Tauopathies are a group of neurodegenerative diseases characterized by misfolding and abnormal accumulation of tau protein in the brain leading to the formation of neurofibrillary tangles. Some of these diseases include Alzheimer’s, Amyotropic lateral sclerosis, Argyrophilic brain disease, Parkinson’s, post traumatic stress disorder, and traumatic brain injury, just to name a few.
Although neurofibrillary tangles are strongly correlated with neurodegeneration, they are so far only known to be a correlation, and may not necessarily a causative factor.
In a study by McCormick et al, published in Biological Psychiatry, 1120 drugs were screened for activity against tau neurotoxicity. The chosen drugs already had FDA approval for human use, but are meant for a variety of other therapeutic uses, unrelated to tau. The goal of this study was to search out a known drug that also happens to target the underlying neurodegenerative pathology of tauopathies.
Finding new uses for already known drugs accelerates the process of discovery and clinical testing because the safety and toxicity profiles are already known.
This drug screen found a positive hit with one compound in particular: azaperone. Azaperone has previously been used in animals as a tranquillizer and as an antipsychotic. This study used a cuticle defective mutant of C. elegans, a roundworm in which most neuronal proteins are similar to human, as the test model.
The animals treated with azaperone produced reduced levels of insoluble tau, compared with untreated animals. Treatment was also shown to prevent loss of motor neurons. The test was carried forward into human HEK293 cells and was found to produce a U-shaped dose response curve. Using either too high or too low concentration of azaperone, the insoluble tau level increased.
Repositioning of known drugs into new uses may prove to be an efficient way to develop new therapies. While the correct dosage for an alternate use may need to be determined, the drug toxicity is already proven to be acceptable.
Many compounds with known therapeutic and toxicity profiles, including azaperone and several additional antipsychotics, are available at LKT Labs.
Antipsychotics available at LKT Labs
McCormick AV, Wheeler JM, et al. Dopamine D2 receptor antagonism suppresses tau aggregation and neurotoxicity. Biol Psychiatry. 2013 Mar 1;73(5):464-471. PMID: 23140663.
Sengupta U, Portelius E, et al. Tau oligomers in cerebrospinal fluid in Alzheimer’s disease. Ann Clin Transl Neurol. 2017 Mar 14;4(4):226-235. PMID: 28382304.