Protective mechanism of testosterone on cognitive impairment in a rat model of Alzheimer's disease
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摘要
Cognitive dysfunction in Alzheimer's disease is strongly associated with a reduction in synaptic plasticity, which may be induced by oxidative stress. Testosterone is beneficial in learning and memory, although the underlying protective mechanism of testosterone on cognitive performance remains unclear. This study explored the protective mechanism of a subcutaneous injection of 0.75 mg testosterone on cognitive dysfunction induced by bilateral injections of amyloid beta 1–42 oligomers into the lateral ventricles of male rats. Morris water maze test results demonstrated that testosterone treatment remarkably reduced escape latency and path length in Alzheimer's disease rat models. During probe trials, testosterone administration significantly elevated the percentage of time spent in the target quadrant and the number of platform crossings. However, flutamide, an androgen receptor antagonist, inhibited the protective effect of testosterone on cognitive performance in Alzheimer's disease rat models. Nissl staining, immunohistochemistry, western blot assay, and enzyme-linked immunosorbent assay results showed that the number of intact hippocampal pyramidal cells, the dendritic spine density in the hippocampal CA1 region, the immune response and expression level of postsynaptic density protein 95 in the hippocampus, and the activities of superoxide dismutase and glutathione peroxidase were increased with testosterone treatment. In contrast, testosterone treatment reduced malondialdehyde levels. Flutamide inhibited the effects of testosterone on all of these indicators. Our data showed that the protective effect of testosterone on cognitive dysfunction in Alzheimer's disease is mediated via androgen receptors to scavenge free radicals, thereby enhancing synaptic plasticity.
Cognitive dysfunction in Alzheimer's disease is strongly associated with a reduction in synaptic plasticity, which may be induced by oxidative stress. Testosterone is beneficial in learning and memory, although the underlying protective mechanism of testosterone on cognitive performance remains unclear. This study explored the protective mechanism of a subcutaneous injection of 0.75 mg testosterone on cognitive dysfunction induced by bilateral injections of amyloid beta 1–42 oligomers into the lateral ventricles of male rats. Morris water maze test results demonstrated that testosterone treatment remarkably reduced escape latency and path length in Alzheimer's disease rat models. During probe trials, testosterone administration significantly elevated the percentage of time spent in the target quadrant and the number of platform crossings. However, flutamide, an androgen receptor antagonist, inhibited the protective effect of testosterone on cognitive performance in Alzheimer's disease rat models. Nissl staining, immunohistochemistry, western blot assay, and enzyme-linked immunosorbent assay results showed that the number of intact hippocampal pyramidal cells, the dendritic spine density in the hippocampal CA1 region, the immune response and expression level of postsynaptic density protein 95 in the hippocampus, and the activities of superoxide dismutase and glutathione peroxidase were increased with testosterone treatment. In contrast, testosterone treatment reduced malondialdehyde levels. Flutamide inhibited the effects of testosterone on all of these indicators. Our data showed that the protective effect of testosterone on cognitive dysfunction in Alzheimer's disease is mediated via androgen receptors to scavenge free radicals, thereby enhancing synaptic plasticity.
Cognitive dysfunction in Alzheimer's disease is strongly associated with a reduction in synaptic plasticity, which may be induced by oxidative stress. Testosterone is beneficial in learning and memory, although the underlying protective mechanism of testosterone on cognitive performance remains unclear. This study explored the protective mechanism of a subcutaneous injection of 0.75 mg testosterone on cognitive dysfunction induced by bilateral injections of amyloid beta 1–42 oligomers into the lateral ventricles of male rats. Morris water maze test results demonstrated that testosterone treatment remarkably reduced escape latency and path length in Alzheimer's disease rat models. During probe trials, testosterone administration significantly elevated the percentage of time spent in the target quadrant and the number of platform crossings. However, flutamide, an androgen receptor antagonist, inhibited the protective effect of testosterone on cognitive performance in Alzheimer's disease rat models. Nissl staining, immunohistochemistry, western blot assay, and enzyme-linked immunosorbent assay results showed that the number of intact hippocampal pyramidal cells, the dendritic spine density in the hippocampal CA1 region, the immune response and expression level of postsynaptic density protein 95 in the hippocampus, and the activities of superoxide dismutase and glutathione peroxidase were increased with testosterone treatment. In contrast, testosterone treatment reduced malondialdehyde levels. Flutamide inhibited the effects of testosterone on all of these indicators. Our data showed that the protective effect of testosterone on cognitive dysfunction in Alzheimer's disease is mediated via androgen receptors to scavenge free radicals, thereby enhancing synaptic plasticity.
