23 Nov 2016

Epilepsy drug a potential treatment for heart attack and stroke

The molecule t-PA (tissue plasminogen activator) is a natural
blood clot buster and can be elevated with an epilepsy drug,
valproic acid. Image: Emw - Own work, CC BY-SA 3.0
by Anne Crawford

Monash University researchers have struck on a novel strategy to counter the blood clotting (thrombosis) that causes conditions including heart attack and ischemic stroke – major causes of death in Australia. Significantly, they have also found that an existing drug, coincidentally used for epilepsy, could potentially be used as a treatment to prevent thrombosis.

Professor Robert Medcalf, who heads the Molecular Neurotrauma and Haemostasis laboratory in the Australian Centre for Blood Diseases (ACBD), said the research started with work exploring the regulation of the molecule t-PA (tissue plasminogen activator), a naturally occurring clot-busting enzyme in the body. The enzyme is rapidly released by the damaged endothelium (lining) of the blood vessel when clotting is initiated to limit the growth of the blood clot.


First author Dr Pia Larsson initially investigated ways of increasing the body’s own production of t-PA to minimise the risk of blood flow-obstructing blood clots. She realised that the t-PA gene was regulated epigenetically, meaning that its DNA is modified chemically. By using agents known to influence this epigenetic process, Dr Larsson demonstrated that the production of t-PA could be increased significantly in mice.

“That created the idea that if you could increase the base levels of the t-PA gene or the enzymes in the animals, maybe making them less likely to form blood clots, that this could be relevant in people prone to have blood clots that form inappropriately,” Professor Medcalf said.

“Having increased levels of this blood clot-busting enzyme in your blood vessels may help to prevent those clots without causing any long-term problems and hopefully without any complications linked with bleeding,” he said.

The research, conducted in a long-standing collaboration with laboratories at the University of Gothenburg, Sweden, and the Heart Research Institute in Sydney, is a departure from the anticoagulation and antiplatelet treatments now commonly used to reduce the risk of thrombosis.

Dr Larsson’s work set the stage for further studies investigating particular drugs that could interfere with the epigenetic pathways involved. Curiously, the researchers found that valproic acid, already used clinically for the unrelated condition epilepsy, fitted the bill, leading to smaller blood clots forming in mice.

“It’s potentially a very significant finding,” Professor Medcalf said. “If you can increase the level of these clot-busting enzymes to the point where you can minimise the frequency of these clots from forming then you could significantly benefit a number of people who have thrombotic complications such as heart attack and ischemic stroke,” he said.

The paper, which appeared in the Journal of Thrombosis and Haemostasis in October attracted a commentary praising the study’s “elegant series of experiments” and noting that the novel strategy using VPA “opens avenues for prophylaxis in a number of thrombosis-related diseases”.

Professor Medcalf commented that “while additional investigations are needed before clinical translation, the results we have achieved thus far are very encouraging”.

Reference

Larsson P, Alwis I, Niego B, Sashindranath M, Fogelstrand P, Wu MC, Glise L, Magnusson M, Daglas M, Bergh N, Jackson SP, Medcalf RL, Jern S. Valproic acid selectively increases vascular endothelial tissue-type plasminogen activator production and reduces thrombus formation in the mouse. J Thromb Haemost. 2016 Oct 5. doi: 10.1111/jth.13527. [Epub ahead of print]
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