Humanin Protects Cortical Neurons from Ischemia and Reperfusion Injury by the Increased Activity of Superoxide Dismutase
Department of Physiology, Guangzhou Medical School, Guangzhou 510182, People's Republic of China.Neurochemical Research (Impact Factor: 2.59). 09/2011; 37(1):153-60. DOI: 10.1007/s11064-011-0593-0
The neuroprotective effects of superoxide dismutase (SOD) against hypoxia/reperfusion (I/R) injury and of humanin (HN) against toxicity by familial amyotrophic lateral sclerosis (ALS)-related mutant SOD led us to hypothesize that HN might have a role to increase the activity of SOD, which might be involved in the protective effects of HN on neuron against Alzheimer's disease-unrelated neurotoxicities. In the present study, we found that 4 h ischemia and 24 h reperfusion induced a significant increase in lactate dehydrogenase (LDH) release, malondialdehyde (MDA) formation and the number of karyopyknotic nuclei (4',6-diamidino-2-phenylindole dihydrochloride nuclear dyeing) and a decrease in the number of Calcein-AM-positive living cells and cell viability. Pretreatment of the cells with HN led to a significant decrease in LDH release, MDA formation and the number of karyopyknotic nuclei, and an increase in the number of Calcein-AM-positive living cells and cell viability in neurons treated with I/R. We also found a significant decrease in SOD activity in neurons treated with I/R only, while pre-treatment with HN before I/R induced a significant increase in the activity of SOD as compared with the I/R group. Our findings implied that HN protects cortical neurons from I/R injury by the increased SOD activity and that the protective effect of HN on neurons against I/R is concentration-dependent.
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ABSTRACT: Humanin (HN) has been identified as an endogenous peptide that inhibited AD-relevant neuronal cell death. HNG, a variant of HN in which the 14th amino acid serine was replaced with glycine, can reduce infarct volume and improve neurological deficits after ischemia/reperfusion injury. In this study, we aimed to exam the neuroprotective effect of HNG on traumatic brain injury (TBI) in mice and explored whether the protective effect was associated with regulating apoptosis and autophagy. Compared to vehicle-treated groups, mice administered HNG intracerebroventricularly (i.c.v.) prior to TBI decreased cells with plasmalemma permeability in injured cortex and hippocampus (h 48, P < 0.01), reduced brain lesion volume (d 14 and 28, P < 0.05), improved motor performance (d 1-4, P < 0.05) and ameliorated performance in Morris water maze test (d 11-13, P < 0.05) post TBI. Reduced lesion volume (d 14, P < 0.05) was also observed even when HNG was administered intraperitoneally (i.p.) at 1 h and 2 h post TBI, and minor amelioration in motor and Morris water maze test deficits was also observed. Immunoblotting results showed that HNG pretreatment (i.c.v.) reversed TBI-induced cleavage of caspase-3 and PARP and decline of Bcl-2, suppressed LC3II, Beclin-1 and Vps34 activation and maintained p62 level in injured cortex and hippocampus post TBI (compared with vehicle). In conclusion, HNG treatment improved morphological and functional outcomes after TBI in mice and the protective effect of HNG against TBI may be associated with down-regulating apoptosis and autophagy.Neuroscience 11/2012; 231. DOI:10.1016/j.neuroscience.2012.11.019 · 3.36 Impact Factor
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ABSTRACT: Hypoxia is one of the major stressors at high altitude. Exposure to hypobaric hypoxia induces several adverse consequences to the structural and functional integrity of brain. In an attempt to understand the proteome modulation, we used 2-DE coupled with MALDI-TOF/TOF for cortex and hippocampus exposed to short-term temporal (0, 3, 6, 12 and 24h) hypobaric hypoxia. This enabled us in the identification of 88 and 73 hypoxia responsive proteins in cortex and hippocampus respectively. We further compared the proteomes of both the regions and identified 37 common proteins along with 49 and 32 specific proteins for cortex and hippocampus respectively. We observed significant up-regulation of glycolytic enzymes like Gapdh, Pgam1, Eno1 and malate-aspartate shuttle enzymes Mdh1 and Got1in cortex as compared to hippocampus deciphering efficient use of energy producing substrates. This was coupled with concomitant increase in expression of antioxidant enzymes like Sod1, Sod2 and Pebp1 in cortex to neutralize the hypoxia-induced reactive oxygen species (ROS) generation. Our comparative proteomics studies demonstrate that efficient use of energy generating pathways in conjugation with abundance of antioxidant enzymes makes cortex less vulnerable to hypoxia than hippocampus.Journal of proteomics 01/2013; 79. DOI:10.1016/j.jprot.2012.12.020 · 3.89 Impact Factor
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ABSTRACT: Humanin (HN) has been proved to be an extensive neuroprotective peptide against AD-related and unrelated insults, but little is know about the effect of HN in inflammation response. Current studies indicated the receptors of HN have a close relationship with immune system, which led us to hypothesize HN might have a role in inflammatory response. In this study, we used lipopolysaccharide (LPS) to induce astrocyte inflammation response. This model in vitro allowed us to study the effect of HN on the pure response of astrocyte without the exogenous influence between cells in vivo. Our results showed that 1.0 μg/ml LPS induced a significant activation of astrocyte, shown as the marked increase in the glial fibrillary acidic protein (GFAP) expression, the cell viability and the number of 5-bromo-2'-deoxyuridine (BrdU)-positive living cells. Pretreatment with HN (5, 10, 20 μM) led to a significant inhibition in astrocyte overactivation in a concentration dependent manner. We also found pretreatment with HN decreased the level of proinflammatory cytokines, interleukin (IL)-6, IL-1β and tumor necrosis factor α (TNFα) induced by LPS. Furthermore, we noticed HN couldn't completely reverse the above inflammatory injury. Our findings imply that HN partly antagonizes inflammation injury induced by LPS and the protective effect of HN on astrocyte is concentration-dependent.Neurochemical Research 03/2013; 38(3). DOI:10.1007/s11064-012-0951-6 · 2.59 Impact Factor
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