EDG receptors as a potential therapeutic target in retinal ischemia–reperfusion injury

Savitz, Sean I; Dhallu, Manjeet; Malhotra, Samit; Mammis, Antonios; Ocava, Lenore; Rosenbaum, Pearl S.; Rosenbaum, Daniel M.

doi:10.1016/j.brainres.2006.05.060

Cited by 19 publications

(12 citation statements)

References 32 publications

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“…These data suggest that maintaining β1 integrin in an activated state may prevent RGC death after ischemia-reperfusion injury as occurs in retinal artery or vein occlusions, and HUTS-21 antibody could also be explored as a neuroprotective agent for the treatment of ischemic optic neuropathy and glaucoma. Because transient-global-cerebral-and retinal ischemia share similar mechanisms [17], [89], our studies also have relevance to stroke.…”

Section: Discussionmentioning

confidence: 84%

β1 Integrin-Focal Adhesion Kinase (FAK) Signaling Modulates Retinal Ganglion Cell (RGC) Survival

et al. 2012

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Extracellular matrix (ECM) integrity in the central nervous system (CNS) is essential for neuronal homeostasis. Signals from the ECM are transmitted to neurons through integrins, a family of cell surface receptors that mediate cell attachment to ECM. We have previously established a causal link between the activation of the matrix metalloproteinase-9 (MMP-9), degradation of laminin in the ECM of retinal ganglion cells (RGCs), and RGC death in a mouse model of retinal ischemia-reperfusion injury (RIRI). Here we investigated the role of laminin-integrin signaling in RGC survival in vitro, and after ischemia in vivo. In purified primary rat RGCs, stimulation of the β1 integrin receptor with laminin, or agonist antibodies enhanced RGC survival in correlation with activation of β1 integrin’s major downstream regulator, focal adhesion kinase (FAK). Furthermore, β1 integrin binding and FAK activation were required for RGCs’ survival response to laminin. Finally, in vivo after RIRI, we observed an up-regulation of MMP-9, proteolytic degradation of laminin, decreased RGC expression of β1 integrin, FAK and Akt dephosphorylation, and reduced expression of the pro-survival molecule bcl-xL in the period preceding RGC apoptosis. RGC death was prevented, in the context of laminin degradation, by maintaining β1 integrin activation with agonist antibodies. Thus, disruption of homeostatic RGC-laminin interaction and signaling leads to cell death after retinal ischemia, and maintaining integrin activation may be a therapeutic approach to neuroprotection.

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Section: Discussionmentioning

confidence: 84%

β1 Integrin-Focal Adhesion Kinase (FAK) Signaling Modulates Retinal Ganglion Cell (RGC) Survival

et al. 2012

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“…Increased LPA signaling promotes retinal cell survival under hypoxic conditions by upregulation of Lpar1 and Lpar2 expression in ganglion cells and the inner retinal layers (Savitz et al, 2006). However, retinopathy models of prematurity in rat neonates, produced by alternating cycles of hypoxia and hyperoxia, showed conflicting results (Yang et al, 2009): while Lpar1 was upregulated in retinal tissue, LPA exposure or Lpar1 overexpression decreased cell viability and LPA 1 inhibition or short hairpin RNA knockdown was protective to cell survival.…”

Section: Stressors and Neuropsychiatric Disordersmentioning

confidence: 99%

Lysophosphatidic Acid Signaling in the Nervous System

Yung

Stoddard

Mirendil

et al. 2015

Neuron

205

172

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Summary The brain is composed of many lipids with varied forms that serve not only as structural components but also as essential signaling molecules. Lysophosphatidic acid (LPA) is an important bioactive lipid species that is part of the lysophospholipid (LP) family. LPA is primarily derived from membrane phospholipids and signals through six cognate G protein-coupled receptors (GPCRs), LPA1-6. These receptors are expressed on most cell types within central and peripheral nervous tissues and have been functionally linked to many neural processes and pathways. This review covers a current understanding of LPA signaling in the nervous system, with particular focus on the relevance of LPA to both physiological and diseased states.

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“…In addition to the potential cardioprotective effects of LPA, LPA signaling has been shown to be neuroprotective during ischemic injury. Treatment of a rat model of retinal ischemia/reperfusion injury with an LPA analog protected neural cells from apoptosis and improved recovery outcomes (235). However, these data are inconclusive, as LPA has also been shown to induce cell death in cerebral vascular cells, umbilical endothelial cells, brain explants, and retinas (236).…”

Section: Atherosclerosis and Cardiovascular Diseasementioning

confidence: 99%