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

详细信息	查看全文 | 推荐本文 |

• 作者：Russell P. Landry^a ; ^b ; Valerie L. Jacobs^a ; ^b ; Edgar Alfonso Romero-Sandoval^a ; ^b ; ^c ; Joyce A. DeLeo^a ; ^b ; ^c ; ^{deleoj@Emmanuel.edu}
• 关键词：ATP ; adenosine tri-phosphate ; BPI-sf ; brief pain inventory short form ; CNS ; central nervous system ; GFAP ; glial fibrillary acidic protein ; GM-CSF ; granulocyte macrophage colony stimulating factor ; Iba-1 ; ionized calcium binding adaptor molecule 1 ; IC50 ; i
• 刊名：Experimental Neurology
• 出版年：2012
• 期刊代码：78_00144886
• 类别：neu
• 出版时间：April, 2012
• 卷：234
• 期：2
• 页码：340-350
• 文件大小：938 K

摘要

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 (LPS) 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-伪), interleukin-1 beta (IL-1尾) and nitrite release (as an indicator of nitric oxide (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-伪 release in rodent microglia with all the doses tested (1-100 渭M), and dose-dependently decreased TNF-伪 release in rodent macrophages. Propentofylline partially decreased TNF-伪 (35%) at 100 渭M 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-1尾 was decreased in LPS-stimulated human microglia following propentofylline at 100 渭M. 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.