神经营养因子假说与抑郁症发病机制的研究进展
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摘要
目前关于抑郁症发病机制的神经营养因子假说研究尚不明确,当前研究多聚焦于脑源性神经营养因子(BDNF)及其前体(proBDNF)和成熟体(mBDNF)在抑郁症中的作用。多个研究显示抑郁症患者proBDNF蛋白水平升高,而mBDNF蛋白水平降低。随着对神经营养因子假说研究的深入,有研究发现组织型纤溶酶原激活剂(tPA)可通过促使proBDNF向mBDNF转化而缓解抑郁症状,纤溶酶原激活物抑制剂-1(PAI-1)可抑制tPA的表达,PAI-1在抑郁症患者中的表达增加。本文对BDNF、proBDNF、mBDNF、tPA及PAI-1与抑郁症之间的关系进行综述,以期为抑郁症的发生机制及诊疗提供参考。
So far, the researches on the neurotrophic factor hypothesis of the pathogenesis of depression is not clear. Current research focuses more on the role of Brain-derived Neurotrophic Factor(BDNF) and its precursor(proBDNF) as well as maturation(mBDNF) in depressive disorder. The researches indicate that the level of proBDNF protein increased while mBDNF protein level decreased in patients with depression. With deepening of the researches on neurotrophic factor hypothesis, it has been found that the tissue-type Plasminogen Activator(tPA) can alleviate the symptoms of depression by promoting the translation of proBDNF into mBDNF, the Plasminogen Activator Inhibitor-1(PAI-1) can inhibit the expression of tPA, the expression of PAI-1 in patients with depression increased. In this article, the relationship among BDNF, proBDNF, mBDNF, tPA and PAI-1 with depression were reviewed, so as to provide references for the pathogenesis, diagnosis and treatment of depressive disorder.
So far, the researches on the neurotrophic factor hypothesis of the pathogenesis of depression is not clear. Current research focuses more on the role of Brain-derived Neurotrophic Factor(BDNF) and its precursor(proBDNF) as well as maturation(mBDNF) in depressive disorder. The researches indicate that the level of proBDNF protein increased while mBDNF protein level decreased in patients with depression. With deepening of the researches on neurotrophic factor hypothesis, it has been found that the tissue-type Plasminogen Activator(tPA) can alleviate the symptoms of depression by promoting the translation of proBDNF into mBDNF, the Plasminogen Activator Inhibitor-1(PAI-1) can inhibit the expression of tPA, the expression of PAI-1 in patients with depression increased. In this article, the relationship among BDNF, proBDNF, mBDNF, tPA and PAI-1 with depression were reviewed, so as to provide references for the pathogenesis, diagnosis and treatment of depressive disorder.
引文
[1] 李涛, 徐一峰. 精神科医生手册[M]. 北京: 人民卫生出版社, 2017: 124-125.
[2] World Health Organization. The global burden of disease: 2004 update[R]. Geneva: WHO, 2008.
[3] 尹营营, 袁勇贵. 抑郁症的遗传学研究进展[J]. 临床精神医学杂志, 2014, 24(4): 277-278.
[4] Diniz CRAF, Casarotto PC, Resstel L, et al. Beyond good and evil: a putative continuum-sorting hypothesis for the functional role of proBDNF/BDNF-propeptide/mBDNF in antidepressant treatment[J]. Neurosci Biobehav Rev, 2018, 90: 70-83.
[5] Yu H, Lv D, Shen M, et al. BDNF mediates the protective effects of scopolamine in reserpine-induced depression-like behaviors via up-regulation of 5-HTT and TPH1[J]. Psychiatry Res, 2018, 271: 328-334.
[6] Stein S, Winnik S, Matter CM. Brain-derived neurotrophic factor Val66Met polymorphism in depression and thrombosis: SIRT1 as a possible mediator[J]. Eur Heart J, 2017, 38(18): 1436-1438.
[7] 陈小容, 操军, 王俊, 等. 血浆脑源性神经营养因子水平与抑郁症的相关性研究[J]. 重庆医科大学学报, 2015, 40(1): 66-69.
