Nanolipidic particles improve the bioavailability and α-secretase inducing ability of epigallocatechin-3-gallate (EGCG) for the treatment of Alzheimer's disease

Abstract

Prevention of amyloidogenic processing of amyloid precursor protein with the use of natural phytochemicals capable of enhancing alpha-secretase activity may be a therapeutic approach for treatment of neurodegenerative diseases including Alzheimer’s Disease (AD) and HIV-associated dementia (HAD). We have recently shown promising preclinical results with the use of green tea polyphenol (-)-epigallocatechin-3-gallate (EGCG) in mouse models of both diseases, however the translation into clinical use has been problematic primarily as a result of poor bioavailability and inefficient delivery to the central nervous system (CNS). While the antioxidant properties of EGCG are well known, we have shown that it is able to promote non-amyloidogenic processing of amyloid precursor protein (APP) by upregulating α-secretase, thus preventing brain beta amyloid plaque formation, a hallmark of AD pathology and common finding in HIV infection. In this preliminary study, we investigated the ability of one preformulation method to improve the oral bioavailability of EGCG. We found that forming nanolipidic EGCG particles improves the neuronal (SweAPP N2a cells) α-secretase enhancing ability in vitro by up to 91% (P<.001) and it’s oral bioavailability in vivo by more than two-fold over free EGCG.

Recent trends in the development of nanophytobioactive compounds and delivery systems for their possible role in reducing oxidative stress in Parkinson&rsquo;s disease models

“…188,189 Some studies suggest that epigallocatehin-3-gallate reduced to approximately 50 nm by co-solubilization methods greatly enhances its bioavailability in a rat brain model of Alzheimer's disease. 190 These studies confirm that catechins can be efficiently encapsulated at a nanosize using a suitable nanotechnology involving nanoliposome, nanoemulsion, or nanoencapsulation techniques, thereby protecting the catechin from the gastrointestinal tract.…”

Amyloid β in hereditary cerebral hemorrhage with amyloidosis-Dutch type

“…Also, the formation of the toxic Aβ peptides from APP could be prevented by increasing α-secretase activity or inhibiting the β-or γ-secretase activity. Epigallocatechin-gallate (EGCG), a compound that is also found in green tea, upregulates α-secretase and thereby promotes non-amyloidogenic processing of APP (Smith et al, 2010). Bryostatin 1 promotes α-secretase processing of APP by activating protein kinase C (Yi et al, 2012) and is currently in phase II clinical trials (Blanchette Rockefeller Neurosciences Institute).…”

Convergent pathogenic pathways in Alzheimer's and Huntington's diseases: shared targets for drug development

“…Another example is (-) epigallocatechin gallate, a compound that provides benefits to patients suffering from systemic amyloidoses by reducing the amount of aggregated protein in tissues such as the heart 139 . It stabilizes a non-toxic form with low β-sheet content of both mHtt and Aß 134,135 , and although some studies report beneficial effects in animal models of AD 140 , delivery to the central nervous system is difficult 141 . Lack of translation of the effects seen in cell culture into mouse models has also been attributed to the high drug-to-amyloid protein ratios that need to be achieved to directly influence aggregation.…”