炎症相关因子在血管性痴呆发病机制中的作用
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摘要
血管性痴呆(vascular dementia,VD)是指由各种脑血管病,包括缺血性脑血管病、出血性脑血管病及急性与慢性缺氧性脑血管病引起的脑功能障碍,进而产生认知功能障碍的临床综合征。血管性痴呆是一种慢性进行性疾病,被认为是仅次于阿尔兹海默症,导致痴呆的第2位原因。目前,血管性痴呆的发病机制尚不明确,有可能与炎症、神经元损伤、胆碱能系统功能障碍、脑白质病变及氧化应激等有关。其中,炎症反应在急性与慢性脑缺血继发性脑损伤中起主要作用。抑制炎症能改善血管性痴呆动物模型的症状,显示炎症可能在血管性痴呆发病机制中发挥重要作用。参与炎症反应的相关因子,如细胞因子等可对中枢神经系统造成损伤。同时,炎症相关因子会触发炎症级联反应,加重脑损伤。本文总结了有关炎症相关因子参与导致血管性痴呆的各种病理损害和促进其发生发展的分子机制的最新研究进展,这些都有助于了解炎症相关因子在血管性痴呆发病机制中的作用。
Vascular dementia(VD) is a clinical syndrome caused by various cerebrovascular diseases, including ischemic cerebrovascular disease, hemorrhagic cerebrovascular disease, and acute and chronic hypoxic cerebrovascular disease. VD is a chronic progressive disease and is believed to be the second leading cause of dementia. The pathogenesis of VD is still unclear and currently thought to be associated with inflammation, neuronal damage, cholinergic system dysfunction, white matter lesions, and oxidative stress. The inflammatory response plays a major role in the secondary brain injury of acute or chronic cerebral ischemia. Inhibition of inflammation can improve the symptoms of VD animal models, which indicates that inflammation may play an important role in the pathogenesis of VD. A series of factors such as cytokines involved in the inflammatory response damage the nerve system, and these inflammation-related factors trigger the inflammatory cascade and aggravate brain damage. This review summarizes recent studies regarding to the roles and molecular mechanisms of these inflammation-related factors in the pathogenesis of VD.
Vascular dementia(VD) is a clinical syndrome caused by various cerebrovascular diseases, including ischemic cerebrovascular disease, hemorrhagic cerebrovascular disease, and acute and chronic hypoxic cerebrovascular disease. VD is a chronic progressive disease and is believed to be the second leading cause of dementia. The pathogenesis of VD is still unclear and currently thought to be associated with inflammation, neuronal damage, cholinergic system dysfunction, white matter lesions, and oxidative stress. The inflammatory response plays a major role in the secondary brain injury of acute or chronic cerebral ischemia. Inhibition of inflammation can improve the symptoms of VD animal models, which indicates that inflammation may play an important role in the pathogenesis of VD. A series of factors such as cytokines involved in the inflammatory response damage the nerve system, and these inflammation-related factors trigger the inflammatory cascade and aggravate brain damage. This review summarizes recent studies regarding to the roles and molecular mechanisms of these inflammation-related factors in the pathogenesis of VD.