[8] Lu B, Pang PT, Woo NH. The yin and yang of neurotrophin action[J]. Nat Rev Neurosci, 2005, 6(8): 603-614.
[9] Brunoni AR, Machado-Vieira R, Zarate CA Jr, et al. Assessment of non-BDNF neurotrophins and GDNF levels after depression treatment with sertraline and transcranial direct current stimulation in a factorial, randomized, sham-controlled trial (SELECT-TDCS): an exploratory analysis[J]. Prog Neuropsychopharmacol Biol Psychiatry, 2015, 56: 91-96.
[10] Su Q, Cheng Y, Jin K, et al. Estrogen therapy increases BDNF expression and improves post-stroke depression in ovariectomy-treated rats[J]. Exp Ther Med, 2016, 12(3): 1843-1848.
[11] Baudry M, Bi X, Aguirre C. Progesterone-estrogen interactions in synaptic plasticity and neuroprotection[J]. Neuroscience, 2013, 239: 280-294.
[12] 刘迪, 唐倩倩, 曹君利. 脑源性生长因子参与疼痛-抑郁共病的研究进展[J]. 中国药理学通报, 2015, 31(1): 26-30.
[13] Molendijk ML, Spinhoven P, Polak M, et al. Serum BDNF concentrations as peripheral manifestations of depression: evidence from a systematic review and meta-analyses on 179 associations (N=9484)[J]. Mol Psychiatry, 2014, 19(7): 791-800.
[14] 胡晓蕊, 沈宗霖, 许秀峰. 脑源性神经营养因子与抑郁症关系的研究[J]. 临床精神医学杂志, 2017, 27(2): 137-139.
[15] Hayley S, Du L, Litteljohn D, et al. Gender and brain regions specific differences in brain derived neurotrophic factor protein levels of depressed individuals who died through suicide[J]. Neurosci Lett, 2015, 600: 12-16.
[16] Kuhlmann SL, Tschorn M, Arolt V, et al. Serum brain-derived neurotrophic factor and stability of depressive symptoms in coronary heart disease patients: a prospective study[J]. Psychoneuroendocrinology, 2017, 77: 196-202.
[17] 王戈, 任路. “肾脑相济”电针疗法对围绝经期抑郁症大鼠海马BDNF、CREB的影响[J].辽宁中医杂志, 2016, 43(4): 858-860.
[18] Aydemir O, Deveci A, Taneli F. The effect of chronic antidepressant treatment on serum brain-derived neurotrophic factor levels in depressed patients: a preliminary study[J]. Prog Neuropsychopharmacol Biol Psychiatry, 2005, 29(2): 261-265.
[19] Zhao G, Zhang C, Chen J, et al. Ratio of mBDNF to proBDNF for differential diagnosis of major depressive disorder and bipolar depression[J]. Mol Neurobiol, 2017, 54(7): 5573-5582.
[20] Zhang F, Luo J, Zhu X. Ketamine ameliorates depressive-like behaviors by tPA-mediated conversion of proBDNF to mBDNF in the hippocampus of stressed rats[J]. Psychiatry Res, 2018, 269: 646-651.
[21] Tripp A, Oh H, Guilloux JP, et al. Brain-derived neurotrophic factor signaling and subgenual anterior cingulate cortex dysfunction in major depressive disorder[J]. Am J Psychiatry, 2012, 169(11): 1194-1202.
[22] Zhang F, Luo J, Min S, et al. Propofol alleviates electroconvulsive shock-induced memory impairment by modulating proBDNF/mBDNF ratio in depressive rats[J]. Brain Res, 2016, 1642: 43-50.
[23] Zhang JC, Yao W, Hashimoto K. Brain-derived Neurotrophic Factor (BDNF)-TrkB signaling in inflammation-related depression and potential therapeutic targets[J]. Curr Neuropharmacol, 2016, 14(7): 721-731.
