Dysfunction of retinal neurons is a major cause of vision impairment in blinding diseases that affect children and adults worldwide. Cellular damage resulting from polyamine catabolism has been demonstrated to be a major player in many neurodegenerative conditions. We have previously shown that inhibition of polyamine oxidase (PAO) using MDL 72527 significantly reduced retinal neurodegeneration and cell death signaling pathways in hyperoxia-mediated retinopathy. In the present study, we investigated the impact of PAO inhibition in limiting retinal neurodegeneration in a model of NMDA ()-induced excitotoxicity. Adult mice (8-10 weeks old) were given intravitreal injections (20 nmoles) of NMDA or NMLA (, control). Intraperitoneal injection of MDL 72527 (40 mg/kg body weight/day) or vehicle (normal saline) was given 24 h before NMDA or NMLA treatment and continued until the animals were sacrificed (varied from 1 to 7 days). Analyses of retinal ganglion cell (RGC) layer cell survival was performed on retinal flatmounts. Retinal cryostat sections were prepared for immunostaining, TUNEL assay and retinal thickness measurements. Fresh frozen retinal samples were used for Western blotting analysis. A marked decrease in the neuronal survival in the RGC layer was observed in NMDA treated retinas compared to their NMLA treated controls, as studied by NeuN immunostaining of retinal flatmounts. Treatment with MDL 72527 significantly improved survival of NeuN positive cells in the NMDA treated retinas. Excitotoxicity induced neurodegeneration was also demonstrated by reduced levels of synaptophysin and degeneration of inner retinal neurons in NMDA treated retinas compared to controls. TUNEL labeling studies showed increased cell death in the NMDA treated retinas. However, treatment with MDL 72527 markedly reduced these changes. Analysis of signaling pathways during excitotoxic injury revealed the downregulation of pro-survival signaling molecules p-ERK and p-Akt, and the upregulation of a pro-apoptotic molecule BID, which were normalized with PAO inhibition. Our data demonstrate that inhibition of polyamine oxidase blocks NMDA-induced retinal neurodegeneration and promotes cell survival, thus offering a new therapeutic target for retinal neurodegenerative disease conditions.

Understanding the adaptation mechanisms of sorghum to drought and the underlying genetic architecture may help to improve its production in a wide range of environments. By crossing a high yielding parent (HYP) and a drought tolerant parent (DTP), we obtained 140 recombinant inbred lines (RILs), which were genotyped with 120 DArT and SSR markers covering 14 linkage groups (LGs). A subset of 100 RILs was evaluated three times in control and drought treatments to genetically dissect their response to water availability. Plants with early heading date (HD) in the drought treatment maintained yield (YLD) level by reducing seed number SN and increasing hundred seed weight (HSW). In contrast, early HD in the control treatment increased SN, HSW and YLD. In total, 133 significant QTL associated with the measured traits were detected in ten hotspot regions. Antagonistic, pleiotropic effects of a QTL cluster mapped on LG-6 may explain the observed trade-offs between SN and HSW: Alleles from DTP reduced SN and the alleles from HYP increased HSW under drought stress, but not in the control treatment. Our results illustrate the importance of considering genetic and environmental factors in QTL mapping to better understand plant responses to drought and to improve breeding programs.