PMID- 28236848 OWN - NLM STAT- MEDLINE DCOM- 20171002 LR - 20231213 IS - 1532-2777 (Electronic) IS - 0306-9877 (Linking) VI - 100 DP - 2017 Mar TI - The fibrinolytic system: A new target for treatment of depression with psychedelics. PG - 46-53 LID - S0306-9877(16)30282-1 [pii] LID - 10.1016/j.mehy.2017.01.013 [doi] AB - Current understanding of the neurobiology of depression has grown over the past few years beyond the traditional monoamine theory of depression to include chronic stress, inflammation and disrupted synaptic plasticity. Tissue plasminogen activator (tPA) is a key factor that not only promotes fibrinolysis via the activation of plasminogen, but also contributes to regulation of synaptic plasticity and neurogenesis through plasmin-mediated activation of a probrain derived neurotrophic factor (BDNF) to mature BDNF. ProBDNF activation could potentially be supressed by competition with fibrin for plasmin and tPA. High affinity binding of plasmin and tPA to fibrin could result in a decrease of proBDNF activation during brain inflammation leading to fibrosis further perpetuating depressed mood. There is a paucity of data explaining the possible role of the fibrinolytic system or aberrant extravascular fibrin deposition in depression. We propose that within the brain, an imbalance between tPA and urokinase plasminogen activator (uPA) and plasminogen activator inhibitor-1 (PAI-1) and neuroserpin favors the inhibitors, resulting in changes in neurogenesis, synaptic plasticity, and neuroinflammation that result in depressive behavior. Our hypothesis is that peripheral inflammation mediates neuroinflammation, and that cytokines such as tumor necrosis factor alpha (TNF-alpha) can inhibit the fibrinolytic system by up- regulating PAI-1 and potentially neuroserpin. We propose that the decrement of the activity of tPA and uPA occurs with downregulation of uPA in part involving the binding and clearance from the surface of neural cells of uPA/PAI-1 complexes by the urokinase receptor uPAR. We infer that current antidepressants and ketamine mitigate depressive symptoms by restoring the balance of the fibrinolytic system with increased activity of tPA and uPA with down-regulated intracerebral expression of their inhibitors. We lastly hypothesize that psychedelic 5-ht2a receptor agonists, such as psilocybin, can improve mood through anti- inflammatory and pro-fibrinolytic effects that include blockade of TNF-alpha activity leading to decreased PAI-1 activity and increased clearance. The process involves disinhibition of tPA and uPA with subsequent increased cleavage of proBDNF which promotes neurogenesis, decreased neuroinflammation, decreased fibrin deposition, normalized glial-neuronal cross-talk, and optimally functioning neuro-circuits involved in mood. We propose that psilocybin can alleviate deleterious changes in the brain caused by chronic stress leading to restoration of homeostatic brain fibrinolytic capacity leading to euthymia. CI - Copyright (c) 2017 Elsevier Ltd. All rights reserved. FAU - Idell, R D AU - Idell RD AD - Department of Behavioral Health, Child and Adolescent Psychiatry, The University of Texas Health Science Center at Tyler, 11937 US HWY 271, Tyler, TX 75708, United States. Electronic address: richard.idell@uthct.edu. FAU - Florova, G AU - Florova G AD - Department of Cellular and Molecular Biology, The University of Texas Health Science Center at Tyler, 11937 US HWY 271, Tyler, TX 75708, United States. FAU - Komissarov, A A AU - Komissarov AA AD - Department of Cellular and Molecular Biology, The University of Texas Health Science Center at Tyler, 11937 US HWY 271, Tyler, TX 75708, United States. FAU - Shetty, S AU - Shetty S AD - Department of Cellular and Molecular Biology, The University of Texas Health Science Center at Tyler, 11937 US HWY 271, Tyler, TX 75708, United States. FAU - Girard, R B S AU - Girard RB AD - Biotechnology Graduate Program, The University of Texas Health Science Center at Tyler, 11937 US HWY 271, Tyler, TX 75708, United States. FAU - Idell, S AU - Idell S AD - Department of Cellular and Molecular Biology, The University of Texas Health Science Center at Tyler, 11937 US HWY 271, Tyler, TX 75708, United States. LA - eng GR - R01 HL133067/HL/NHLBI NIH HHS/United States PT - Journal Article DEP - 20170123 PL - United States TA - Med Hypotheses JT - Medical hypotheses JID - 7505668 RN - 0 (Antidepressive Agents) RN - 0 (Hallucinogens) RN - 0 (Neuropeptides) RN - 0 (Plasminogen Activator Inhibitor 1) RN - 0 (Receptor, Serotonin, 5-HT2A) RN - 0 (Receptors, Urokinase Plasminogen Activator) RN - 0 (SERPINE1 protein, human) RN - 0 (Serpins) RN - 2RV7212BP0 (Psilocybin) RN - 690G0D6V8H (Ketamine) RN - EC 3.4.21.68 (PLAT protein, human) RN - EC 3.4.21.68 (Tissue Plasminogen Activator) RN - EC 3.4.21.7 (Fibrinolysin) RN - EC 3.4.21.73 (Urokinase-Type Plasminogen Activator) SB - IM MH - Animals MH - Antidepressive Agents/therapeutic use MH - Brain/metabolism MH - Depressive Disorder, Major/*therapy MH - Fibrinolysin/metabolism MH - Fibrinolysis/*physiology MH - Hallucinogens/pharmacology/*therapeutic use MH - Humans MH - Inflammation MH - Ketamine/therapeutic use MH - Models, Theoretical MH - Neuropeptides/metabolism MH - Plasminogen Activator Inhibitor 1/metabolism MH - Psilocybin/therapeutic use MH - Receptor, Serotonin, 5-HT2A/metabolism MH - Receptors, Urokinase Plasminogen Activator/metabolism MH - Serpins/metabolism MH - Tissue Plasminogen Activator/metabolism MH - United States MH - Urokinase-Type Plasminogen Activator/metabolism MH - Neuroserpin EDAT- 2017/02/27 06:00 MHDA- 2017/10/03 06:00 CRDT- 2017/02/27 06:00 PHST- 2016/06/22 00:00 [received] PHST- 2016/11/10 00:00 [revised] PHST- 2017/01/21 00:00 [accepted] PHST- 2017/02/27 06:00 [entrez] PHST- 2017/02/27 06:00 [pubmed] PHST- 2017/10/03 06:00 [medline] AID - S0306-9877(16)30282-1 [pii] AID - 10.1016/j.mehy.2017.01.013 [doi] PST - ppublish SO - Med Hypotheses. 2017 Mar;100:46-53. doi: 10.1016/j.mehy.2017.01.013. Epub 2017 Jan 23.