[24] Bus BA, Molendijk ML, Tendolkar I, et al. Chronic depression is associated with a pronounced decrease in serum brain-derived neurotrophic factor over time[J]. Mol Psychiatry, 2015, 20(5): 602-608.
[25] 师佳, 戴丹, 李洋洋, 等. 脑卒中后抑郁大鼠海马小胶质细胞脑源性神经营养因子及酪氨酸激酶受体B蛋白的表达[J]. 中华老年心脑血管病杂志, 2018, 20(1): 83-87.
[26] Yoshimura R, Kishi T, Hori H, et al. Serum proBDNF/BDNF and response to fluvoxamine in drug-na?ve first-episode major depressive disorder patients[J]. Ann Gen Psychiatry, 2014, 13: 19.
[27] Castrén E, Antila H. Neuronal plasticity and neurotrophic factors in drug responses[J]. Mol Psychiatry, 2017, 22(8): 1085-1095.
[28] Zhou L, Xiong J, Lim Y, et al. Upregulation of blood proBDNF and its receptors in major depression[J]. J Affect Disord, 2013, 150(3): 776-784.
[29] Jiang H, Chen S, Li C, et al. The serum protein levels of the tPA-BDNF pathway are implicated in depression and antidepressant treatment[J]. Transl Psychiatry, 2017, 7(4): e1079.
[30] Cao W, Duan J, Wang X, et al. Early enriched environment induces an increased conversion of proBDNF to BDNF in the adult rat's hippocampus[J]. Behav Brain Res, 2014, 265: 76-83.
[31] Pang PT, Teng HK, Zaitsev E, et al. Cleavage of proBDNF by tPA/plasmin is essential for long-term hippocampal plasticity[J]. Science, 2004, 306(5695): 487-491.
[32] Tang M, Jiang P, Li H, et al. Antidepressant-like effect of n-3 PUFAs in CUMS rats: role of tPA/PAI-1 system[J]. Physiol Behav, 2015, 139: 210-215.
[33] Hoirisch-Clapauch S, Mezzasalma MA, Nardi AE. Pivotal role of tissue plasminogen activator in the mechanism of action of electroconvulsive therapy[J]. J Psychopharmacol, 2014, 28(2): 99-105.
[34] Cho KS, Kwon KJ, Choi CS, et al. Valproic acid induces astrocyte-dependent neurite outgrowth from cultured rat primary cortical neuron via modulation of tPA/PAI-1 activity[J]. Glia, 2013, 61(5): 694-709.
[35] Jiang H, Li X, Chen S, et al. Plasminogen activator inhibitor-1 in depression: results from animal and clinical studies[J]. Sci Rep, 2016, 6: 30464.
[36] Lee TW, Tsang VW, Birch NP. Physiological and pathological roles of tissue plasminogen activator and its inhibitor neuroserpin in the nervous system[J]. Front Cell Neurosci, 2015, 9: 396.
[37] Idell RD, Florova G, Komissarov AA, et al. The fibrinolytic system: a new target for treatment of depression with psychedelics[J]. Med Hypotheses, 2017, 100: 46-53.
[38] Shi Y, You J, Yuan Y, et al. Plasma BDNF and tPA are associated with late-onset geriatric depression[J]. Psychiatry Clin Neurosci, 2010, 64(3): 249-254.
[39] Sartori CR, Vieira AS, Ferrari EM, et al. The antidepressive effect of the physical exercise correlates with increased levels of mature BDNF, and proBDNF proteolytic cleavage-related genes, p11 and tPA[J]. Neuroscience, 2011, 180: 9-18.
[40] Yang L, Zhang Z, Sun D, et al. Low serum BDNF may indicate the development of PSD in patients with acute ischemic stroke[J]. Int J Geriatr Psychiatry, 2011, 26(5): 495-502.
[41] Madani R, Nef S, Vassalli JD. Emotions are building up in the field of extracellular proteolysis[J]. Trends Mol Med, 2003, 9(5): 183-185.
