Creutzfeldt-Jakob disease (CJD), a transmissible spongiform encephalopathy that has traditionally been encountered at stable low levels (1 per one million population), has been on the increase in European countries in recent years, conceivably as a result of an epidemic a decade ago of bovine spongiform encephalopathy (BSE) in British cows that later entered the food chain. This invariably fatal neurodegenerative disease is believed to be caused by prions, an agent of disease transmission unlike better-known viruses, bacterial and other infectious microbes. When coincubated with the abnormal, disease-related form of the prion protein, cultured neuronal cells undergo a type of apoptotic cell death. Aoptosis inhibition has therefore been suggested as a promising therapeutic strategy. Various methods of preventing apoptosis have been proposed for the treatment of Creutzfeldt-Jakob disease, including blockade of increases in intracellular calcium levels, regulation of the balance between reactive oxygen species and antioxidant defense mechanisms and regulation of the expression of the proto-oncogene Bcl-2.

Flupirtine maleate (Asta Medica's Katadolon), a marketed non-opioid analgesic that acts as an NMDA antagonist but does not bind to NMDA receptors, is the first drug to be considered as a potential treatment for CJD. Flupirtine has shown cytoprotective effects in neuronal cells treated with PrP106-126, a toxic form of the prion protein, significantly reducing the noxious effects of the peptide at concentrations above 1 mcg/ml. Flupirtine prevents apoptotic cell death in cultured neurons by normalizing intracellular glutathione (GSH) levels and by inducing the expression of the Bcl-2 protein. Flupirtine also prevents apoptosis in other cell systems, including ischemia-induced apoptosis in human retinal pigment epithelial cells and apoptosis in human endothelial cells induced by reactive oxygen species. Flupirtine has favorable pharmacokinetics and good safety in humans, and is considered an excellent candidate for clinical testing in the treatment of Creutzfeldt-Jakob disease. Clinical trials, believed to be the first ever conducted for this indication, are now underway.

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