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

Abstract

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, approximately 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 micrometer). 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.

Distinct Requirements for p38α and c-Jun N-terminal Kinase Stress-activated Protein Kinases in Different Forms of Apoptotic Neuronal Death

“…Thus, JNK is required for death induced by withdrawal of nerve growth factor from sympathetic neurons (2, 3), excitotoxicity-and ␤-amyloid-induced apoptosis of hippocampal neurons (5,36), apoptosis during early brain development (6), and 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine-induced apoptosis of dopaminergic neurons (7). The use of SB203580 has implicated a p38 contribution to axotomy-induced apoptosis of retinal ganglion cells (8), glutamate-induced apoptosis of cerebellar granule neurons (9) and ceramide-induced death of cortical neurons (10). However, it has recently been revealed that SB203580 exhibits higher specificity for kinases other than p38 (11), and at the concentrations typically used to target p38 it can even inhibit JNK-dependent death (13).…”

The upregulation of GLAST-1 is an indirect antiapoptotic mechanism of GDNF and neurturin in the adult CNS

“…9 Furthermore, MK-801 and the AMPA receptor antagonist DNQX have been shown to protect RGCs from apoptosis after optic nerve injury. [10][11][12][13] These findings indicate that glutamate-dependent activation of NMDA and AMPA-kainate receptors is an important trigger of apoptotic cell death in injured adult RGCs.…”

Differential activation of the c-Jun N-terminal kinase/stress-activated protein kinase and p38 mitogen-activated protein kinase signal transduction pathways in the mouse brain upon infection with neurovirulent influenza A virus

“…These descriptions are consistent with the present observation that activation of p38 MAPK parallels the neuroinflammatory process during virus infection of the brain. It is expected that in combination with antiviral treatment (Mori et al, 2002b), a therapeutic intervention against the MAPK pathways, using a JNK inhibitor and a p38 inhibitor (Kikuchi et al, 2000;Lee et al, 2000;Mielke & Herdegen, 2000), may suppress apoptotic neuronal death and neuroinflammation during acute virus encephalitis and minimize neurological sequelae. …”

“…Significant function of the p38 MAPK pathway has been reported in the apoptotic cascade in cultured neurons (Kummer et al, 1997;Horstmann et al, 1998;Ghatan et al, 2000;Zou et al, 2002). Activation of p38 MAPK has also been attributed to axotomy-induced apoptosis of retinal ganglion cells in rats, although the role played by p38 activation in apoptosis regulation differs in a cell-type-or stimulation-dependent manner (Kikuchi et al, 2000).…”