Investigation of the PSD-95 / nNOS protein interaction as a target for antidepressant activity
Citation:Marika Doucet, 'Investigation of the PSD-95 / nNOS protein interaction as a target for antidepressant activity', [thesis], Trinity College (Dublin, Ireland). School of Pharmacy & Pharmaceutical Sciences, 2013, pp 266
Doucet TCD THESIS 10285 Investigation of.pdf (PDF) 123.3Mb
Previous studies have demonstrated that nitric oxide (NO) synthase inhibitors are as efficacious as tricyclic antidepressants in preclinical antidepressant screening procedures and in attenuating behavioural deficits associated with animal models of depression. Ketamine, an N-methyl-D- aspartate receptor (NMDA-R) antagonist is also effective in preclinical studies and has additionally shown promising therapeutic effects with production of a rapid and sustained antidepressant response in depressed patients who are resistant to conventional monoaminergic treatments. The antidepressant effects of ketamine are consistent with a role for glutamatergic transmission in the pathophysiology of depression. The use of ketamine in the clinic is however hampered due to the risk for side effects. The NMDA-R complex gates Ca2+, which interacts with calmodulin to subsequently activate nitric oxide synthase (NOS). It was hypothesized that uncoupling nNOS from the NMDA-R through the scaffolding protein PSD-95 would produce behavioural antidepressant effects similar to NOS inhibitors. Previous approaches to uncouple nNOS from the NMDA-R have used lentiviral delivery of genes designed to specifically disrupt the PSD-95/nNOS interface. Based on these studies, a protein fragment was created encoding the first 300 amino acids of nNOS that contained the motif necessary for binding to PSD-95 (nNOS decoy) to competitively inhibit the PSD-95/nNOS interaction. The effects of two small-molecule inhibitors at the PSD-95/nNOS interface 2-((1H-benzo[d] [1,2,3]triazol-5-ylamino) methyl)-4,6-dichlorophenol (IC87201) and 4- (3,5-dichloro-2-hydroxy-benzylamino)-2-hydroxybenzoic acid (ZL006), which demonstrated efficacy in neurological disorders involving overactivation of glutamatergic neurotransmission and excitotoxicity (i.e. stroke and pain states) were also assessed.
Author: Doucet, Marika
Dev, Kumlesh K.
Publisher:Trinity College (Dublin, Ireland). School of Pharmacy & Pharmaceutical Sciences
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Type of material:thesis
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