Bertram KM, Baglole CJ, Phipps RP, Libby RT. Molecular regulation of cigarette smoke induced-oxidative stress in human retinal pigment epithelial cells: implications for age-related macular degeneration.

Stress is a part of daily life. However, molecular mechanisms underlying the activation of limbic-hypothalamic-pituitaryadrenal (LHPA) axis remains unknown. In this study, we explored whether activation of the mitogen-activated kinase kinase 4 (MKK4)-c-Jun-N-terminal kinase (JNK) signaling pathway may play a role in the activation of the LHPA axis. We found that forced-swim stress induced elevation of activated MKK4 in the hippocampal formation, amygdala, and hypothalamus. Unlike MKK4, a high basal level of JNK activity is present in many brain areas of unstressed mice. Forced-swim stress significantly elevated JNK activity in the hypothalamus and amygdala and, to a lesser extent, in the cortex, CA1 and CA3 regions, and the dentate gyrus. To further investigate the role of MKK4 and JNK in induction of stress responses, we investigated whether a different stress, namely, restraint stress, induced activation of MKK4 or JNK in the brain. We found that restraint stress also induced elevation of activated MKK4 and JNK in the hippocampal formation, amygdala, and hypothalamus. Because MKK4 and JNK were activated within 5 min following stress, we propose that the MKK4-JNK signaling may be an early neural event in the initiation of neuroendocrine, autonomic and behavioral stress responses.

Diabetic retinopathy is a leading cause of vision loss. The primary clinical hallmarks are vascular changes that appear to contribute to the loss of sight. In a number of neurodegenerative disorders there is an appreciation that increased levels of excitatory amino acids are excitotoxic. The primary amino acid responsible appears to be the neurotransmitter glutamate. This review examines the nature of glutamatergic signaling at the retina and the growing evidence from clinical and animal model studies that glutamate may be playing similar excitotoxic roles at the diabetic retina.

Purpose To compare the concentration of amino acids in subretinal and vitreous fluid of patients with primary rhegmatogenous retinal detachment to that of control vitreous. Methods This prospective, observational study measured amino-acid levels in subretinal fluid of patients undergoing scleral buckle placement (n ¼ 20) and vitreous fluid in patients undergoing pars plana vitrectomy (n ¼ 5) for primary retinal detachment. Vitreous fluid from patients undergoing vitrectomy for macular hole (n ¼ 7) or epiretinal membrane (n ¼ 3) served as a control. Subretinal fluid and control vitreous were analysed using high-pressure liquid chromatography. Retinal detachment vitreous was analysed using capillary electrophoresis-laser-induced fluorescence. Results Mean levels of glutamate (27.071.7 lM), aspartate (4.174.0 lM), and glycine (44.1731.0 lM) in subretinal fluid and glutamate (13.4711.9 lM) in the vitreous were significantly elevated in retinal detachment compared to control vitreous. A significant, positive association was observed between levels of aspartate and glutamate in subretinal fluid (Spearman's correlation coefficient: 0.74, Po0.01). Mean arginine levels did not differ significantly between subretinal fluid and control vitreous. Levels of alanine, tyrosine, valine, isoleucine, leucine, and phenylalanine were significantly lower in subretinal fluid compared to control vitreous (all Po0.01). Conclusions Glutamate levels in subretinal fluid and vitreous of patients with primary retinal detachment is significantly elevated in comparison to control vitreous. This finding lends further support to the hypothesis that elevated glutamate levels may result from ischaemia of the outer retina secondary to retinal detachment.