[42] von K?nel R, Dimsdale JE, Adler KA, et al. Effects of depressive symptoms and anxiety on hemostatic responses to acute mental stress and recovery in the elderly[J]. Psychiatry Res, 2004, 126(3): 253-264.
[43] Pawlak R, Magarinos AM, Melchor J, et al. Tissue plasminogen activator in the amygdala is critical for stress-induced anxiety-like behavior[J]. Nat Neurosci, 2003, 6(2): 168-174.
[44] 董丽婷, 徐治, 王辉, 等. 抑郁症的tPA-纤溶酶原系统功能紊乱假说[J]. 国际精神病学杂志, 2015, 42(2): 110-113.
[45] Lahlou-Laforet K, Alhenc-Gelas M, Pornin M, et al. Relation of depressive mood to plasminogen activator inhibitor, tissue plasminogen activator, and fibrinogen levels in patients with versus without coronary heart disease[J]. Am J Cardiol, 2006, 97(9): 1287-1291.
[46] Tsai SJ, Hong CJ, Liou YJ, et al. Plasminogen activator inhibitor-1 gene is associated with major depression and antidepressant treatment response[J]. Pharmacogenet Genomics, 2008, 18(10): 869-875.
[47] Elomaa AP, Koivumaa-Honkanen H, Niskanen L, et al. Self-reported sleep disturbance is associated with elevated levels of PAI-1 in individuals with a recorded history of depressive symptoms[J]. Prog Neuropsychopharmacol Biol Psychiatry, 2013, 47: 46-51.
[2] World Health Organization. The global burden of disease: 2004 update[R]. Geneva: WHO, 2008.
[3] 尹营营, 袁勇贵. 抑郁症的遗传学研究进展[J]. 临床精神医学杂志, 2014, 24(4): 277-278.
[4] Diniz CRAF, Casarotto PC, Resstel L, et al. Beyond good and evil: a putative continuum-sorting hypothesis for the functional role of proBDNF/BDNF-propeptide/mBDNF in antidepressant treatment[J]. Neurosci Biobehav Rev, 2018, 90: 70-83.
[5] Yu H, Lv D, Shen M, et al. BDNF mediates the protective effects of scopolamine in reserpine-induced depression-like behaviors via up-regulation of 5-HTT and TPH1[J]. Psychiatry Res, 2018, 271: 328-334.
[6] Stein S, Winnik S, Matter CM. Brain-derived neurotrophic factor Val66Met polymorphism in depression and thrombosis: SIRT1 as a possible mediator[J]. Eur Heart J, 2017, 38(18): 1436-1438.
[7] 陈小容, 操军, 王俊, 等. 血浆脑源性神经营养因子水平与抑郁症的相关性研究[J]. 重庆医科大学学报, 2015, 40(1): 66-69.
[8] Lu B, Pang PT, Woo NH. The yin and yang of neurotrophin action[J]. Nat Rev Neurosci, 2005, 6(8): 603-614.
[9] Brunoni AR, Machado-Vieira R, Zarate CA Jr, et al. Assessment of non-BDNF neurotrophins and GDNF levels after depression treatment with sertraline and transcranial direct current stimulation in a factorial, randomized, sham-controlled trial (SELECT-TDCS): an exploratory analysis[J]. Prog Neuropsychopharmacol Biol Psychiatry, 2015, 56: 91-96.
[10] Su Q, Cheng Y, Jin K, et al. Estrogen therapy increases BDNF expression and improves post-stroke depression in ovariectomy-treated rats[J]. Exp Ther Med, 2016, 12(3): 1843-1848.
[11] Baudry M, Bi X, Aguirre C. Progesterone-estrogen interactions in synaptic plasticity and neuroprotection[J]. Neuroscience, 2013, 239: 280-294.
[12] 刘迪, 唐倩倩, 曹君利. 脑源性生长因子参与疼痛-抑郁共病的研究进展[J]. 中国药理学通报, 2015, 31(1): 26-30.
[13] Molendijk ML, Spinhoven P, Polak M, et al. Serum BDNF concentrations as peripheral manifestations of depression: evidence from a systematic review and meta-analyses on 179 associations (N=9484)[J]. Mol Psychiatry, 2014, 19(7): 791-800.
