title: Catechins protect neurons against mitochondrial toxins and HIV proteins via activation of the BDNF pathway.
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.
authors.affiliation: Department of Neurology, Johns Hopkins University, Baltimore, MD 21287, USA.
authors.forename: Samir
authors.initials: S
authors.lastname: Nath
authors.forename: Muznabanu
authors.initials: M
authors.lastname: Bachani
authors.forename: Deepti
authors.initials: D
authors.lastname: Harshavardhana
authors.forename: Joseph P
authors.initials: JP
authors.lastname: Steiner
mesh_terms: D000818:Animals; D019380:Anti-HIV Agents / Q000494:pharmacology*; D019208:Brain-Derived Neurotrophic Factor / Q000819:agonists / Q000235:genetics / Q000378:metabolism*; D002392:Catechin / Q000031:analogs & derivatives* / Q000494:pharmacology; D004622:Embryo, Mammalian; D005786:Gene Expression Regulation / Q000187:drug effects; D015699:HIV Envelope Protein gp120 / Q000037:antagonists & inhibitors* / Q000235:genetics; D057166:High-Throughput Screening Assays; D006624:Hippocampus / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D006801:Humans; D008928:Mitochondria / Q000187:drug effects* / Q000378:metabolism; D009474:Neurons / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D018696:Neuroprotective Agents / Q000494:pharmacology*; D009574:Nitro Compounds / Q000494:pharmacology; D018384:Oxidative Stress; D061251:Primary Cell Culture; D011422:Propionates / Q000494:pharmacology; D011498:Protein Precursors / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism; D051381:Rats; D000077185:Resveratrol; D015398:Signal Transduction / Q000187:drug effects; D013237:Stereoisomerism; D013267:Stilbenes / Q000494:pharmacology; D054322:tat Gene Products, Human Immunodeficiency Virus / Q000037:antagonists & inhibitors* / Q000235:genetics
chemical_list: D019380:Anti-HIV Agents; D019208:Brain-Derived Neurotrophic Factor; D015699:HIV Envelope Protein gp120; D018696:Neuroprotective Agents; D009574:Nitro Compounds; D011422:Propionates; D011498:Protein Precursors; D013267:Stilbenes; D054322:tat Gene Products, Human Immunodeficiency Virus; C579455:BDNF protein, human; D002392:Catechin; C045651:epigallocatechin gallate; D000077185:Resveratrol; C015392:3-nitropropionic acid