Neuroprotective effects of high affinity sigma 1 receptor selective compounds

Robert T. Luedtke, Evelyn Perez, Shaohua Yang, Ran Liu, Suwanna Vangveravong, Zhude Tu, Robert H. MacH, James W. Simpkins

Research output: Contribution to journalArticle

17 Citations (Scopus)

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.

Original languageEnglish
Pages (from-to)17-26
Number of pages10
JournalBrain Research
Volume1441
DOIs
StatePublished - 2 Mar 2012

Fingerprint

Neuroprotective Agents
Haloperidol
Stroke
sigma Receptors
Pentazocine
Indoles
Cytoprotection
Dopamine D2 Receptors
Middle Cerebral Artery Infarction
Dopamine Receptors
sigma-1 receptor
Craniocerebral Trauma
Antipsychotic Agents
Glutamic Acid
Cell Line
In Vitro Techniques
Neuroprotection

Keywords

  • Neuroprotection
  • Sigma 1 receptors
  • Sigma receptors

Cite this

Luedtke, Robert T. ; Perez, Evelyn ; Yang, Shaohua ; Liu, Ran ; Vangveravong, Suwanna ; Tu, Zhude ; MacH, Robert H. ; Simpkins, James W. / Neuroprotective effects of high affinity sigma 1 receptor selective compounds. In: Brain Research. 2012 ; Vol. 1441. pp. 17-26.
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Neuroprotective effects of high affinity sigma 1 receptor selective compounds. / Luedtke, Robert T.; Perez, Evelyn; Yang, Shaohua; Liu, Ran; Vangveravong, Suwanna; Tu, Zhude; MacH, Robert H.; Simpkins, James W.

In: Brain Research, Vol. 1441, 02.03.2012, p. 17-26.

Research output: Contribution to journalArticle

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