Modeling of Parkinson's disease by intrastriatal administration of streptozotocin

Abstract

Parkinson's disease (PD) is a highly heterogeneous and therefore a possible cause of translation failure of drugs from animal testing to human treatments can be because existing models cannot replicate the entire spectrum of PD features. One of the theories of the origin of neurodegenerative diseases assumes metabolic dysfunction as a common fundamental thread of disease development. Intracerebroventricular administration of streptozotocin induces insulin resistance in the brain (Alzheimer's disease animal model). The aim of this project is to examine whether metabolic dysfunction caused by direct application of streptozotocin to brain region affected in PD (striatum) can induce characteristic PD symptoms. Adult male Wistar rats were given streptozotocin bilaterally or unilaterally in striatum. PET scan, cognitive, behavioural and motoric functions were tested one month after administration. Metabolite and protein analysis was done by untargeted metabolomics, ELISA and Western blot. Rats administered bilaterally showed motoric deficit, cognitive deficit of spatial learning and memory, fear conditioned and recognition memory, and anxiety-like behaviour, accompanied by impaired brain glucose uptake and metabolism. The results provide first evidence that bilateral intrastriatal administration of streptozotocin (particularly lower dose) can cause development of the hallmark PD symptoms. As metabolic dysfunction is increasingly associated with PD, an animal model with hypermetabolism in the early-on could be a better PD model for testing diverse therapeutics and the results could be better translated to humans. Further characterization is needed for understanding possible underlying mechanism and development of a new animal model for unique PD endophenotype expressing motoric, cognitive and metabolic symptomatology.

Keywords: Dementia; Motoric deficit; Parkinson's disease; Streptozotocin.