引文
Aliev G,Priyadarshini M,Reddy VP,Grieg NH,Kaminsky Y,Cacabelos R,Md Ashraf G,Jabir NR,Kamal MA,Nikolenko VN,Zamyatnin AA,Benberin VV,Bachurin SO(2014)Oxidative stress mediated mitochondrial and vascular lesions as markers in the pathogenesis of Alzheimer disease.Curr Med Chem 21:2208-2217.
Asih PR,Tegg ML,Sohrabi H,Carruthers M,Gandy SE,Saad F,Verdile G,Ittner LM(2017)Martins RN multiple mechanisms linking type 2 diabetes and Alzheimer’s disease:testosterone as a modifier.J Alzheimers Dis 59:445-466.
Aybek H,Ercan F,Aslan D,Sahiner T(2007)Determination of malondialdehyde,reduced glutathione levels and APOE4 allele frequency in late-onset Alzheimer’s disease in Denizli,Turkey.Clin Biochem 40:172-176.
Benice TS,Raber J(2009)Dihydrotestosterone modulates spatial working-memory performance in male mice.J Neurochem110:902-911.
Candemir M,Semiz S,Yonguc GN,Ozdemir MB,Abban-Mete G,Adiguzel E(2013)Effect of testosterone propionate on hippocampal pyramidal neuron number in female rats.Singapore Med J54:315-320.
Cherry JD,Olschowka JA,Banion MK(2014)Neuroinflammation and M2 microglia:the good,the bad,and the inflamed.J Neuroinflamm 11:1-15.
Chung WS,Welsh CA,Barres BA,Stevens B(2015)“Do glia drive synaptic and cognitive impairment in disease?”Nat Neurosci18:1539-1545.
Driscoll I,Hamilton DA,Yeo RA,Brooks WM,Sutherland RJ(2005)Virtual navigation in humans:the impact of age,sex,and hormones on place learning.Horm Behav 47:326-335.
Edinger KL,Frye CA(2004)Testosterone’s analgesic,anxiolytic,and cognitive enhancing effects may be due in part to actions of its 5a-reduced metabolites in the hippocampus.Behav Neurosci118:1352-1364.
Elena AK,Iliya NS,Lyudmila AT,Reddy VP,Aliev G,Kaminsky YG(2014)Pathogenesis of Alzheimer disease:role of oxidative stress,amyloid-βpeptides,systemic ammonia and erythrocyte energy metabolism.CNS Neurol Disord Drug Targets 13:112-119.
Ganjei JK(2010)Targeting amyloid precursor protein secretases:Alzheimer’s disease and beyond.Drug News Perspect 23:573-584.
Grimm A,Mensah-Nyagan AG,Eckert A(2016)Alzheimer,mitochondria and gender.Neurosci Biobehav Rev 67:89-101.
Holland J,Bandelow S,Hogervorst E(2011)Testosterone levels and cognition in elderly men:a review.Maturitas 69:322-337.
Huo DS,Sun JF,Zhang BF,Yan XS,Wang H,Jia JX,Yang ZJ(2016)Protective effects of testosterone on cognitive dysfunction in Alzheimer’s disease model rats induced by oligomeric beta amyloid peptide 1-42.J Toxicol Environ Health A 79:856-863.
Jia JX,Cui CL,Yan XS,Zhang BF,Song W,Huo DS,Wang H,Yang ZJ(2016)Effects of testosterone on synaptic plasticity mediated by androgen receptors in male SAMP8 mice.J Toxicol Environ Health A 79:849-855.