[14] 胡晓蕊, 沈宗霖, 许秀峰. 脑源性神经营养因子与抑郁症关系的研究[J]. 临床精神医学杂志, 2017, 27(2): 137-139.
[15] Hayley S, Du L, Litteljohn D, et al. Gender and brain regions specific differences in brain derived neurotrophic factor protein levels of depressed individuals who died through suicide[J]. Neurosci Lett, 2015, 600: 12-16.
[16] Kuhlmann SL, Tschorn M, Arolt V, et al. Serum brain-derived neurotrophic factor and stability of depressive symptoms in coronary heart disease patients: a prospective study[J]. Psychoneuroendocrinology, 2017, 77: 196-202.
[17] 王戈, 任路. “肾脑相济”电针疗法对围绝经期抑郁症大鼠海马BDNF、CREB的影响[J].辽宁中医杂志, 2016, 43(4): 858-860.
[18] Aydemir O, Deveci A, Taneli F. The effect of chronic antidepressant treatment on serum brain-derived neurotrophic factor levels in depressed patients: a preliminary study[J]. Prog Neuropsychopharmacol Biol Psychiatry, 2005, 29(2): 261-265.
[19] Zhao G, Zhang C, Chen J, et al. Ratio of mBDNF to proBDNF for differential diagnosis of major depressive disorder and bipolar depression[J]. Mol Neurobiol, 2017, 54(7): 5573-5582.
[20] Zhang F, Luo J, Zhu X. Ketamine ameliorates depressive-like behaviors by tPA-mediated conversion of proBDNF to mBDNF in the hippocampus of stressed rats[J]. Psychiatry Res, 2018, 269: 646-651.
[21] Tripp A, Oh H, Guilloux JP, et al. Brain-derived neurotrophic factor signaling and subgenual anterior cingulate cortex dysfunction in major depressive disorder[J]. Am J Psychiatry, 2012, 169(11): 1194-1202.
[22] Zhang F, Luo J, Min S, et al. Propofol alleviates electroconvulsive shock-induced memory impairment by modulating proBDNF/mBDNF ratio in depressive rats[J]. Brain Res, 2016, 1642: 43-50.
[23] Zhang JC, Yao W, Hashimoto K. Brain-derived Neurotrophic Factor (BDNF)-TrkB signaling in inflammation-related depression and potential therapeutic targets[J]. Curr Neuropharmacol, 2016, 14(7): 721-731.
[24] Bus BA, Molendijk ML, Tendolkar I, et al. Chronic depression is associated with a pronounced decrease in serum brain-derived neurotrophic factor over time[J]. Mol Psychiatry, 2015, 20(5): 602-608.
[25] 师佳, 戴丹, 李洋洋, 等. 脑卒中后抑郁大鼠海马小胶质细胞脑源性神经营养因子及酪氨酸激酶受体B蛋白的表达[J]. 中华老年心脑血管病杂志, 2018, 20(1): 83-87.
[26] Yoshimura R, Kishi T, Hori H, et al. Serum proBDNF/BDNF and response to fluvoxamine in drug-na?ve first-episode major depressive disorder patients[J]. Ann Gen Psychiatry, 2014, 13: 19.
[27] Castrén E, Antila H. Neuronal plasticity and neurotrophic factors in drug responses[J]. Mol Psychiatry, 2017, 22(8): 1085-1095.
[28] Zhou L, Xiong J, Lim Y, et al. Upregulation of blood proBDNF and its receptors in major depression[J]. J Affect Disord, 2013, 150(3): 776-784.
[29] Jiang H, Chen S, Li C, et al. The serum protein levels of the tPA-BDNF pathway are implicated in depression and antidepressant treatment[J]. Transl Psychiatry, 2017, 7(4): e1079.
[30] Cao W, Duan J, Wang X, et al. Early enriched environment induces an increased conversion of proBDNF to BDNF in the adult rat's hippocampus[J]. Behav Brain Res, 2014, 265: 76-83.