引文
[1] Zhang LG,Wang LJ,Shen QQ,et al.Paeoniflorin improves regional cerebral blood flow and suppresses inflammatory factors in the hippocampus of rats with vascular dementia[J].Chin J Integr Med,2017,23(9):696-702
[2] Chi GC,Fitzpatrick AL,Sharma M,et al.Inflammatory biomarkers predict domain-specific cognitive decline in older adults[J].J Gerontol A Biol Sci Med Sci,2017,72(6):796-803
[3] Heringa SM,van den Berg E,Reijmer YD,et al.Markers of low-grade inflammation and endothelial dysfunction are related to reduced information processing speed and executive functioning in an older population - the Hoorn Study[J].Psychoneuro endocrinology,2014,40:108-118
[4] Belkhelfa M,Beder N,Mouhoub D,et al.The involvement of neuroinflammation and necroptosis in the hippocampus during vascular dementia[J].J Neuroimmunol,2018,320:48-57
[5] Omoigui S.The Interleukin-6 inflammation pathway from cholesterol to aging--role of statins,bisphosphonates and plant polyphenols in aging and age-related diseases[J].Immun Ageing,2007,4:1
[6] Zuliani G,Guerra G,Ranzini M,et al.High interleukin-6 plasma levels are associated with functional impairment in older patients with vascular dementia[J].Int J Geriatr Psychiatry,2007,22(4):305-311
[7] Zuliani G,Ranzini M,Guerra G,et al.Plasma cytokines profile in older subjects with late onset Alzheimer’s disease or vascular dementia[J].J Psychiatr Res,2007,41(8):686-693
[8] Trollor JN,Smith E,Agars E,et al.The association between systemic inflammation and cognitive performance in the elderly:the Sydney Memory and Ageing Study[J].Age (Dordr),2012,34(5):1295- 1308
[9] Pires PW,McClain JL,Hayoz SF,et al.Mineralocorticoid receptor antagonism prevents obesity-induced cerebral artery remodeling and reduces white matter injury in rats[J].Microcirculation,2018,25(5):e12460
[10] Bednarska-Makaruk M,Graban A,Winiewska A,et al.Association of adiponectin,leptin and resistin with inflammatory markers and obesity in dementia[J].Biogerontology,2017,18(4):561-580
[11] Sudduth TL,Powell DK,Smith CD,et al.Induction of hyperhomocysteinemia models vascular dementia by induction of cerebral microhemorrhages and neuroinflammation[J].J Cereb Blood Flow Metab,2013,33(5):708-715
[12] Jain S,Sharma B.Effect of ruthenium red,a ryanodine receptor antagonist in experimental diabetes induced vascular endothelial dysfunction and associated dementia in rats[J].Physiol Behav,2016,164(Pt A):140-150
[13] Wu L,Feng XT,Hu YQ,et al.Global Gene Expression Profile of the Hippocampus in a Rat Model of Vascular Dementia[J].Tohoku J Exp Med,2015,237(1):57-67
[14] Uiterwijk R,Huijts M,Staals J,et al.Endothelial activation is associated with cognitive performance in patients with hypertension[J].Am J Hypertens,2016,29(4):464-469
[15] Zhang XL,Zheng SL,Dong FR,et al.Nimodipine improves regional cerebral blood flow and suppresses inflammatory factors in the hippocampus of rats with vascular dementia[J].J Int Med Res,2012,40(3):1036-1045
[16] Aung HH,Tsoukalas A,Rutledge JC,et al.A systems biology analysis of brain microvascular endothelial cell lipotoxicity[J].BMC Syst Biol,2014,8:80
[17] Jain S,Sharma BM,Sharma B.Calcium channel blockade and peroxisome proliferator activated receptor γ agonism diminish cognitive loss and preserve endothelial function during diabetes mellitus[J].Curr Neurovasc Res,2016,13(1):33-44
[18] Miwa K,Okazaki S,Sakaguchi M,et al.Interleukin-6,interleukin-6 receptor gene variant,small-vessel disease and incident dementia[J].Eur J Neurol,2016,23(3):656-663
[19] Kim Y,Kong M,An J,et al.Genetic dissection of susceptibility to vascular dementia[J].Psychiatr Genet,2011,21(2):69-76
[20] Yang EJ,Cai M,Lee JH.Neuroprotective effects of electroacupuncture on an animal model of bilateral common carotid artery occlusion[J].Mol Neurobiol,2016,53(10):7228-7236
