Al-Nema, Mayasah and Gaurav, Anand and Lee, Ming Tatt and Okechukwu, Patrick and Nimmanpipug, Piyarat and Lee, Vannajan Sanghiran (2022) Evaluation of the acute oral toxicity and antipsychotic activity of a dual inhibitor of PDE1B and PDE10A in rat model of schizophrenia. PLoS ONE, 17 (12). ISSN 1932-6203, DOI https://doi.org/10.1371/journal.pone.0278216.
Full text not available from this repository.Abstract
Phosphodiesterase 1B (PDE1B) and PDE10A are dual-specificity PDEs that hydrolyse both cyclic adenosine monophosphate and cyclic guanosine monophosphate, and are highly expressed in the striatum. Several reports have suggested that PDE10A inhibitors may present a promising approach for the treatment of positive symptoms of schizophrenia, whereas PDE1B inhibitors may present a novel mechanism to modulate cognitive deficits. Previously, we have reported a novel dual inhibitor of PDE1B and PDE10A, compound 2 (3-fluorophenyl)(2-methyl-2,3-dihydro-4H-benzob]1,4]oxazin-4-yl )methanone] which has shown inhibitory activity for human recombinant PDE1B and PDE10A in vitro. In the present study, the safety profile of compound 2 has been evaluated in rats in the acute oral toxicity study, as well as; the antipsychotic-like effects in the rat model of schizophrenia. Compound 2 was tolerated up to 1 g/kg when administered at a single oral dose. Additionally, compound 2 has strongly suppressed ketamine-induced hyperlocomotion, which presented a model for the positive symptoms of schizophrenia. It has also shown an ability to attenuate social isolation induced by chronic administration of ketamine and enhanced recognition memory of rats in the novel object recognition test. Altogether, our results suggest that compound 2 represents a promising therapy for the treatment of the three symptomatic domains of schizophrenia.
| Item Type: | Article |
|---|---|
| Funders: | Centre of Excellence in Research, Value Innovation and Entrepreneurship (CERVIE), UCSI University, Malaysia (Grant No: Proj-2019-In-FPS-018 & REIG-FPS-2020/065), Visiting Professor Grant from Chiang Mai University, Thailand (Grant No: R000026614) |
| Uncontrolled Keywords: | Phosphodiesterase 10A inhibitor; Presynaptic dopamine function; Negative symptoms; Discovery; Memory; Ketamine; Antioxidant; Involvement; Potent; Brain |
| Subjects: | R Medicine > R Medicine (General) R Medicine > RM Therapeutics. Pharmacology |
| Divisions: | Faculty of Science > Department of Chemistry |
| Depositing User: | Ms. Juhaida Abd Rahim |
| Date Deposited: | 20 Nov 2023 09:42 |
| Last Modified: | 20 Nov 2023 09:43 |
| URI: | http://eprints.um.edu.my/id/eprint/40266 |
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