Jia JX,Cui CL,Song W,Yan XS,Huo DS,Wang H,Yang ZJ(2015)Effects of testosterone treatment on synaptic plasticity and behavior in senescence accelerated mice.J Toxicol Environ Health A78:1311-1320.
Jia JX,Kang L,Li S,Geng D,Fan P,Wang L,Cui HX(2013)Amelioratory effects of testosterone treatment on cognitive performance deficits induced by soluble Aβ1-42 oligomers injected into the hippocampus.Horm Behav 64:477-486.
Jing W,Michael FJ,Yu FX(2016)Glia and TRPM2 channels in plasticity of central nervous system and Alzheimer’s diseases.Neural Plast 7:1-7.
Kerr JE,Allore RJ,Beck SG,Handa RJ(1995)Distribution of hormonal regulation of androgen receptor(AR)and AR messenger ribonucleic acid in the rat hippocampus.Endocrinology 136:3213-3221.
Kim E,Sheng M(2004)PDZ domain proteins of synapses.Nat Rev Neurosci 5:771-781.
Kritzer M(2004)The distribution of immunoreactivity for intracellular androgen receptors in the cerebral cortex of hormonally intact adult male and female rats:localization in pyramidal neurons making corticocortical connections.Cereb Cortex 14:268-280.
Leranth C,Petnehazy O,MacLusky NJ(2003)Gonadal hormones affect spine synaptic density in the CA1 hippocampal subfield of male rats.J Neurosci 23:1588-1592.
Leranth C,Hajszan T,MacLusky NJ(2004)Androgens increase spine synapse density in the CA1 hippocampal subfield of ovariectomized female rats.J Neurosci 24:495-499.
Li S,Kang L,Zhang C,Xie GS,Li N,Zhang Y,Du J,Cui HX(2013)Effects of dihydrotestosterone on synaptic plasticity of hippocampus in male SAMP8 mice.Exp Gerontol 48:778-785.
Li X,Schwartz PE,Rissman EF(1997)Distribution of estrogen receptor-β-like immunoreactivity in rat forebrain.Neuroendocrinology 66:63-67.
Liu L,Orozco IJ,Planel E,Wen Y,Bretteville A,Krishnamurthy P,Wang L,Herman M,Figueroa H,Yu WH,Arancio O,Duff K(2008)A transgenic rat that develops Alzheimer’s disease-like amyloid pathology,deficits in synaptic plasticity and cognitive impairment.Neurobiol Dis 31:46-57.
Liu L,Li J,Zhao F,Wang H,Qu Y,Mu D(2015)Nitric oxide synthase in hypoxic or ischemic brain injury.Rev Neurosci 26:105-117.
Marron TU,Guerini V,Rusmini P,Sau D,Brevini TA,Martini L,Poletti A(2005)Androgen-induced neurite outgrowth is mediated by neuritin in motor neurones.J Neurochem 92:10-20.
Miwa S,Saretzki G(2017)Telomerase and mTOR in the brain:the mitochondria connection.Neural Regen Res 12:358-361.
Mukai H,Kimoto T,Hojo Y,Kawato S,Murakami G,Higo S,Hatanaka Y,Ogiue-Ikeda M(2010)Modulation of synaptic plasticity by brain estrogen in the hippocampus.Biochim Biophys Acta1800:1030-1044.
Norenberg MD,Rama Rao KV,Jayakumar AR(2009)Signaling factors in the mechanism of ammonia neurotoxicity.Metab Brain Dis 24:103-117.
Nunez JL,Jurgens HA,Juraska JM(2000)Androgens reduce cell death in the developing rat visual cortex.Brain Res Dev Brain Res125:83-88.
Osborne DM,Edinger KL,Frye CA(2009)Chronic administration of androgens with actions at estrogen receptor beta have anti-anxiety and cognitive-enhancing effects in male rats.Age 31:191-198.
Pan WS,Han S,Kang L,Li S,Du J,Cui HX(2016)Effects of dihydrotestosterone on synaptic plasticity of the hippocampus in mild cognitive impairment male SAMP8 mice.Exp Ther Med 12:1455-1463.
