title: Neuroprotective effects of high affinity Σ1 receptor selective compounds.
abstract: We previously reported that the antipsychotic drug haloperidol, a multifunctional D2-like dopamine and sigma receptor subtype antagonist, has neuroprotective properties. In this study we further examined the association between neuroprotection and receptor antagonism by evaluating a panel of novel compounds with varying affinity at sigma and D2-like dopamine receptors. These compounds were evaluated using an in vitro cytotoxicity assay that utilizes a hippocampal-derived cell line, HT-22, in the presence or absence of varying concentrations (5 to 20 mM) of glutamate. While haloperidol was found to be a potent neuroprotective agent in this in vitro cell assay, the prototypic sigma 1 receptor agonist (+)-pentazocine was found not to be neuroprotective. Subsequently, the potency for the neuroprotection of HT-22 cells was evaluated for a) three SV series indoles which have nMolar affinity at D2-like receptors but varying affinity at sigma 1 receptor and b) two benzyl phenylacetamides sigma 1 receptor selective compounds which bind with low affinity at D2-like receptors but have nMolar affinity for the sigma 1 receptor. We observed that cytoprotection correlated with the affinity of the compounds for sigma 1 receptors. Based upon results from the HT-22 cell-based in vitro assay, two phenylacetamides, LS-127 and LS-137, were further evaluated in vivo using a transient middle cerebral artery occlusion (t-MCAO) model of stroke. At a dose of 100 μg/kg, both LS-127 and LS-137 attenuated infarct volume by approximately 50%. These studies provide further evidence that sigma 1 receptor selective compounds can provide neuroprotection in cytotoxic situations. These results also demonstrate that sigma 1 receptor selective benzyl phenylacetamides are candidate pharmacotherapeutic agents that could be used to minimize neuronal death after a stroke or head trauma.
authors.affiliation: Department of Pharmacology and Neuroscience, Institute for Aging and Alzheimer's Disease Research, University of North Texas Health Science Center at Fort Worth, Fort Worth, TX 76107, USA. robert.luedtke@unthsc.edu
authors.forename: Robert R
authors.initials: RR
authors.lastname: Luedtke
authors.forename: Evelyn
authors.initials: E
authors.lastname: Perez
authors.forename: Shao-Hua
authors.initials: SH
authors.lastname: Yang
authors.forename: Ran
authors.initials: R
authors.lastname: Liu
authors.forename: Suwanna
authors.initials: S
authors.lastname: Vangveravong
authors.forename: Zhude
authors.initials: Z
authors.lastname: Tu
authors.forename: Robert H
authors.initials: RH
authors.lastname: Mach
authors.forename: James W
authors.initials: JW
authors.lastname: Simpkins
mesh_terms: D000081:Acetamides / Q000737:chemistry / Q000378:metabolism / Q000627:therapeutic use; D000818:Animals; D014150:Antipsychotic Agents / Q000737:chemistry / Q000378:metabolism / Q000627:therapeutic use; D005260:Female; D057809:HEK293 Cells; D006801:Humans; D020244:Infarction, Middle Cerebral Artery / Q000378:metabolism / Q000517:prevention & control; D051379:Mice; D018696:Neuroprotective Agents / Q000737:chemistry / Q000378:metabolism* / Q000627:therapeutic use; D010423:Pentazocine / Q000737:chemistry / Q000378:metabolism / Q000627:therapeutic use; D011485:Protein Binding / Q000502:physiology; D051381:Rats; D017207:Rats, Sprague-Dawley; D017448:Receptors, Dopamine D2 / Q000378:metabolism; D017480:Receptors, sigma / Q000819:agonists / Q000378:metabolism*; D016896:Treatment Outcome; D000097605:Sigma-1 Receptor
chemical_list: D000081:Acetamides; D014150:Antipsychotic Agents; D018696:Neuroprotective Agents; D010423:Pentazocine; D017448:Receptors, Dopamine D2; D017480:Receptors, sigma; D000097605:Sigma-1 Receptor