Browsing by Subject "p38"
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Item DIFFERENTIAL ACTIVATION OF P38 AND C-JUN N-TERMINAL KINASE IN THE VISUAL PATHWAY FOLLOWING OPTIC NERVE CRUSH(2013-04-12) Liu, YangPurpose: p38 and c-jun N-terminal kinase (JNK) are two major stress-activated signaling pathways. In this study, we compared the activation of p38 and JNK in the retina, optic nerve, and superior colliculus after optic nerve crush (ONC) in adult mice. Methods: ONC was performed unilaterally in adult mice. The damage to the retinal ganglion cell (RGC) layer and superior colliculus (SC) was determined by Nissl and black gold II staining. The activation of p38 and JNK in the retina, optic nerve, and superior colliculus was examined by immunofluorescence staining. Results: Starting from 4 weeks after ONC, there were very few RGCs remaining in the RGC layer and fewer neurons (P < 0.05) in the contralateral SC compared to the control group. The volume of the contralateral SC was smaller (P < 0.01) than that of the control group. Phosphorylated JNK (p-JNK) was observed mainly on the proximal side of the optic nerve crush site as early as 1 hour after ONC. The expression of phosphorylated c-JUN was detected in the RGC layer starting 24 hours after ONC. The activation of p38 started 3 days post-ONC and was observed on both sides of the crush site. An increase of phosphorylated p38 (p-p38) was detected in the inner nuclear layer of the retina from 3 through 28 days following ONC. Two weeks after ONC, both p-JNK and p-p38 increased in the contralateral SC; however, the p38 activation was also observed in the ipsilateral SC. Conclusions: Optic nerve crush induces damage in both the RGC layer and the superior colliculus. p38 and JNK activation are differently modulated by optic nerve crush, and might play different roles in neuronal death in the retina and superior colliculus.Item PRESENILIN-1 IS INVOLVED IN THE AGE-PROVOKING EFFECT OF REPEATED ETHANOL WITHDRAWAL.(2014-03) Metzger, Daniel; Das, Hriday; Jung, MariannaAlcohol is the most abused drug in the United States, and its abuse often creates a medical disorder (alcoholism) of which symptoms include withdrawal syndromes upon the abrupt cessation of drinking. Ethanol withdrawal (EW) syndromes (e.g. anxiety and seizure) are largely hyperexcitatory due to the upregulation of excitatory molecule, glutamate. We have previously demonstrated that repeated exposure to and withdrawal (called repeated EW herein) from ethanol hastens brain aging through increasing stress-activated protein p38. In this study, we intended to characterize the effects of repeated EW on the expression of age-related protein presenilin-1 (PS1) and PS1's relationship with p38. PS1 has been shown to be over-expressed in the brain with Alzheimer's disease. Young adult or old rats received a control diet or an ethanol diet for 4 weeks and withdrawn for two weeks. This procedure was repeated once more. Rats were then humanely sacrificed at the end of the ethanol program and whole brains were collected to measure PS1 level using an immunoblot method. Separately, HT22 cells were exposed to glutamate (5 mM) for 24 hours with or without the inhibitor of p38 (SB203580) treatment and then tested for PS1 levels. PS1 expression was significantly higher in old rats than young rats and in repeated EW rats than control diet rats. Glutamate treatment dramatically increases PS1 level in a manner that is attenuated by cotreatment with p38 inhibitor. These data suggest that repeated EW acts as an age-provoking stressor through PS1-upregulation. The increase in PS1 appears to be mediated through glutamate-induced p38. These observations provide a new mechanistic insight into glutamate-p38-PS1 link underlying the aging-like effect of repeated EW. Supported by NIH/AA018747 and IAADR. Purpose (a): In this study, we intended to characterize the effects of repeated EW on the expression of age-related protein presenilin-1 (PS1) and PS1's relationship with p38. PS1 has been shown to be over-expressed in the brain with Alzheimer's disease. Methods (b): Young adult or old rats received a control diet or an ethanol diet for 4 weeks and withdrawn for two weeks. This procedure was repeated once more. Rats were then humanely sacrificed at the end of the ethanol program and whole brains were collected to measure PS1 level using an immunoblot method. Separately, HT22 cells were exposed to glutamate (5 mM) for 24 hours with or without the inhibitor of p38 (SB203580) treatment and then tested for PS1 levels. Results (c): PS1 expression was significantly higher in old rats than young rats and in repeated EW rats than control diet rats. Glutamate treatment dramatically increases PS1 level in a manner that is attenuated by cotreatment with p38 inhibitor. These data suggest that repeated EW acts as an age-provoking stressor through PS1-upregulation. The increase in PS1 appears to be mediated through glutamate-induced p38. Conclusions (d): These observations provide a new mechanistic insight into glutamate-p38-PS1 link underlying the aging-like effect of repeated EW.