Paxinos G,Watson C(1986)The rat brain in stereotaxic coordinates,2nd edition.Orlando,FL,USA,Academic Press.
Phan A,Suschkov S,Molinaro L(2015)Rapid increases in immature synapses parallel estrogen-induced hippocampal learning enhancements.Proc Natl Acad Sci U S A 29:16018-16023.
Pradip KK,Anuradha K,Shivika R,Supriya S,Santoshkumar T,Chandishwar N,Neetu T(2016)Mechanism of oxidative stress and synapse dysfunction in the pathogenesis of Alzheimer’s disease:understanding the therapeutics strategies.Mol Neurobiol53:648-661.
Rege SD,Geetha T,Broderick TL,Babu JR(2015)Resveratrol protectsβamyloid-induced oxidative damage and memory associated proteins in H19-7 hippocampal neuronal cells.Curr Alzheimer Res 12:147-156.
Rodrigo GR,Mauricio NM,Karina VS,Daniel AS,Laura MM(2017)Involvement of astrocytes in Alzheimer’s disease from a neuroinflammatory and oxidative stress perspective.Front Mol Neurosci10:1-20.
Rosario ER,Chang L,Head EH,Stanczyk FZ,Pike CJ(2011)Brain levels of sex steroid hormones in men and women during normal aging and in Alzheimer’s disease.Neurobiol Aging 32:604-613.
Rosario ER,Pike CJ(2008)Androgen regulation ofβ-amyloid protein and the risk of Alzheimer’s disease.Brain Res Rev 57:444-453.
Selkoe DJ(2011)Alzheimer’s disease.Cold Spring Harb Perspect Biol 3:1-16.
Smith CC,Smith LA,Bredemann TM,McMahon LL(2016)17βEstradiol recruits GluN2B-containing NMDARs and ERK during Induction of long-term potentiation at temporoammonic-CA1synapses.Hippocampus 26:110-117.
Smith MA,Richey Harris PL,Sayre L M,Joseph S,Beckman,George Perry(1997)Widespread peroxynitrite mediated damage in Alzheimer’s disease.J Neurosci 17:2653-2657.
Song L,Li X,Bai XX,Gao J,Wang CY(2017)Calycosin improves cognitive function in a transgenic mouse model of Alzheimer’s disease by activating the protein kinase C pathway.Neural Regen Res 12:1870-1876.
Sonmez A,Say?n O,Gurgen SG,Calisir M(2015)Neuroprotective effects of MK-801 against traumatic brain injury in immature rats.Neurosci Lett 597:137-142.
Spritzer MD,Daviau ED,Coneeny,MK,Engelman SM,Prince WT,Rodriguez-Wisdom KN(2011)Effects of testosterone on spatial learning and memory in adult male rats.Horm Behav 59:484-496.
Spritzer MD,Galea LA(2007)Testosterone and dihydrotestosterone,but not estradiol,enhance survival of new hippocampal neurons in adult male rats.Neurobiology 67:1321-1333.
Tadatsugu T,Azusa M,Kenichi S,Chiaki K(2008)Participation of the cholinergic system in ameliorating effect of vasopressin fragment by Group I metabotropic glutamate receptor blockade.JPharmacol Sci 108:335-340.
Tramutola A,Lanzillotta C,Perluigi M,Butterfield DA(2017)Oxidative stress,protein modification and Alzheimer disease.Brain Res Bull 133:88-96.
Wang CY,Wang ZY,Xie JW,Wang T,Wang X,Xu Y,Cai JH(2016)Dl-3-n-butylphthalide-induced upregulation of antioxidant defense is involved in the enhancement of cross talk between CREBand Nrf2 in an Alzheimer’s disease mouse model.Neurobiol Aging 38:32-46.
Wang X,Hu X,Yang Y,Takata T,Sakurai T(2016)Nicotinamide mononucleotide protects againstβ-amyloid oligomer-induced cognitive impairment and neuronal death.Brain Res 15:1643:1-9.
Yang GF,Ji JG,Peng LW,He SZ(2011)Oxidative proteins in human brains separated and identified by proteomics technology.Zhongguo Zuzhi Gongcheng Yanjiu 15:1990-1993.