[21] Luo XQ,Li A,Yang X,et al.Paeoniflorin exerts neuroprotective effects by modulating the M1/M2 subset polarization of microglia/macrophages in the hippocampal CA1 region of vascular dementia rats via cannabinoid receptor 2[J].Chin Med,2018,13:14
[22] Ritz MF,Grond-Ginsbach C,Kloss M,et al.Identification of inflammatory,metabolic,and cell survival pathways contributing to cerebral small vessel disease by postmortem gene expression microarray[J].Curr Neurovasc Res,2016,13(1):58-67
[23] Mei ZG,Tan,LJ,Wang JF,et al.Fermented Chinese formula Shuan-Tong-Ling attenuates ischemic stroke by inhibiting inflammation and apoptosis[J].Neural Regen Res,2017,12(3):425-432
[24] Kaur J,Sharma S,Sandhu M,et al.Neurokinin-1 receptor inhibition reverses ischaemic brain injury and dementia in bilateral common carotid artery occluded rats:possible mechanisms[J].Inflammopharmacology,2016,24(4):133-143
[25] Tucsek Z,Noa Valcarcel-Ares M,Tarantini S,et al.Hypertension-induced synapse loss and impairment in synaptic plasticity in the mouse hippocampus mimics the aging phenotype:implications for the pathogenesis of vascular cognitive impairment[J].Geroscience,2017,39(4):385-406
[26] Singh P,Sharma B.Reversal in cognition impairments,cholinergic dysfunction,and cerebral oxidative stress through the modulation of ryanodine receptors (ryrs) and cysteinyl leukotriene-1 (CysLT1) receptors[J].Curr Neurovasc Res,2016,13(1):10-21
[27] Lee LL,Aung HH,Wilson DW,et al.Triglyceride-rich lipoprotein lipolysis products increase blood-brain barrier transfer coefficient and induce astrocyte lipid droplets and cell stress[J].Am J Physiol Cell Physiol,2017,312(4):C500-C516
[28] Hase Y,Craggs L,Hase M,et al.Effects of environmental enrichment on white matter glial responses in a mouse model of chronic cerebral hypoperfusion[J].J Neuroinflammation,2017,14(1):81
[29] Siracusa R,Impellizzeri D,Cordaro M,et al.Anti-Inflammatory and Neuroprotective Effects of Co-UltraPEALut in a Mouse Model of Vascular Dementia[J].Front Neurol,2017,8:233
[30] Shen D,Tian X,Sang W,et al.Effect of Melatonin and Resveratrol against Memory Impairment and Hippocampal Damage in a Rat Model of Vascular Dementia[J].Neuroimmuno-modulation,2016,23(5-6):318-331
[31] Olsson B,Hertze J,Lautner R,et al.Microglial markers are elevated in the prodromal phase of Alzheimer’s disease and vascular dementia[J].J Alzheimers Dis,2013,33(1):45-53
[32] Ma J,Bo SH,Lu XT,et al.Protective effects of carnosine on white matter damage induced by chronic cerebral hypoperfusion[J].Neural Regen Res,2016,11(9):1438-1444
[33] Choi BR,Kim DH,Back DB,et al.Characterization of White Matter Injury in a Rat Model of Chronic Cerebral Hypoperfusion[J].Stroke,2016,47(2):542-547
[34] Hase Y,Horsburgh K,Ihara M,et al.White matter degeneration in vascular and other ageing-related dementias[J].J Neurochem,2018,144(5):617-633
[35] Lee KM,Bang J,Kim BY,et al.Fructus mume alleviates chronic cerebral hypoperfusion-induced white matter and hippocampal damage via inhibition of inflammation and downregulation of TLR4 and p38 MAPK signaling[J].BMC Complement Altern Med,2015,15:125
[36] Lin H,Satizabal C,Xie Z,et al.Whole blood gene expression and white matter Hyperintensities[J].Mol Neurodegener,2017,12(1):67
[37] Miralbell J,Soriano JJ,Spulber G,et al.Structural brain changes and cognition in relation to markers of vascular dysfunction[J].Neurobiol Aging,2012,33(5):1003.e9-17
[38] Jiang J,Trollor JN,Brown DA,et al.An inverse relationship between serum macrophage inhibitory cytokine-1 levels and brain white matter integrity in community-dwelling older individuals[J].Psychoneuroendocrinology,2015,62:80-88
