Tauopathies include dementias such as Alzheimer’s disease and frontotemporal dementia, and are characterized by tau aggregation and progressive neurodegeneration.
To examine drugs which might have neuroprotective potential, the authors of this study screened a drug library containing 1120 compounds approved for human use. The ability to suppress tau-induced behavioral effects in a Caenorhabditis elegans model of tauopathy was examined. They found that dopamine D2 receptor antagonists azaperone, flupenthixol, perphenazine, and zotepine were effective in this model.
The antipsychotic azaperone, improved the motility of tau transgenic worms, reduced levels of insoluble tau, and was protective against neurodegeneration. Azaperone also reduced insoluble tau in a human cell culture model of tau aggregation.
Reduction of dopamine signaling through the dopamine D2 receptor in gene knockouts in Caenorhabditis elegans or RNA interference knockdown in human cell culture had similar protective effects against tau toxicity. The authors suggest that dopamine D2 receptor antagonists hold promise as potential neuroprotective agents against tau aggregation and neurotoxicity. However, they noted that there may be a limited therapeutic window for this effect, since high doses of antipsychotics appear to drive tau pathology instead. They noted that elderly schizophrenic patients treated chronically with neuroleptics had an increased incidence of neurofibrillary pathology compared to schizophrenics not treated with neuroleptics.
McCormick AV, Wheeler JM, Guthrie CR, Liachko NF, Kraemer BC: Dopamine D2 Receptor Antagonism Suppresses Tau Aggregation and Neurotoxicity. Biological Psychiatry [Epub ahead of print, Nov. 6, 2012; doi:pii: S0006-3223(12)00807-4. 10.1016/j.biopsych.2012.08.027]