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Journal article
A novel dopamine D3R agonist SK609 with norepinephrine transporter inhibition promotes improvement in cognitive task performance in rodent and non-human primate models of Parkinson's disease
Experimental neurology, Vol.335, 113514
Jan 2021
PMID: 33141071
Featured in Collection : UN Sustainable Development Goals @ Drexel
Abstract
Mild cognitive impairment is present in a number of neurodegenerative disorders including Parkinson's disease (PD). Mild cognitive impairment in PD (PD-MCI) often manifests as deficits in executive functioning, attention, and spatial and working memory. Clinical studies have suggested that the development of mild cognitive impairment may be an early symptom of PD and may even precede the onset of motor impairment by several years. Dysfunction in several neurotransmitter systems, including dopamine (DA), norepinephrine (NE), may be involved in PD-MCI, making it difficult to treat pharmacologically. In addition, many agents used to treat motor impairment in PD may exacerbate cognitive impairment. Thus, there is a significant unmet need to develop therapeutics that can treat both motor and cognitive impairments in PD. We have recently developed SK609, a selective, G-protein biased signaling agonist of dopamine D3 receptors. SK609 was successfully used to treat motor impairment and reduce levodopa-induced dyskinesia in a rodent model of PD. Further characterization of SK609 suggested that it is a selective norepinephrine transporter (NET) inhibitor with the ability to increase both DA and NE levels in the prefrontal cortex. Pharmacokinetic analysis of SK609 under systemic administration demonstrated 98% oral bioavailability and high brain distribution in striatum, hippocampus and prefrontal cortex. To evaluate the effects of SK609 on cognitive deficits of potential relevance to PD-MCI, we used unilateral 6-hydroxydopamine (6-OHDA) lesioned rats and 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-treated cynomolgus macaques, with deficits in performance in a sustained attention and an object retrieval task, respectively. SK609 dose dependently improved the performance of 6-OHDA-lesioned rats, with peak performance achieved using a 4 mg/kg dose. This improvement was predominantly due to a significant reduction in the number of misses and false alarm errors, contributing to an increase in sustained attention. In MPTP-lesioned monkeys, this same dose also improved performance in an object retrieval task, significantly reducing cognitive errors (barrier reaches) and motor errors (fine motor dexterity problems). These data demonstrate that SK609 with its unique pharmacological effects on modulating both DA and NE can ameliorate cognitive impairment in PD models and may provide a therapeutic option to treat both motor and cognitive impairment in PD patients.
•In addition to motor impairment, PD patients suffer from mild cognitive impairment (PD-MCI).•PD-MCI manifests as deficits in attention, flexibility and spatial and working memory.•SK609 is a D3R agonist and NET inhibitor and improves motor impairment in PD.•SK609 improved sustained attention task performance in PD rats by reducing errors.•SK609 improved object retrieval task performance in PD-NHPs by reducing motor errors.
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Details
- Title
- A novel dopamine D3R agonist SK609 with norepinephrine transporter inhibition promotes improvement in cognitive task performance in rodent and non-human primate models of Parkinson's disease
- Creators
- Jay S. Schneider - Thomas Jefferson UniversityCourtney A. Marshall - Drexel UniversityLauren Keibel - Drexel UniversityNathaniel W. Snyder - Temple UniversityMichael P. Hill - Atuka Inc, Toronto, Ontario, Canada.Jonathan M. Brotchie - Atuka Inc, Toronto, Ontario, Canada.Tom H. Johnston - Atuka Inc, Toronto, Ontario, Canada.Barry D. Waterhouse - Rowan UniversitySandhya Kortagere - Drexel University
- Publication Details
- Experimental neurology, Vol.335, 113514
- Publisher
- Elsevier
- Resource Type
- Journal article
- Language
- English
- Academic Unit
- Microbiology and Immunology; A.J. Drexel Autism Institute
- Identifiers
- 991019167860604721
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