[39] Denes A,Drake C,Stordy J,et al.Interleukin-1 mediates neuroinflammatory changes associated with diet-induced atherosclerosis[J].J Am Heart Assoc,2012,1(3):e002006
[40] Lénárt N,Brough D,Dénes á,et al.Inflammasomes link vascular disease with neuroinflammation and brain disorders[J].J Cereb Blood Flow Metab,2016,36(10):1668-1685
[41] Couch Y,Akbar N,Davis S,et al.Inflammatory Stroke Extracellular Vesicles Induce Macrophage Activation[J].Stroke,2017,48(8):2292-2296
[42] Roth S,Singh V,Tiedt S,et al.Brain-released alarmins and stress response synergize in accelerating atherosclerosis progression after stroke[J].Sci Transl Med,2018,10(432).pii:eaao1313
[43] Ueno M.Elucidation of mechanism of blood-brain barrier damage for prevention and treatment of vascular dementia[J].Rinsho Shinkeigaku,2017,57(3):95-109
[44] Takechi R,Galloway S,Pallebage-Gamarallage MM,et al.Probucol prevents blood-brain barrier dysfunction in wild-type mice induced by saturated fat or cholesterol feeding[J].Clin Exp Pharmacol Physiol,2013,40(1):45-52
[45] Wang F,Zou Z,Gong Y,et al.Regulation of human brain microvascular endothelial cell adhesion and barrier functions by memantine[J].J Mol Neurosci,2017,62(1):123-129
[46] Du SQ,Wang XR,Zhu W,et al.Acupuncture inhibits TXNIP-associated oxidative stress and inflammation to attenuate cognitive impairment in vascular dementia rats[J].CNS Neurosci Ther,2018,24(1):39-46
[47] Cai ZY,Yan Y,Sun SQ,et al.Minocycline attenuates cognitive impairment and restrains oxidative stress in the hippocampus of rats with chronic cerebral hypoperfusion[J].Neurosci Bull,2008,24(5):305-313
[48] Wang J,Zhang HY,Tang XC.Cholinergic deficiency involved in vascular dementia:possible mechanism and strategy of treatment[J].Acta Pharmacol Sin,2009,30(7):879-888
[49] Kim MS,Bang JH,Lee J,et al.Fructus mume Ethanol Extract Prevents Inflammation and Normalizes the Septohippocampal Cholinergic System in a Rat Model of Chronic Cerebral Hypoperfusion[J].J Med Food,2016,19(2):196-204
[2] Chi GC,Fitzpatrick AL,Sharma M,et al.Inflammatory biomarkers predict domain-specific cognitive decline in older adults[J].J Gerontol A Biol Sci Med Sci,2017,72(6):796-803
[3] Heringa SM,van den Berg E,Reijmer YD,et al.Markers of low-grade inflammation and endothelial dysfunction are related to reduced information processing speed and executive functioning in an older population - the Hoorn Study[J].Psychoneuro endocrinology,2014,40:108-118
[4] Belkhelfa M,Beder N,Mouhoub D,et al.The involvement of neuroinflammation and necroptosis in the hippocampus during vascular dementia[J].J Neuroimmunol,2018,320:48-57
[5] Omoigui S.The Interleukin-6 inflammation pathway from cholesterol to aging--role of statins,bisphosphonates and plant polyphenols in aging and age-related diseases[J].Immun Ageing,2007,4:1
[6] Zuliani G,Guerra G,Ranzini M,et al.High interleukin-6 plasma levels are associated with functional impairment in older patients with vascular dementia[J].Int J Geriatr Psychiatry,2007,22(4):305-311
[7] Zuliani G,Ranzini M,Guerra G,et al.Plasma cytokines profile in older subjects with late onset Alzheimer’s disease or vascular dementia[J].J Psychiatr Res,2007,41(8):686-693
[8] Trollor JN,Smith E,Agars E,et al.The association between systemic inflammation and cognitive performance in the elderly:the Sydney Memory and Ageing Study[J].Age (Dordr),2012,34(5):1295- 1308
[9] Pires PW,McClain JL,Hayoz SF,et al.Mineralocorticoid receptor antagonism prevents obesity-induced cerebral artery remodeling and reduces white matter injury in rats[J].Microcirculation,2018,25(5):e12460
[10] Bednarska-Makaruk M,Graban A,Winiewska A,et al.Association of adiponectin,leptin and resistin with inflammatory markers and obesity in dementia[J].Biogerontology,2017,18(4):561-580
