Artimisinin and risk of CNS damage

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http://aac.asm.org/cgi/content/abstract/46/3/821

Antimicrobial Agents and Chemotherapy, March 2002, p. 821-827, Vol.

46, No. 3

0066-4804/02/$04.00+0 DOI: 10.1128/AAC.46.3.821-827.2002

Copyright © 2002, American Society for Microbiology. All Rights

Reserved.

Neurotoxic Mode of Action of Artemisinin

e Schmuck,1* Elke Roehrdanz,1, K. Haynes,2 and Regine

Kahl3

Pharma Research Center, Bayer AG, D-42096, Wuppertal,1 Department of

Toxicology, Heinrich Heine University Düsseldorf, 40225 Düsseldorf,

Germany,3 Department of Chemistry, The Hong Kong University of

Science and Technology, Clear Water Bay, Kowloon, Hong Kong2

Received 25 June 2001/ Returned for modification 31 July 2001/

Accepted 21 December 2001

We recently described a screening system designed to detect

neurotoxicity of artemisinin derivatives based on primary neuronal

brain stem cell cultures (G. Schmuck and R. K. Haynes, Neurotoxicity

Res. 2:37-49, 2000). Here, we probe possible mechanisms of this brain

stem-specific neurodegeneration, in which artemisinin-sensitive

neuronal brain stem cell cultures are compared with nonsensitive

cultures (cortical neurons, astrocytes). Effects on the cytoskeleton

of brain stem cell cultures, but not that of cortical cell cultures,

were visible after 7 days. However, after a recovery period of 7

days, this effect also became visible in cortical cells and more

severe in brain stem cell cultures. Neurodegeneration appears to be

induced by effects on intracellular targets such as the cytoskeleton,

modulation of the energy status by mitochondrial or metabolic

defects, oxidative stress or excitotoxic events. Artemisinin reduces

intracellular ATP levels and the potential of the inner mitochondrial

membrane below the cytotoxic concentration range in all three cell

cultures, with these effects being most dominant in the brain stem

cultures. Surprisingly, there were substantial effects on cortical

neurons after 7 days and on astrocytes after 1 day. Artemisinin

additionally induces oxidative stress, as observed as an increase of

reactive oxygen species and of lipid peroxidation in both neuronal

cell types. Interestingly, an induction of expression of AOE was only

seen in astrocytes. Here, manganese superoxide dismutase (MnSOD)

expression was increased more than 3-fold and catalase expression was

increased more than 1.5-fold. In brain stem neurons, MnSOD expression

was dose dependently decreased. Copper-zinc superoxide dismutase and

glutathione peroxidase, two other antioxidant enzymes that were

investigated, did not show any changes in their mRNA expression in

all three cell types after exposure to artemisinin.

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* Corresponding author. Mailing address: BAYER AG, Pharma Research

Centre, Aprather Weg, D-42096 Wuppertal, Germany. Phone: 0049 202

368830. Fax: 0049 202 364137. E-mail: GABRIELE.SCHMUCK.GS@bayer-

ag.de.