Effect of Chronic Treatment with D2 Allosteric Modulator PAOPA on the Expression of Cerebral Dopamine Neurotrophic Factor (CDNF) in Select Brain Regions

Impairment in dopaminergic pathways has been implicated in several detrimental neuropsychiatric and neurodegenerative disorders, including schizophrenia and Parkinson’s disease. Current approved therapeutic drugs for such conditions treat the symptoms, not the underlying cause, as this requires long-term usage that often causes severe extrapyramidal side effects. A novel allosteric modulator, 3(R)-[(2(S)-pyrrolidinylcarbonyl)amino]-2-oxo-1-pyrrolidineacetamide (PAOPA), selectively attenuates the dopamine D2 receptor and effectively modulates schizophrenia-like symptoms in preclinical animal models. The pharmacokinetics and toxicological evaluation for this drug also presented its effectiveness in reaching targeted therapeutic regions without showing hematological and metabolic abnormalities in chronic treatment. Recent studies have revealed that cerebral dopamine neurotrophic factor (CDNF), an ER located protein secreted upon ER stress, has long-term neuroprotective and neuro-restorative effects on dopaminergic neurons. Given the therapeutic role of PAOPA and the restorative effect of CDNF in the dopaminergic pathway, this study examined the chronic effect of PAOPA treatment on CDNF protein expression in brain regions implicated in neurological disorders. Immunoblot results revealed a 232% striatal increase in CDNF after 7 days of daily injection. Although the mechanism is not entirely understood, this study provides more insight into the potential signalling pathways affected by PAOPA treatment. As extracellular receptor kinase (ERK1/2) is proposed to upregulate CDNF expression following an unfolded protein response and PAOPA treatment increases ERK1/2 expression, PAOPA may indirectly affect CDNF expression by modulating ERK1/2 expression. The restorative effects of CDNF implicate it in the therapeutic mechanism for the potential antipsychotic drug, PAOPA.