Skip to main content

Advertisement

SpringerLink
Log in

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

  • Published:
Journal of NeuroVirology Aims and scope Submit manuscript

An Editorial to this article was published on 13 September 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.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2
Fig. 3
Fig. 4
Fig. 5
Fig. 6
Fig. 7
Fig. 8
Fig. 9

Similar content being viewed by others

References

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

    Article  PubMed  CAS  Google Scholar 

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

    Article  PubMed  CAS  Google Scholar 

  • 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–H1043

    Article  PubMed  CAS  Google Scholar 

  • 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):197–204

    PubMed  CAS  Google Scholar 

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

    Article  PubMed  CAS  Google Scholar 

  • 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):113–124

    PubMed  CAS  Google Scholar 

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

    Article  PubMed  CAS  Google Scholar 

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

    Article  PubMed  CAS  Google Scholar 

  • 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):e00050

    Article  PubMed  Google Scholar 

  • 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):226–235

    Article  PubMed  CAS  Google Scholar 

  • 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):e11951

    Article  PubMed  Google Scholar 

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

    Article  PubMed  CAS  Google Scholar 

  • 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):869–881

    Article  PubMed  CAS  Google Scholar 

  • 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):257–270

    Article  CAS  Google Scholar 

  • 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):397–402

    Article  PubMed  CAS  Google Scholar 

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

    Article  PubMed  CAS  Google Scholar 

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

    PubMed  CAS  Google Scholar 

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

    Article  PubMed  CAS  Google Scholar 

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

    Article  PubMed  CAS  Google Scholar 

  • 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):2495–2499

    PubMed  CAS  Google Scholar 

  • 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):373–380

    Article  PubMed  CAS  Google Scholar 

  • 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):352–365

    Article  PubMed  CAS  Google Scholar 

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

    Article  PubMed  CAS  Google Scholar 

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

    Article  PubMed  CAS  Google Scholar 

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

    Article  PubMed  CAS  Google Scholar 

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

    Article  PubMed  CAS  Google Scholar 

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

    Article  PubMed  CAS  Google Scholar 

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

    PubMed  CAS  Google Scholar 

  • 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):2857–2864

    Article  PubMed  Google Scholar 

  • 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):567–575

    Article  PubMed  CAS  Google Scholar 

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

    Article  PubMed  CAS  Google Scholar 

  • 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):1975–1981

    Article  PubMed  CAS  Google Scholar 

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

    Article  PubMed  CAS  Google Scholar 

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

    Article  PubMed  CAS  Google Scholar 

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

    Article  PubMed  CAS  Google Scholar 

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

    Article  PubMed  CAS  Google Scholar 

  • 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 4:283–296

    Article  PubMed  CAS  Google Scholar 

  • 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):551–564

    Article  PubMed  CAS  Google Scholar 

  • 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):1065–1070

    PubMed  CAS  Google Scholar 

Download references

Acknowledgments

We thank Tanya Malpica-Llanos for technical assistance, Norman Haughey for providing rat neuronal cultures, and Avindra Nath at the National Institute of Neurological Diseases and Stroke, National Institutes of Health for carefully reading the manuscript and for helpful discussion/comments.

Author information

Author notes

  1. Joseph P. Steiner

    Present address: Neurotherapeutics Development Unit, NINDS Translational Neuroscience Center, 10 Center Drive Bldg. 10/7C105, Bethesda, MD, 20892, USA

Authors and Affiliations

  1. Department of Neurology, Johns Hopkins University, 600 North Wolfe Street, Baltimore, MD, 21287, USA

    Samir Nath, Muznabanu Bachani, Deepti Harshavardhana & Joseph P. Steiner

Authors
  1. Samir Nath
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Muznabanu Bachani
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Deepti Harshavardhana
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Joseph P. Steiner
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Joseph P. Steiner.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Nath, S., Bachani, M., Harshavardhana, D. et al. Catechins protect neurons against mitochondrial toxins and HIV proteins via activation of the BDNF pathway. J. Neurovirol. 18, 445–455 (2012). https://doi.org/10.1007/s13365-012-0122-1

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s13365-012-0122-1

Keywords

Search

Navigation