Browsing by Subject "Sigma Receptors"
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Item Pharmacological Assessment of Novel Phenylacetamide as a Sigma 1 Receptor Ligand(2014-05-01) Malik, Maninder; Robert LuedtkeThe symptoms of psychosis have been categorized as positive, negative and cognitive. Traditionally drug discovery in psychiatric disorders has focused on positive symptoms of the disease. However, cognitive impairment is equally prevalent and represents a major impediment to the recovery of patients. Hence, research on the drug discovery and development that can improve overall quality of life of patients with neuropsychiatric conditions is important. The main aim of this project was to evaluate a selective and potent sigma 1 receptor phenylacetamide (LS-1-137) as a potential pharmacotherapeutic agent for treating neuropsychiatric disorders and associated cognitive impairment. The sigma 1 receptor is an endoplasmic reticulum (ER) resident protein located on the interface of ER and mitochondria. The sigma 1 receptor is a 25 KDa protein that shares no amino acid sequence homology with any other known mammalian proteins. The research being done on these novel receptors suggests that rather than being a classical receptor-signaling unit sigma 1 receptors act as a molecular chaperone. Several studies suggest sigma 1 receptor ligands modulate abnormal neurotransmission that contributes to the pathogenesis of several CNS disorders. In recent studies by our laboratory, it was found that our novel sigma 1 receptor ligand, LS-1-137 (developed by our collaborators Mach and colleagues) exhibit neuroprotection both in vitro and in vivo. In this project we further characterized LS-1-137 as a potential treatment option for cognitive and neuropsychiatric disorders. Our fundamental hypothesis is that sigma 1 receptor selective compounds represent a potential neuroprotective pharmacotherapy for treating psychosis and cognitive deficits associated with neuropsychiatric disorders. LS-1-137 was evaluated in a 2, 5-dimethoxy-4-iodoamphetamine (DOI) induced head twitch response (HTR) model and a scopolamine-induced cognition impairment model. Our findings suggest that LS-1-137 attenuates the DOI-induced HTR and alleviates scopolamine-induced impairment in learning. Our in vitro data suggest that LS-1-137 is an agonist at sigma 1 receptors and triggers the release of BDNF from rat astrocytes. Furthermore, rotarod and swim test studies indicated that unlike currently prescribed neuroleptics, LS-1-137 does not compromise the agility or muscular coordination of animals. Therefore, in this dissertation we have assessed a novel pharmacotherapeutic agent that may treat the psychosis and cognitive dysfunction associated with neuropsychiatric disorders.Item THE EFFECT OF LS-1-137, A NOVEL PHENYLACETAMIDE SIGMA 1 RECEPTOR SELECTIVE AGONIST ON SCOPOLAMINE-DEPENDENT COGNITIVE DEFICIT IN C57BL/6J MICE.(2014-03) Malik, Maninder; Rangel-Barajas, Claudia; Griffin, Suzy; Sumien, Nathalie; Singh, Meharvan; Maurice, Tangui; Mach, Robert; Luedtke, Robert R.Cognitive deficits are observed in aged population and in patients with Alzheimer’s Disease, Parkinson’s Disease, traumatic brain injury and stroke. Cognitive deficits often involve alterations in brain signaling. Currently available therapeutic drugs provide only symptomatic relief and generally become ineffective as disease progresses. Therefore, novel therapeutic agents are needed to retard and/or arrest the progressive loss of memory forming cells. Scopolamine-induced memory impairment model provides a relatively rapid and reversible screening paradigm for cognition enhancement drug discovery. In this study, mice were administered scopolamine and were used to evaluate the ability of LS-1-137, a novel drug, to improve the cognitive deficits. Our study results indicate that LS-1-137 may represent a novel therapeutic agent for the treatment of age and disease related cognitive deficits. Purpose (a): Cognitive deficits are observed in patients with Alzheimer’s Disease, Parkinson’s Disease, traumatic brain injury and stroke. These deficits often involve alterations in cholinergic signaling. Currently available therapeutic drugs provide only symptomatic relief and generally become ineffective as a neurodegenerative disorder progresses. Therefore, novel therapeutic agents are needed to retard and/or arrest the progressive loss of memory forming cells. Methods (b): A filtration-binding assay was used to characterize the binding properties of a novel sigma compound at D2-like dopamine receptors, muscarinic receptors and at sigma receptors. Co-immunoprecipitation assay was used for the quantification of Sigma 1 receptor-binding immunoglobulin protein (BiP) complex formation. LS-1-137 mediated brain-derived neurotrophic factor (BDNF) release was analyzed using enzyme-linked immunosorbent assay (ELISA). In this study, male C57BL/6J mice injected with scopolamine were used as experimental model to evaluate the in vivo cognitive properties of the test drug. The neuroprotective properties were evaluated using water maze and active avoidance test. Results (c): LS-1-137 binds with high affinity (Ki = 3.2 nM) at sigma 1 receptors and is 80-fold selective for sigma 1 compared to sigma 2 receptor. LS-1-137 binds with low affinity at D2-like (D2, D3 and D4) dopamine and muscarinic receptors. LS-1-137 was found to partially reverse the learning and memory deficits associated with scopolamine administration using a water maze test and an active avoidance task. LS-1-137 treatment modulates sigma 1 receptor- BiP complex formation and also triggers the release of BDNF from rat astrocytes. Conclusions (d): LS-1-137 may represent a novel candidate cognitive enhancer for the treatment of cholinergic muscarinic-dependent cognitive deficits.