A role for polyamines in retinal ganglion cell excitotoxic death

Abstract

Neuronal death due to excessive activation of N-methyl-D-aspartate (NMDA) receptors is a hallmark of neurodegenerative diseases. The polyamines: putrescine, spermine, and spermidine, bind to specific sites on the NMDA receptor and promote its activation, but their role in NMDA-induced neuronal death is ill defined. In this study, we characterized the role of polyamines in excitotoxic death of retinal ganglion cells (RGCs), a population of central neurons susceptible to NMDAinduced damage. Our data show that endogenous arginase I, the rate limiting enzyme for polyamine biosynthesis, is expressed in the intact, adult retina. Intraocular injection of NMDA visibly increased arginase I expression in Mü ller cells, the predominant glial cell-type in the mammalian retina. Inhibition of polyamine synthesis using di-fluoro-methyl-ornithine (DFMO) was markedly neuroprotective, while injection of exogenous polyamines in conjunction with NMDA exacerbated RGC death. Blockade of the polyamine binding sites on NMDA receptors using the non-competitive antagonist ifenprodil was neuroprotective, suggesting that polyamines contribute to excitotoxic death, at least partly, by binding to NMDA receptors. Importantly, we also demonstrate that NMDA leads to activation of both the Erk1/2 and PI3 K/Akt pathways, but only the PI3 K/Akt kinase was required for di-fluoro-methylornithine-induced RGC survival. In summary, our study reveals that polyamines modulate neuronal death in the retina via different mechanisms that potentiate NMDA-triggered excitotoxicity.

Spermidine Ameliorates Neurodegeneration in a Mouse Model of Normal Tension Glaucoma

“…Previously, it was reported that polyamines potentiate NMDA-triggered excitotoxicity. 42 However, we show that spermidine ameliorates retinal degeneration in the GCL. This discrepancy may be explained by various factors concerning experimental procedures including the route of polyamine administration, the nature of the molecules used (spermidine, putrescine, or spermine) and the dose.…”

Arginase Activity Mediates Retinal Inflammation in Endotoxin-Induced Uveitis

“…Polyamines have multiple physiological and pathological functions including vascularization, tissue repair, and neural toxicity. [51][52][53] However, it is still questionable whether their function is proinflammatory or anti-inflammatory. 54,55 We have previously demonstrated that inhibiting NOX2/NADPH oxidase blocks inflammatory responses in mouse models of EIU and diabetic retinopathy.…”

Targets of polyamine dysregulation in major depression and suicide: Activity-dependent feedback, excitability, and neurotransmission

“…In cardiac cells, this ODC1 induction is caused by the activation of extracellular signal-regulated kinases 1 and 2 (ERK1/2; also known as P42/P44 MAPK), and P13K/Akt pathways (Pernet et al, 2007; Zhang et al, 2014b). ODC1 activation by ERK1/2 is also dependent on Ca 2+ -mediated activation of calpain (Moldoveanu et al, 2002).…”