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.

HIV-1 gp120 Upregulates Brain-Derived Neurotrophic Factor (BDNF) Expression in BV2 Cells via the Wnt/β-Catenin Signaling Pathway

“…Considerable experimental data indicate that the HIV-1 exterior envelope glycoprotein gp120 (HIV-1 gp120), which is shed from the virus, can cause neurotoxicity by multiple mechanisms (Nath et al 2012). Out recent study found that HIV-1 gp120 in postmortem tissues of the spinal cord dorsal horn was significantly higher in the pain-positive HIV-1 patients, compared to the pain-negative HIV-1 patients (Yuan et al 2014).…”

Adaptive Cellular Stress Pathways as Therapeutic Targets of Dietary Phytochemicals: Focus on the Nervous System

“…Curcumin treatment also reduced neuronal and microvessel degeneration in the retina in a rat model of ischemiareperfusion injury (Wang et al, 2011c). Catechins protected cultured neurons against death induced by the mitochondrial toxin 3-nitropropionic acid (3NP) (Nath et al, 2012). Administration of luteolin to rats for 13 days beginning immediately after experimental stroke resulted in increased survival of neurons in the ischemic cerebral cortex and improved functional outcome .…”

Challenging Oneself Intermittently to Improve Health

“…Epicatchins have been found to have broad neuroprotective actions against oxidative and metabolic stress in experimental models relevant to the pathogenesis of stroke, Alzheimer's and Parkinson's diseases, and HIV dementia (Sutherland et al, 2006;Lin et al, 2009;Schroeder et al, 2009;Nath et al, 2012). Studies of cultured neural cells suggest that the underlying mechanisms involve activation of the PI3 kinase -Akt pathways and stimulation of BDNF production (Jang et al, 2010;Nath et al, 2012). Epicatechins may also reduce the risk of cardiovascular disease by lowering levels of pro-atherosclerotic lipids and reducing blood pressure (Moore et al, 2009;Ellam and Williamson, 2013).…”