The P11, tPA/plasminogen system and brain-derived neurotrophic factor: Implications for the pathogenesis of major depression and the therapeutic mechanism of antidepressants.
Major depressive disorder (MDD) is a common disabling psychiatric illness with an unknown etiology. Evidence from animal and human studies suggests that a disturbance in serotonergic (5-HT) activity and/or brain-derived neurotrophic factor (BDNF) signaling may be implicated in the pathogenesis of MDD. Recently, a protein, p11, has been found to increase the number of 5-HT(1B) receptors on the surface of cells and enhance 5-HT(1B) receptor function. Furthermore, mice over-expressing p11 acted as if they were undergoing treatment with antidepressants and p11 knockout mice exhibit a depression-like phenotype and reduced behavioural reactions to an antidepressant. As tissue-type plasminogen activator (tPA)/plasminogen proteolytic cascade is implicated in the cleavage of proBDNF to BDNF, and p11, a component of the Annexin II, which can greatly enhance the activation of plasmin by tPA, it is proposed that p11 may act through the tPA/plasminogen/BDNF pathway to achieve its antidepressant effect. Attempts to confirm this hypothesis may lead to new directions in the study of the pathogenesis of MDD and the development of a novel intervention for this disorder. In addition, BDNF is also implicated in several psychiatric diseases such as schizophrenia, bipolar disorder, attention-deficit hyperactivity disorder and Alzheimer's disease; whether p11 and other components related to the tPA/plasminogen pathway may be related to the pathogenesis of these diseases needs further exploration.
Tsai
Shih-Jen
SJ
Department of Psychiatry, Taipei Veterans General Hospital and Division of Psychiatry, School of Medicine, National Yang-Ming University, No. 201 Shih-Pai Road, Sec. 2, 11217 Taipei, Taiwan. sjtsai@vghtpe.gov.tw
D000818:Animals; D017306:Annexin A2 / Q000378:metabolism*; D000928:Antidepressive Agents / Q000008:administration & dosage*; D001921:Brain / Q000187:drug effects / Q000378:metabolism*; D019208:Brain-Derived Neurotrophic Factor / Q000378:metabolism*; D003865:Major Depressive Disorder / Q000188:drug therapy* / Q000378:metabolism*; D006801:Humans; D008959:Models, Neurological; D044302:Receptor, Serotonin, 5-HT1B / Q000378:metabolism; D009418:S100 Proteins / Q000378:metabolism*; D010959:Tissue Plasminogen Activator / Q000378:metabolism*; D000099248:S100 Calcium Binding Protein A10
D017306:Annexin A2; D000928:Antidepressive Agents; D019208:Brain-Derived Neurotrophic Factor; D044302:Receptor, Serotonin, 5-HT1B; D009418:S100 Proteins; D010959:Tissue Plasminogen Activator; D000099248:S100 Calcium Binding Protein A10