Frontotemporal dementia is caused by a breakdown of nerve cells in the frontal and temporal region of the brain (fronto-temporal lobe), which leads to, among other symptoms, a change in personality and behavior. The cause of some forms of frontotemporal dementia is a genetically determined reduction of a hormone-like growth factor, progranulin. Scientists arround Doctor Anja Capell and Professor Christian Haass have now shown that various drugs that are already on the market to treat malaria, angina pectoris or heart rhythm disturbances can increase the production of progranulin. Accordingly, these drugs are good candidates for treatment of this specific form of frontotemporal dementia.
Progranulin is needed in the human brain as a protective factor for sensitive nerve cells, too little progranulin therefore results in a progressive neuronal cell death. As for almost every other gene, there are also two copies of the progranulin gene in the cell. In patients with progranulin dependent frontotemporal dementia, one of the two copies is defective, leading to a 50 percent reduction in progranulin levels. To rescue the lack of progranulin, the researchers tested various substances for their ability to stimulate the remaining progranulin production and identified a drug called bafilomycin (BafA1). They then examined the molecular mechanism underlying the impact of BafA1 on progranulin more closely. Growth factors such as progranulin are produced in cellular membrane inclusions, known as vesicles. BafA1 has an alkalizing effect on these vesicles: After administration of BafA1 the interior of the vesicles is less acidic – and this increases the production of progranulin.
This observation encouraged the researchers to investigate further alkalizing substances for their ability to raise progranulin levels. Among the substances that passed the test were three drugs that are already on the market to treat various diseases: a medication for angina pectoris (bepridil), one for heart rhythm problems (amiodarone) and the widely used malaria drug chloroquine. Chloroquine increased the progranulin level not only in experiments with mouse cells to normal, but also in cells from patients with the defective progranulin gene.
In a clinical study in collaboration with the University of London, the team will now investigate whether chloroquine actually helps against progranulin dependent frontotemporal dementia.
MEDICA.de; Source: Deutsches Zentrum für Neurodegenerative Erkrankungen e.V. (DZNE)