Original Article

Exp Neurobiol 2009; 18(1): 48-56

Published online June 30, 2009

© The Korean Society for Brain and Neural Sciences

Regulation of the Activity of Tissue Plasminogen Activator and Plasminogen Activator Inhibitor-1 by Zinc in Rat Primary Astrocytes

Soon Young Lee1†, Hee Jin Kim2†, So Hyun Joo1, Kyung Ja Kwon1, Jongmin Lee1, Seol-Heui Han1, Jae Young Cho1, Jae Hoon Cheong2, Kwang Ho Ko3 and Chan Young Shin1*

1Department of Pharmacology, Research Institute of Biomedical Science, School of Medicine and Center for Geriatric Neuroscience Research, Institute of Biomedical Science and Technology, Konkuk University, Seoul 143-701, 2Department of Pharmacology, School of Pharmacy, Samyook University, Seoul 139-742, 3Department of Pharmacology, College of Pharmacy, Seoul National University, Seoul 151-742, Korea

Correspondence to: *To whom correspondence should be addressed.
These authors equally contributed to this work.
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Tissue-type plasminogen activator (tPA) is a serine proteinase which plays important roles in functional and structural synaptic plasticity, neural migration, as well as excitotoxic injuries in several pathological situations including ischemic stroke, seizure and Alzheimer's disease (AD). It has been suggested that a divalent cation zinc also plays pathological roles in ischemia and seizure. Interestingly, it has been suggested that zinc and tPA may negatively regulate the activity or the level of each other by mechanism involving physical interaction between the two. In the present study, we investigated the effect of zinc in tPA activity and expression in rat primary astrocyte. Astrocytes were transiently exposed to 20∼200ՌM Zn2+ for 2 h and then were recovered for 24 h. In the culture supernatants, zinc treatment concentration-dependently inhibited the activity of tPA which was determined by casein-plasminogen zymography. There was only marginal changes, if any, in the level of tPA mRNA and protein. On the other hand, the activity of an endogenous inhibitor of tPA, plasminogen activator inhibitor-1 (PAI-1) as well as its expression was increased by zinc treatment in a concentration-dependant manner. These results suggest that zinc-induced decrease in tPA activity was also, at least in part, regulated by indirect way by regulating the level of PAI-1. The decrease in tPA activity may be a part of body's plan to reduce excitotoxic neural injury in a condition of elevated zinc in the brain.

Keywords: tissue-type plasminogen activator (tPA), zinc, plasminogen activator inhibitor (PAI)-1, neuronal damage, astrocyte