[31] Pang PT, Teng HK, Zaitsev E, et al. Cleavage of proBDNF by tPA/plasmin is essential for long-term hippocampal plasticity[J]. Science, 2004, 306(5695): 487-491.
[32] Tang M, Jiang P, Li H, et al. Antidepressant-like effect of n-3 PUFAs in CUMS rats: role of tPA/PAI-1 system[J]. Physiol Behav, 2015, 139: 210-215.
[33] Hoirisch-Clapauch S, Mezzasalma MA, Nardi AE. Pivotal role of tissue plasminogen activator in the mechanism of action of electroconvulsive therapy[J]. J Psychopharmacol, 2014, 28(2): 99-105.
[34] Cho KS, Kwon KJ, Choi CS, et al. Valproic acid induces astrocyte-dependent neurite outgrowth from cultured rat primary cortical neuron via modulation of tPA/PAI-1 activity[J]. Glia, 2013, 61(5): 694-709.
[35] Jiang H, Li X, Chen S, et al. Plasminogen activator inhibitor-1 in depression: results from animal and clinical studies[J]. Sci Rep, 2016, 6: 30464.
[36] Lee TW, Tsang VW, Birch NP. Physiological and pathological roles of tissue plasminogen activator and its inhibitor neuroserpin in the nervous system[J]. Front Cell Neurosci, 2015, 9: 396.
[37] Idell RD, Florova G, Komissarov AA, et al. The fibrinolytic system: a new target for treatment of depression with psychedelics[J]. Med Hypotheses, 2017, 100: 46-53.
[38] Shi Y, You J, Yuan Y, et al. Plasma BDNF and tPA are associated with late-onset geriatric depression[J]. Psychiatry Clin Neurosci, 2010, 64(3): 249-254.
[39] Sartori CR, Vieira AS, Ferrari EM, et al. The antidepressive effect of the physical exercise correlates with increased levels of mature BDNF, and proBDNF proteolytic cleavage-related genes, p11 and tPA[J]. Neuroscience, 2011, 180: 9-18.
[40] Yang L, Zhang Z, Sun D, et al. Low serum BDNF may indicate the development of PSD in patients with acute ischemic stroke[J]. Int J Geriatr Psychiatry, 2011, 26(5): 495-502.
[41] Madani R, Nef S, Vassalli JD. Emotions are building up in the field of extracellular proteolysis[J]. Trends Mol Med, 2003, 9(5): 183-185.
[42] von K?nel R, Dimsdale JE, Adler KA, et al. Effects of depressive symptoms and anxiety on hemostatic responses to acute mental stress and recovery in the elderly[J]. Psychiatry Res, 2004, 126(3): 253-264.
[43] Pawlak R, Magarinos AM, Melchor J, et al. Tissue plasminogen activator in the amygdala is critical for stress-induced anxiety-like behavior[J]. Nat Neurosci, 2003, 6(2): 168-174.
[44] 董丽婷, 徐治, 王辉, 等. 抑郁症的tPA-纤溶酶原系统功能紊乱假说[J]. 国际精神病学杂志, 2015, 42(2): 110-113.
[45] Lahlou-Laforet K, Alhenc-Gelas M, Pornin M, et al. Relation of depressive mood to plasminogen activator inhibitor, tissue plasminogen activator, and fibrinogen levels in patients with versus without coronary heart disease[J]. Am J Cardiol, 2006, 97(9): 1287-1291.
[46] Tsai SJ, Hong CJ, Liou YJ, et al. Plasminogen activator inhibitor-1 gene is associated with major depression and antidepressant treatment response[J]. Pharmacogenet Genomics, 2008, 18(10): 869-875.
[47] Elomaa AP, Koivumaa-Honkanen H, Niskanen L, et al. Self-reported sleep disturbance is associated with elevated levels of PAI-1 in individuals with a recorded history of depressive symptoms[J]. Prog Neuropsychopharmacol Biol Psychiatry, 2013, 47: 46-51.