang of neurotrophin action. Nat Rev Neurosci 6(8):603–614PubMedCrossRef

Ma M, Nath A (1997) Molecular determinants for cellular uptake of Tat protein of human immunodeficiency virus type 1 in brain cells. J Virol 71(3):2495–2499PubMed

Magnuson DS et al (1995) Human immunodeficiency virus type 1 tat activates non-N-methyl-d-aspartate excitatory amino acid receptors and causes neurotoxicity. Ann Neurol 37(3):373–380PubMedCrossRef

Mandel SA et al (2008) Simultaneous manipulation of multiple brain targets by green tea catechins: a potential neuroprotective strategy for Alzheimer and Parkinson diseases. CNS Neurosci Ther 14(4):352–365PubMedCrossRef

Mattson MP, Haughey NJ, Nath A (2005) Cell death in HIV dementia. Cell Death Differ 12(Suppl 1):893–904PubMedCrossRef

McArthur JC et al (2010) Human immunodeficiency virus-associated neurocognitive disorders: mind the gap. Ann Neurol 67(6):699–714PubMedCrossRef

Meeker RB et al (2011) Protein changes in CSF of HIV-infected patients: evidence for loss of neuroprotection. J Neurovirol 17(3):258–273PubMedCrossRef

Moldzio R et al (2010) Effects of epigallocatechin gallate on rotenone-injured murine brain cultures. J Neural Transm 117(1):5–12PubMedCrossRef

Mosmann T (1983) Rapid colorimetric assay for cellular growth and survival: application to proliferation and cytotoxicity assays. J Immunol Methods 65(1–2):55–63PubMedCrossRef

Nath A et al (1996) Identification of a human immunodeficiency virus type 1 Tat epitope that is neuroexcitatory and neurotoxic. J Virol 70(3):1475–1480PubMed

Nosheny RL et al (2004) Human immunodeficiency virus type 1 glycoprotein gp120 reduces the levels of brain-derived neurotrophic factor in vivo: potential implication for neuronal cell death. Eur J Neurosci 20(11):2857–2864PubMedCrossRef

Park JW et al (2009) Green tea polyphenol (−)-epigallocatechin gallate reduces neuronal cell damage and up-regulation of MMP-9 activity in hippocampal CA1 and CA2 areas following transient global cerebral ischemia. J Neurosci Res 87(2):567–575PubMedCrossRef

Richard T et al (2011) Neuroprotective properties of resveratrol and derivatives. Ann N Y Acad Sci 1215:103–108PubMedCrossRef

Rothman SM, Griffioen KJ, Wan R, Mattson MP (2012) Brain-derived neurotrophic factor as a regulator of systemic and brain energy metabolism and cardiovascular health. Ann N Y Acad Sci. doi:10.1111/j.1749-6632.2012.06525.x

Schifitto G et al (2009) Selegiline and oxidative stress in HIV-associated cognitive impairment. Neurology 73(23):1975–1981PubMedCrossRef

Teng HK et al (2005) ProBDNF induces neuronal apoptosis via activation of a receptor complex of p75NTR and sortilin. J Neurosci 25(22):5455–5463PubMedCrossRef

Turchan J et al (2001) Estrogen protects against the synergistic toxicity by HIV proteins, methamphetamine and cocaine. BMC Neurosci 2:3PubMedCrossRef

Turchan J et al (2003) Oxidative stress in HIV demented patients and protection ex vivo with novel antioxidants. Neurology 60(2):307–314PubMedCrossRef

Wei IH et al (2011) (−)-Epigallocatechin gallate attenuates NADPH-d/nNOS expression in motor neurons of rats following peripheral nerve injury. BMC Neurosci 12:52PubMedCrossRef

Weinreb O et al (2009) Neuroprotective molecular mechanisms of (−)-epigallocatechin-3-gallate: a reflective outcome of its antioxidant, iron chelating and neuritogenic properties. Genes Nutr 4:283–296PubMedCrossRef

Yin ST et al (2009) Epigallocatechin-3-gallate induced primary cultures of rat hippocampal neurons death linked to calcium overload and oxidative stress. Naunyn Schmiedebergs Arch Pharmacol 379(6):551–564PubMedCrossRef

Yoo KY et al (2010) (−)-Epigallocatechin-3-gallate increases cell proliferation and neuroblasts in the subgranular zone of the dentate gyrus in adult mice. Phytother Res 24(7):1065–1070PubMed

Title: Catechins protect neurons against mitochondrial toxins and HIV proteins via activation of the BDNF pathway
Authors: Samir Nath
Muznabanu Bachani
Deepti Harshavardhana
Joseph P. Steiner
Publication date: 01-12-2012
Publisher: Springer US
Published in: Journal of NeuroVirology / Issue 6/2012
Print ISSN: 1355-0284
Electronic ISSN: 1538-2443
DOI: https://doi.org/10.1007/s13365-012-0122-1

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Catechins protect neurons against mitochondrial toxins and HIV proteins via activation of the BDNF pathway

Abstract

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Abstract

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