Glycogen synthase kinase-3 (GSK-3) is a serine-threonine kinase ubiquitously expressed and involved in the regulation of many cell functions. GSK-3 phosphorylates the microtubule-associated protein tau in mammalian cells. This hyperphosphorylation is an early event in neurodegenerative conditions, such as Alzheimer’s disease. CDK-5 also shows relations with Alzheimer’s disease. GSK-3 is one of the most attractive therapeutic targets for the development of selective inhibitors as new promising drugs for severe unmet pathologies, such as type-2 diabetes, bipolar disorders, stroke, and Alzheimer’s disease, and different tau pathologies, such as Pick’s disease, supranuclear palsy, and frontotemporal dementia. In this study, Manzamine A is an orally active beta-carboline alkaloid. It inhibits specifically GSK-3β and CDK-5 with IC₅₀s of 10.2 and 1.5μM, respectively. In addition, Manzamine A targets vacuolar ATPases and inhibits autophagy in pancreatic cancer cells. Manzamine A has antimalarial and anticancer activities. It also shows potent activity against HSV-1.

Manzamine A inhibits CDK-5 and proves to be effective in decreasing tau phosphorylation after treatment in a human neuroblastoma cell line. In addition, it increases acidity in pancreatic cancer cells and non-malignant Vero cells. Manzamine A is a potent inhibitor of autophagy by preventing autophagosome turnover. Moreover, Manzamine A (10 µM; 2 hours; AsPC-1 cells) clearly induced an accumulation of p62 confirming inhibition of autophagosome turnover.

In summary, Manzamine A proves to be effective in decreasing tau hyperphosphorylation on human neuroblastoma cell lines. It constitutes a promising scaffold from which more potent and selective GSK-3 inhibitors could be as potential therapeutic agents for Alzheimer’s disease.

Reference:

Hamann M, et al. J Nat Prod. 2007;70(9):1397-1405.;Kallifatidis G, et al. Mar Drugs. 2013;11(9):3500-3516. Published 2013 Sep 17.