| Propentofylline, a CNS glial modulator does not decrease pain in post-herpetic neuralgia patients: In vitro evidence for differential responses in human and rodent microglia and macrophages. | |
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MedLine Citation:
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PMID: 22119425 Owner: NLM Status: Publisher |
Abstract/OtherAbstract:
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There is a growing body of preclinical evidence for the potential involvement of glial cells in neuropathic pain conditions. Several glial-targeted agents are in development for the treatment of pain conditions. Here we report the failure of a glial modulating agent, propentofylline, to decrease pain reported in association with post-herpetic neuralgia. We offer new evidence to help explain why propentofylline failed in patients by describing in vitro functional differences between rodent and human microglia and macrophages. We directly compared the proinflammatory response induced by lipopolysaccharide with or without propentofylline using rat postnatal microglia, rat peritoneal macrophages, human fetal microglia, human peripheral macrophages and human immortalized THP-1 cells. We measured tumor necrosis factor-alpha (TNF-α), interleukin-1 beta (IL-1β) and nitrite release (as an indicator of NO) as downstream indicators. We found that LPS treatment did not induce nitrite in human microglia, macrophages or THP-1 cells; however LPS treatment did induce nitrite release in rat microglia and macrophages. Following LPS exposure, propentofylline blocked TNF-α release in rodent microglia with all the doses tested (1-100μM), and dose-dependently decreased TNF-α release in rodent macrophages. Propentofylline partially decreased TNF-α (35%) at 100μM in human microglia, macrophages and THP-1 macrophages. Propentofylline blocked nitrite release from LPS stimulated rat microglia and inhibited nitrite in LPS-stimulated rat macrophages. IL-1β was decreased in LPS-stimulated human microglia following propentofylline at 100μM. Overall, human microglia were less responsive to LPS stimulation and propentofylline treatment than the other cell types. Our data demonstrate significant functional differences between cell types and species following propentofylline treatment and LPS stimulation. These results may help explain the differential behavioral effects of propentofylline observed between rodent models of pain and the human clinical trial. |
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Authors:
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Russell P Landry; Valerie L Jacobs; Edgar Alfonso Romero-Sandoval; Joyce A Deleo |
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Publication Detail:
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Type: JOURNAL ARTICLE Date: 2011-11-15 |
Journal Detail:
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Title: Experimental neurology Volume: - ISSN: 1090-2430 ISO Abbreviation: - Publication Date: 2011 Nov |
Date Detail:
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Created Date: 2011-11-28 Completed Date: - Revised Date: - |
Medline Journal Info:
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Nlm Unique ID: 0370712 Medline TA: Exp Neurol Country: - |
Other Details:
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Languages: ENG Pagination: - Citation Subset: - |
Copyright Information:
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Copyright © 2011. Published by Elsevier Inc. |
Affiliation:
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Department of Pharmacology and Toxicology, Dartmouth Medical School, Hanover, NH 03755, USA; Neuroscience Center at Dartmouth, Lebanon, NH 03756, USA. |
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From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine
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