Yin H,Xu L,Porter NA(2011)Free radical lipid peroxidation:mechanisms and analysis.Chem Rev 111:5944-5972.
Zhang Y,Guo JH,Yan HJ,et al.(2016)Bone marrow mesenchymal stem cell transplantation improves behavior performance of senile dementia rats.Zhongguo Zuzhi Gongcheng Yanjiu 20:5371-5377.
Asih PR,Tegg ML,Sohrabi H,Carruthers M,Gandy SE,Saad F,Verdile G,Ittner LM(2017)Martins RN multiple mechanisms linking type 2 diabetes and Alzheimer’s disease:testosterone as a modifier.J Alzheimers Dis 59:445-466.
Aybek H,Ercan F,Aslan D,Sahiner T(2007)Determination of malondialdehyde,reduced glutathione levels and APOE4 allele frequency in late-onset Alzheimer’s disease in Denizli,Turkey.Clin Biochem 40:172-176.
Benice TS,Raber J(2009)Dihydrotestosterone modulates spatial working-memory performance in male mice.J Neurochem110:902-911.
Candemir M,Semiz S,Yonguc GN,Ozdemir MB,Abban-Mete G,Adiguzel E(2013)Effect of testosterone propionate on hippocampal pyramidal neuron number in female rats.Singapore Med J54:315-320.
Cherry JD,Olschowka JA,Banion MK(2014)Neuroinflammation and M2 microglia:the good,the bad,and the inflamed.J Neuroinflamm 11:1-15.
Chung WS,Welsh CA,Barres BA,Stevens B(2015)“Do glia drive synaptic and cognitive impairment in disease?”Nat Neurosci18:1539-1545.
Driscoll I,Hamilton DA,Yeo RA,Brooks WM,Sutherland RJ(2005)Virtual navigation in humans:the impact of age,sex,and hormones on place learning.Horm Behav 47:326-335.
Edinger KL,Frye CA(2004)Testosterone’s analgesic,anxiolytic,and cognitive enhancing effects may be due in part to actions of its 5a-reduced metabolites in the hippocampus.Behav Neurosci118:1352-1364.
Elena AK,Iliya NS,Lyudmila AT,Reddy VP,Aliev G,Kaminsky YG(2014)Pathogenesis of Alzheimer disease:role of oxidative stress,amyloid-βpeptides,systemic ammonia and erythrocyte energy metabolism.CNS Neurol Disord Drug Targets 13:112-119.
Ganjei JK(2010)Targeting amyloid precursor protein secretases:Alzheimer’s disease and beyond.Drug News Perspect 23:573-584.
Grimm A,Mensah-Nyagan AG,Eckert A(2016)Alzheimer,mitochondria and gender.Neurosci Biobehav Rev 67:89-101.
Holland J,Bandelow S,Hogervorst E(2011)Testosterone levels and cognition in elderly men:a review.Maturitas 69:322-337.
Huo DS,Sun JF,Zhang BF,Yan XS,Wang H,Jia JX,Yang ZJ(2016)Protective effects of testosterone on cognitive dysfunction in Alzheimer’s disease model rats induced by oligomeric beta amyloid peptide 1-42.J Toxicol Environ Health A 79:856-863.
Jia JX,Cui CL,Yan XS,Zhang BF,Song W,Huo DS,Wang H,Yang ZJ(2016)Effects of testosterone on synaptic plasticity mediated by androgen receptors in male SAMP8 mice.J Toxicol Environ Health A 79:849-855.
Jia JX,Cui CL,Song W,Yan XS,Huo DS,Wang H,Yang ZJ(2015)Effects of testosterone treatment on synaptic plasticity and behavior in senescence accelerated mice.J Toxicol Environ Health A78:1311-1320.
Jia JX,Kang L,Li S,Geng D,Fan P,Wang L,Cui HX(2013)Amelioratory effects of testosterone treatment on cognitive performance deficits induced by soluble Aβ1-42 oligomers injected into the hippocampus.Horm Behav 64:477-486.
