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The Journal of Neuroscience, July 1, 2000, 20(13):5037-5044

Role of p38 Mitogen-Activated Protein Kinase in Axotomy-Induced Apoptosis of Rat Retinal Ganglion Cells

Masashi Kikuchi^{1, 2}, Lalitha Tenneti², and Stuart A. Lipton^{1, 2}

¹ Center for Neuroscience and Aging, The Burnham Institute, La Jolla, California 92307, and ² CNS Research Institute, Brigham and Women's Hospital, Division of Neuroscience, Children's Hospital, and Program in Neuroscience, Harvard Medical School, Boston, Massachusetts 02115

p38 is a member of the mitogen-activated protein (MAP) kinase superfamily and mediates intracellular signal transduction. Recent studies suggest that p38 is involved in apoptotic signaling in several cell types, including neurons. In the mammalian retina, ~50% of the retinal ganglion cells (RGCs) die by apoptosis during development. Additionally, transection of the optic nerve close to the eye bulb causes apoptotic cell death of RGCs in adulthood. We investigated the role of p38 in axotomy-induced apoptosis of RGCs. One day after axotomy, activated (phosphorylated) p38 was visualized by immunocytochemistry in the nuclei of RGCs, but not in control retinas. Phosphorylated p38 was first detected on immunoblots 12 hr after axotomy, reached a maximum at 1 d, and then decreased. To investigate possible roles of p38 in RGC death, a p38 MAP kinase inhibitor, SB203580, was administered intravitreally at the time of axotomy and repeated at 5 and 10 d. Assayed 14 d after axotomy, SB203580 increased the number of surviving RGCs in a dose-dependent manner (the minimum effective concentration was 1.6 µM). Furthermore, MK801, a selective inhibitor of NMDA receptors, not only showed protective effects against RGC apoptosis but also attenuated p38 MAP kinase activation in a dose-dependent manner. Our findings imply that p38 is in the signaling pathway to RGC apoptosis mediated by glutamate neurotoxicity through NMDA receptors after damage to the optic nerve. p38 inhibitors could be potentially useful for the treatment of optic nerve trauma and neurodegenerative diseases that affect RGCs, such as glaucoma.

Key words: mitogen-activated protein kinase; p38; axotomy; retinal ganglion cells; apoptosis; glutamate; NMDA; optic nerve

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Copyright © 2000 Society for Neuroscience  0270-6474/00/20135037-08$05.00/0

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