[11] Sudduth TL,Powell DK,Smith CD,et al.Induction of hyperhomocysteinemia models vascular dementia by induction of cerebral microhemorrhages and neuroinflammation[J].J Cereb Blood Flow Metab,2013,33(5):708-715
[12] Jain S,Sharma B.Effect of ruthenium red,a ryanodine receptor antagonist in experimental diabetes induced vascular endothelial dysfunction and associated dementia in rats[J].Physiol Behav,2016,164(Pt A):140-150
[13] Wu L,Feng XT,Hu YQ,et al.Global Gene Expression Profile of the Hippocampus in a Rat Model of Vascular Dementia[J].Tohoku J Exp Med,2015,237(1):57-67
[14] Uiterwijk R,Huijts M,Staals J,et al.Endothelial activation is associated with cognitive performance in patients with hypertension[J].Am J Hypertens,2016,29(4):464-469
[15] Zhang XL,Zheng SL,Dong FR,et al.Nimodipine improves regional cerebral blood flow and suppresses inflammatory factors in the hippocampus of rats with vascular dementia[J].J Int Med Res,2012,40(3):1036-1045
[16] Aung HH,Tsoukalas A,Rutledge JC,et al.A systems biology analysis of brain microvascular endothelial cell lipotoxicity[J].BMC Syst Biol,2014,8:80
[17] Jain S,Sharma BM,Sharma B.Calcium channel blockade and peroxisome proliferator activated receptor γ agonism diminish cognitive loss and preserve endothelial function during diabetes mellitus[J].Curr Neurovasc Res,2016,13(1):33-44
[18] Miwa K,Okazaki S,Sakaguchi M,et al.Interleukin-6,interleukin-6 receptor gene variant,small-vessel disease and incident dementia[J].Eur J Neurol,2016,23(3):656-663
[19] Kim Y,Kong M,An J,et al.Genetic dissection of susceptibility to vascular dementia[J].Psychiatr Genet,2011,21(2):69-76
[20] Yang EJ,Cai M,Lee JH.Neuroprotective effects of electroacupuncture on an animal model of bilateral common carotid artery occlusion[J].Mol Neurobiol,2016,53(10):7228-7236
[21] Luo XQ,Li A,Yang X,et al.Paeoniflorin exerts neuroprotective effects by modulating the M1/M2 subset polarization of microglia/macrophages in the hippocampal CA1 region of vascular dementia rats via cannabinoid receptor 2[J].Chin Med,2018,13:14
[22] Ritz MF,Grond-Ginsbach C,Kloss M,et al.Identification of inflammatory,metabolic,and cell survival pathways contributing to cerebral small vessel disease by postmortem gene expression microarray[J].Curr Neurovasc Res,2016,13(1):58-67
[23] Mei ZG,Tan,LJ,Wang JF,et al.Fermented Chinese formula Shuan-Tong-Ling attenuates ischemic stroke by inhibiting inflammation and apoptosis[J].Neural Regen Res,2017,12(3):425-432
[24] Kaur J,Sharma S,Sandhu M,et al.Neurokinin-1 receptor inhibition reverses ischaemic brain injury and dementia in bilateral common carotid artery occluded rats:possible mechanisms[J].Inflammopharmacology,2016,24(4):133-143
[25] Tucsek Z,Noa Valcarcel-Ares M,Tarantini S,et al.Hypertension-induced synapse loss and impairment in synaptic plasticity in the mouse hippocampus mimics the aging phenotype:implications for the pathogenesis of vascular cognitive impairment[J].Geroscience,2017,39(4):385-406
[26] Singh P,Sharma B.Reversal in cognition impairments,cholinergic dysfunction,and cerebral oxidative stress through the modulation of ryanodine receptors (ryrs) and cysteinyl leukotriene-1 (CysLT1) receptors[J].Curr Neurovasc Res,2016,13(1):10-21
[27] Lee LL,Aung HH,Wilson DW,et al.Triglyceride-rich lipoprotein lipolysis products increase blood-brain barrier transfer coefficient and induce astrocyte lipid droplets and cell stress[J].Am J Physiol Cell Physiol,2017,312(4):C500-C516
[28] Hase Y,Craggs L,Hase M,et al.Effects of environmental enrichment on white matter glial responses in a mouse model of chronic cerebral hypoperfusion[J].J Neuroinflammation,2017,14(1):81