Jing W,Michael FJ,Yu FX(2016)Glia and TRPM2 channels in plasticity of central nervous system and Alzheimer’s diseases.Neural Plast 7:1-7.
Kerr JE,Allore RJ,Beck SG,Handa RJ(1995)Distribution of hormonal regulation of androgen receptor(AR)and AR messenger ribonucleic acid in the rat hippocampus.Endocrinology 136:3213-3221.
Kim E,Sheng M(2004)PDZ domain proteins of synapses.Nat Rev Neurosci 5:771-781.
Kritzer M(2004)The distribution of immunoreactivity for intracellular androgen receptors in the cerebral cortex of hormonally intact adult male and female rats:localization in pyramidal neurons making corticocortical connections.Cereb Cortex 14:268-280.
Leranth C,Petnehazy O,MacLusky NJ(2003)Gonadal hormones affect spine synaptic density in the CA1 hippocampal subfield of male rats.J Neurosci 23:1588-1592.
Leranth C,Hajszan T,MacLusky NJ(2004)Androgens increase spine synapse density in the CA1 hippocampal subfield of ovariectomized female rats.J Neurosci 24:495-499.
Li S,Kang L,Zhang C,Xie GS,Li N,Zhang Y,Du J,Cui HX(2013)Effects of dihydrotestosterone on synaptic plasticity of hippocampus in male SAMP8 mice.Exp Gerontol 48:778-785.
Li X,Schwartz PE,Rissman EF(1997)Distribution of estrogen receptor-β-like immunoreactivity in rat forebrain.Neuroendocrinology 66:63-67.
Liu L,Orozco IJ,Planel E,Wen Y,Bretteville A,Krishnamurthy P,Wang L,Herman M,Figueroa H,Yu WH,Arancio O,Duff K(2008)A transgenic rat that develops Alzheimer’s disease-like amyloid pathology,deficits in synaptic plasticity and cognitive impairment.Neurobiol Dis 31:46-57.
Liu L,Li J,Zhao F,Wang H,Qu Y,Mu D(2015)Nitric oxide synthase in hypoxic or ischemic brain injury.Rev Neurosci 26:105-117.
Marron TU,Guerini V,Rusmini P,Sau D,Brevini TA,Martini L,Poletti A(2005)Androgen-induced neurite outgrowth is mediated by neuritin in motor neurones.J Neurochem 92:10-20.
Miwa S,Saretzki G(2017)Telomerase and mTOR in the brain:the mitochondria connection.Neural Regen Res 12:358-361.
Mukai H,Kimoto T,Hojo Y,Kawato S,Murakami G,Higo S,Hatanaka Y,Ogiue-Ikeda M(2010)Modulation of synaptic plasticity by brain estrogen in the hippocampus.Biochim Biophys Acta1800:1030-1044.
Norenberg MD,Rama Rao KV,Jayakumar AR(2009)Signaling factors in the mechanism of ammonia neurotoxicity.Metab Brain Dis 24:103-117.
Nunez JL,Jurgens HA,Juraska JM(2000)Androgens reduce cell death in the developing rat visual cortex.Brain Res Dev Brain Res125:83-88.
Osborne DM,Edinger KL,Frye CA(2009)Chronic administration of androgens with actions at estrogen receptor beta have anti-anxiety and cognitive-enhancing effects in male rats.Age 31:191-198.
Pan WS,Han S,Kang L,Li S,Du J,Cui HX(2016)Effects of dihydrotestosterone on synaptic plasticity of the hippocampus in mild cognitive impairment male SAMP8 mice.Exp Ther Med 12:1455-1463.
Paxinos G,Watson C(1986)The rat brain in stereotaxic coordinates,2nd edition.Orlando,FL,USA,Academic Press.
Phan A,Suschkov S,Molinaro L(2015)Rapid increases in immature synapses parallel estrogen-induced hippocampal learning enhancements.Proc Natl Acad Sci U S A 29:16018-16023.
