Lysophosphatidylcholine induces glial cell activation: Role of rho kinase

Abstract

Lysophosphatidylcholine (LPC), a major phospholipid component of atherogenic oxidized LDL, is implicated in atherosclerosis and, recently, in neurodegenerative diseases. We investigated the immunomodulatory functions of LPC in the central nervous system (CNS) using both an in vivo rat model, and in vitro culture systems of human primary astrocytes and a microglia cell line, HMO6. Compared with PBS injection, 20 nmol LPC-injection into the rat striatum increased astrocyte and microglial accumulation and elevated iNOS expression; concomitantly a time-dependent decrease in number of neurons was exhibited. In vitro studies on astrocytes and HMO6 cells showed that LPC increased the gene expression of proinflammatory factors IL-1beta, COX-2, and GM-CSF. LPC also induced chemotactic responses in HMO6 cells. Inhibition of rho kinase by fasudil, Y27632, or expressing a dominant negative form of rho kinase inhibited the LPC-induced IL-1beta mRNA expression in both astrocytes and HMO6. Moreover, intraperitoneal fasudil injection inhibited the LPC-induced microglial accumulation and iNOS expression and also was effective in protecting against neuronal loss. Silencing G2A, a specific receptor for LPC, inhibited proinflammatory gene expression and HMO6 migration. Overall, our results indicate that LPC induced considerable neuroinflammatory reactivity in glia mediated by rho kinase-dependent pathways with inhibition of these pathways conferring significant extents of neuroprotection.

Elevated Levels of RhoA in the Optic Nerve Head of Human Eyes With Glaucoma

“…In an in vivo rat model of glaucoma, intraperitoneal injection of the Rho kinase inhibitor fasudil protected against neuronal loss. 23,24 These findings would support our hypothesis that abnormal activity of Rho/Rho kinase pathway may participate in the pathophysiology of glaucoma. 10 This should encourage further studies into the role of Rho GTPase-regulated cytoskeletal organization and contractile tension during optic nerve atrophy.…”

Fasudil Mesylate Protects PC12 Cells from Oxidative Stress Injury via the Bax-Mediated Pathway

“…It was reported that the mechanisms by which fasudil acts against cerebral infarction were thought to involve an increase in regional CBF and amelioration of endothelial damage (Rikitake et al 2005;Satoh et al 2010) and a decrease in the inflammatory response (Satoh et al 1999;Sheikh et al 2009) by ROCK inhibition; however, recently it has shown that fasudil induces neuroprotection and neurogenesis by acting directly on neurons and astrocytes (Yamashita et al 2007;Huang et al 2009a;Ding et al 2009). We previously have shown that fasudil mesylate protected rats against brain ischemia and reperfusion injury in vivo ).…”

Cdk5/p25-Induced Cytosolic PLA2-Mediated Lysophosphatidylcholine Production Regulates Neuroinflammation and Triggers Neurodegeneration

“…Additionally, this trigger has to be sustained either by p25 production or by other toxic insults to cause neuronal damage. However, an earlier study showed significant reduction of neurons after LPC injection (Sheikh et al, 2009). This differential observation could be due to the differences in the form of commercial LPC, injection site and susceptibilities of different neuronal subtypes to a toxic insult.…”

“…5J ) and the results mirror the in vitro experiment findings. Although some studies used PBS to dissolve commercial LPC (Sheikh et al, 2009), Chloroform/Methanol (1:2) was used as a vehicle in our experiments to keep the solvent constant for the commercial LPC as well as the lipid extract treatments. Lipid extract did not dissolve in PBS due to the poor hydrating nature of the lipids other than LPC.…”