[29] Siracusa R,Impellizzeri D,Cordaro M,et al.Anti-Inflammatory and Neuroprotective Effects of Co-UltraPEALut in a Mouse Model of Vascular Dementia[J].Front Neurol,2017,8:233
[30] Shen D,Tian X,Sang W,et al.Effect of Melatonin and Resveratrol against Memory Impairment and Hippocampal Damage in a Rat Model of Vascular Dementia[J].Neuroimmuno-modulation,2016,23(5-6):318-331
[31] Olsson B,Hertze J,Lautner R,et al.Microglial markers are elevated in the prodromal phase of Alzheimer’s disease and vascular dementia[J].J Alzheimers Dis,2013,33(1):45-53
[32] Ma J,Bo SH,Lu XT,et al.Protective effects of carnosine on white matter damage induced by chronic cerebral hypoperfusion[J].Neural Regen Res,2016,11(9):1438-1444
[33] Choi BR,Kim DH,Back DB,et al.Characterization of White Matter Injury in a Rat Model of Chronic Cerebral Hypoperfusion[J].Stroke,2016,47(2):542-547
[34] Hase Y,Horsburgh K,Ihara M,et al.White matter degeneration in vascular and other ageing-related dementias[J].J Neurochem,2018,144(5):617-633
[35] Lee KM,Bang J,Kim BY,et al.Fructus mume alleviates chronic cerebral hypoperfusion-induced white matter and hippocampal damage via inhibition of inflammation and downregulation of TLR4 and p38 MAPK signaling[J].BMC Complement Altern Med,2015,15:125
[36] Lin H,Satizabal C,Xie Z,et al.Whole blood gene expression and white matter Hyperintensities[J].Mol Neurodegener,2017,12(1):67
[37] Miralbell J,Soriano JJ,Spulber G,et al.Structural brain changes and cognition in relation to markers of vascular dysfunction[J].Neurobiol Aging,2012,33(5):1003.e9-17
[38] Jiang J,Trollor JN,Brown DA,et al.An inverse relationship between serum macrophage inhibitory cytokine-1 levels and brain white matter integrity in community-dwelling older individuals[J].Psychoneuroendocrinology,2015,62:80-88
[39] Denes A,Drake C,Stordy J,et al.Interleukin-1 mediates neuroinflammatory changes associated with diet-induced atherosclerosis[J].J Am Heart Assoc,2012,1(3):e002006
[40] Lénárt N,Brough D,Dénes á,et al.Inflammasomes link vascular disease with neuroinflammation and brain disorders[J].J Cereb Blood Flow Metab,2016,36(10):1668-1685
[41] Couch Y,Akbar N,Davis S,et al.Inflammatory Stroke Extracellular Vesicles Induce Macrophage Activation[J].Stroke,2017,48(8):2292-2296
[42] Roth S,Singh V,Tiedt S,et al.Brain-released alarmins and stress response synergize in accelerating atherosclerosis progression after stroke[J].Sci Transl Med,2018,10(432).pii:eaao1313
[43] Ueno M.Elucidation of mechanism of blood-brain barrier damage for prevention and treatment of vascular dementia[J].Rinsho Shinkeigaku,2017,57(3):95-109
[44] Takechi R,Galloway S,Pallebage-Gamarallage MM,et al.Probucol prevents blood-brain barrier dysfunction in wild-type mice induced by saturated fat or cholesterol feeding[J].Clin Exp Pharmacol Physiol,2013,40(1):45-52
[45] Wang F,Zou Z,Gong Y,et al.Regulation of human brain microvascular endothelial cell adhesion and barrier functions by memantine[J].J Mol Neurosci,2017,62(1):123-129
[46] Du SQ,Wang XR,Zhu W,et al.Acupuncture inhibits TXNIP-associated oxidative stress and inflammation to attenuate cognitive impairment in vascular dementia rats[J].CNS Neurosci Ther,2018,24(1):39-46
[47] Cai ZY,Yan Y,Sun SQ,et al.Minocycline attenuates cognitive impairment and restrains oxidative stress in the hippocampus of rats with chronic cerebral hypoperfusion[J].Neurosci Bull,2008,24(5):305-313
[48] Wang J,Zhang HY,Tang XC.Cholinergic deficiency involved in vascular dementia:possible mechanism and strategy of treatment[J].Acta Pharmacol Sin,2009,30(7):879-888
[49] Kim MS,Bang JH,Lee J,et al.Fructus mume Ethanol Extract Prevents Inflammation and Normalizes the Septohippocampal Cholinergic System in a Rat Model of Chronic Cerebral Hypoperfusion[J].J Med Food,2016,19(2):196-204