Pradip KK,Anuradha K,Shivika R,Supriya S,Santoshkumar T,Chandishwar N,Neetu T(2016)Mechanism of oxidative stress and synapse dysfunction in the pathogenesis of Alzheimer’s disease:understanding the therapeutics strategies.Mol Neurobiol53:648-661.
Rege SD,Geetha T,Broderick TL,Babu JR(2015)Resveratrol protectsβamyloid-induced oxidative damage and memory associated proteins in H19-7 hippocampal neuronal cells.Curr Alzheimer Res 12:147-156.
Rodrigo GR,Mauricio NM,Karina VS,Daniel AS,Laura MM(2017)Involvement of astrocytes in Alzheimer’s disease from a neuroinflammatory and oxidative stress perspective.Front Mol Neurosci10:1-20.
Rosario ER,Chang L,Head EH,Stanczyk FZ,Pike CJ(2011)Brain levels of sex steroid hormones in men and women during normal aging and in Alzheimer’s disease.Neurobiol Aging 32:604-613.
Rosario ER,Pike CJ(2008)Androgen regulation ofβ-amyloid protein and the risk of Alzheimer’s disease.Brain Res Rev 57:444-453.
Selkoe DJ(2011)Alzheimer’s disease.Cold Spring Harb Perspect Biol 3:1-16.
Smith CC,Smith LA,Bredemann TM,McMahon LL(2016)17βEstradiol recruits GluN2B-containing NMDARs and ERK during Induction of long-term potentiation at temporoammonic-CA1synapses.Hippocampus 26:110-117.
Smith MA,Richey Harris PL,Sayre L M,Joseph S,Beckman,George Perry(1997)Widespread peroxynitrite mediated damage in Alzheimer’s disease.J Neurosci 17:2653-2657.
Song L,Li X,Bai XX,Gao J,Wang CY(2017)Calycosin improves cognitive function in a transgenic mouse model of Alzheimer’s disease by activating the protein kinase C pathway.Neural Regen Res 12:1870-1876.
Sonmez A,Say?n O,Gurgen SG,Calisir M(2015)Neuroprotective effects of MK-801 against traumatic brain injury in immature rats.Neurosci Lett 597:137-142.
Spritzer MD,Daviau ED,Coneeny,MK,Engelman SM,Prince WT,Rodriguez-Wisdom KN(2011)Effects of testosterone on spatial learning and memory in adult male rats.Horm Behav 59:484-496.
Spritzer MD,Galea LA(2007)Testosterone and dihydrotestosterone,but not estradiol,enhance survival of new hippocampal neurons in adult male rats.Neurobiology 67:1321-1333.
Tadatsugu T,Azusa M,Kenichi S,Chiaki K(2008)Participation of the cholinergic system in ameliorating effect of vasopressin fragment by Group I metabotropic glutamate receptor blockade.JPharmacol Sci 108:335-340.
Tramutola A,Lanzillotta C,Perluigi M,Butterfield DA(2017)Oxidative stress,protein modification and Alzheimer disease.Brain Res Bull 133:88-96.
Wang CY,Wang ZY,Xie JW,Wang T,Wang X,Xu Y,Cai JH(2016)Dl-3-n-butylphthalide-induced upregulation of antioxidant defense is involved in the enhancement of cross talk between CREBand Nrf2 in an Alzheimer’s disease mouse model.Neurobiol Aging 38:32-46.
Wang X,Hu X,Yang Y,Takata T,Sakurai T(2016)Nicotinamide mononucleotide protects againstβ-amyloid oligomer-induced cognitive impairment and neuronal death.Brain Res 15:1643:1-9.
Yang GF,Ji JG,Peng LW,He SZ(2011)Oxidative proteins in human brains separated and identified by proteomics technology.Zhongguo Zuzhi Gongcheng Yanjiu 15:1990-1993.
Yin H,Xu L,Porter NA(2011)Free radical lipid peroxidation:mechanisms and analysis.Chem Rev 111:5944-5972.
Zhang Y,Guo JH,Yan HJ,et al.(2016)Bone marrow mesenchymal stem cell transplantation improves behavior performance of senile dementia rats.Zhongguo Zuzhi Gongcheng Yanjiu 20:5371-5377.