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

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Abstract

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.

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Data Availability

The datasets generated during and/or analyszed during the current study are available from the corresponding author on reasonable request.

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Acknowledgements

This work was supported by the Ontario Mental Health Foundation and Canadian Institute of Health Research. We thank all the members of the Mishra lab at the McMaster University Health Sciences Center for their invaluable input and support.

Funding

This work was supported financially by the Canadian Institutes of Health Research (Grant No. 126004).

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Authors and Affiliations

  1. Department of Psychiatry and Behavioural Neurosciences, McMaster University, 1280 Main Street West, Hamilton, ON, L8N 3Z5, Canada

    Yuxin Tian, Ritesh Daya, Jayant Bhandari, Hetshree Joshi, Sharon Thomson, Vidhi Patel & Ram Mishra

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  1. Yuxin Tian
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Contributions

Yuxin Tian was involved in all aspects of the study including conceptualization, data curation, formal analysis, project administration, and manuscript writing, editing, and review. Ritesh Daya was involved in funding acquisition, study conceptualization, formal analysis, project supervision, and review of the manuscript. Jayant Bhandari was involved in study investigation, methodology, data curation, and review of the manuscript. Hetshree Joshi was involved in formal analysis, manuscript writing and review. Sharon Thomson was involved in study investigation, methodology, data curation, formal analysis, manuscript writing, editing, and review. Vidhi Patel was involved in study methodology, data curation, formal analysis, and manuscript revision. Ram Mishra was the principal investigator of the study and managed all aspects of the study from funding and resource acquisition to conceptualization of study to data curation and formal analysis, and review of the manuscript.

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Correspondence to Ram Mishra.

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Conflict of interest

Yuxin Tian, Ritesh Daya, Jayant Bhandari, Hetshree Joshi, Sharon Thomson, Vidhi Patel and Ram Mishra declares that he has no conflict of interest.

Ethical Approval

All applicable international, national, and/or institutional guidelines for the care and use of animals were followed. The study was approved by the ethics committee (Animal Research Ethics Board) of McMaster University, Hamilton, Canada (animal utilization protocol number: 10-08-59). No human subjects were involved in this study. Legal and ethical approval was obtained prior to the initiation of research work carried out on animals and experiments were performed in accordance with the policies of the Canadian Council on Animal Care.

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Tian, Y., Daya, R., Bhandari, J. et al. Effect of Chronic Treatment with D2 Allosteric Modulator PAOPA on the Expression of Cerebral Dopamine Neurotrophic Factor (CDNF) in Select Brain Regions. Int J Pept Res Ther 27, 2551–2557 (2021). https://doi.org/10.1007/s10989-021-10272-2

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