More MS news articles for April 2001

DNA-Binding Drugs Inhibit Stress-Induced Neuronal Death

WESTPORT, CT (Reuters Health) Apr 13 - Two sequence-selective DNA binding drugs, mithramycin A and chromomycin A3, potently inhibit apoptosis and DNA damage in rat cortical neurons caused by oxidative stress, according to a report in the March issue of Annals of Neurology.

Neuronal apoptosis probably underlies the damage caused by neurodegenerative disorders ranging from Parkinson's disease to multiple sclerosis, the authors explain, so strategies that inhibit components of the apoptotic pathway may prove useful in treating such conditions.

Based on recent data suggesting the involvement of DNA-binding proteins Sp1 and Sp3 in apoptosis-associated transcription, Dr. Rajiv R. Ratan and colleagues from Harvard Medical School in Boston tested the ability of mithramycin A and chromomycin A3, which displace Sp1 from DNA, to inhibit stress-induced apoptosis and DNA damage in embryonic rat cortical neurons.

Mithramycin A and chromomycin A3 significantly reduced the DNA binding of Sp1 and Sp3 and completely prevented neuronal death caused by depletion of the antioxidant glutathione, the authors report. Even when added as late as 8 hours after glutathione depletion, mithramycin A completely prevented cell death, the researchers note, probably by selectively inhibiting the synthesis of one or more apoptotic pathway proteins.

Mithramycin A also inhibited the apoptosis usually induced by the DNA-damaging agent camptothecin, the report indicates.

"The pluripotency of mithramycin A raises the possibility that it targets a pathway of cell death common to many death stimuli," Dr. Ratan told Reuters Health. "The dysregulation of apoptosis is believed to underlie neuronal loss in a host of neurological diseases. However, the critical, unanswered question is whether apoptosis is activated as the result of cell damage that is beyond repair."

"While our studies with mithramycin are promising, we have much work to do," Dr. Ratan concluded. "Ideally, we would want a drug that inhibits apoptosis, but also stimulates cellular repair mechanisms. We hope that mithramycin A is such an agent."

Ann Neurol 2001;49:345-354.

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