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EPO, the growth magical factor

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This is the slide show presented during the 29th International Conference on Public Mental Health and Neuroscience

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EPO, the growth magical factor

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  2. 2. NEURO-PROTECTIVE EFFECTS OF ERYTHROPOIETIN Reza Nejat, M.D., Anesthesiologist, FCCM former Assistant Professor, SBMU, Bazarganan Hospital,Tehran, IRAN 2
  3. 3. Neuro-protective effects of EPO  Viault (1890)  Carnot and Deflandre (1906)  There must be hormone to increase erythropoiesis in high altitude, it regulates erythropoiesis  Jacobson (1957) and Nathan (1964):  the kidney is the major site but not the sole site of Epo production.  Goldwasser and his team (1977):  prepared 8 mg of highly purified human Epo 3
  4. 4. Neuro-protective effects of EPO  EPO:  Is required for:  survival,  Proliferation,  differentiation  of erythroid progenitor cells in bone marrow, and  Prevents apoptosis in progenitor cells 4
  5. 5. Neuro-protective effects of EPO  EPO:  Produced by renal interstitial cells having a neuron-like shape and express marker antigens found in neuronal cells  Ito cells in the liver produces EPO; very similar to the EPO- producing renal fibroblast-like interstitial cells, 5
  6. 6. Neuro-protective effects of EPO  Epo and Epo-R  EPO-R  belongs to the cytokine receptor superfamily  consists of:  an extracellular domain,  a transmembrane domain,  an intracellular domain. 6
  7. 7. Neuro-protective effects of EPO Cold Spring Harb Perspect Med 2013;3:a011619 7
  8. 8. Neuro-protective effects of EPO  EPO and EPO-R can be found in the:  Nervous system,  Cardiovascular system,  Digestive system,  Endocrine system,  Female and male reproductive system,  Respiratory system  Spleen 8
  9. 9. Neuro-protective effects of EPO  EPO production and secretion:  regulated by the tissue oxygen supply (kidney, liver, brain)  via activation of the hypoxia- inducible factor 1 (HIF-1) pathway 9
  10. 10. Neuro-protective effects of EPO  HIF:  a heterodimeric protein α- and β-subunits  HIF α-subunits (1, 2, 3): regulated by oxygen tension, in normoxia hydroxylated,  degraded by pVHL in hypoxia not hydroxylated  HIF β-subunit: constitutively expressed. 10
  11. 11. Neuro-protective effects of EPO the expression of EPO-R is: not sensitive to hypoxia??? regulated by: pro-inflammatory cytokines: TNFα, IL-1β erythropoietin probably other unidentified factors 11
  12. 12. Neuro-protective effects of EPO In EPO or EPO-R knock-out mice: Apoptosis increases prior to the onset of anemia There seems to be a functional role of EPO/EPO-R signaling rather than erythropoiesis 12
  13. 13. Neuro-protective effects of EPO Cytokine-Jak-STAT signaling is an evolutionary ancient mechanism 13
  14. 14. Neuro-protective effects of EPO  auto-phosphorylation of JAK-2 results in activation of several signaling pathways: RAS/MAPK with the ability to activate STAT5 up-regulating antiapoptotic proteins Bcl-2 and Bcl-XL EPO+EPO-R activates JAK-2 RAS/MAPK STAT5 upregulation of Bcl-2, Bcl-XL 14
  15. 15. Neuro-protective effects of EPO  auto-phosphorylation of JAK-2 results in activation of several signaling pathways: PI3K/AKT: inhibits pro-apoptotic molecules and prevents release of cytochrome c from mitochondria PI3K/AKT inhibition of activation of JAK-2 EPO+EPO-R GSK-3β caspase -3/-9 BAD 15
  16. 16. Neuro-protective effects of EPO  auto-phosphorylation of JAK-2 results in activation of several signaling pathways: PI3K/AKT: Phosphorylation of GATA-1 Inhibition of BAD, GSK and caspase-3/-9 results in aborting apoptosis PI3K/AKT inhibition of activation of JAK-2 EPO+EPO-R GSK-3β caspase -3/-9 BAD 16
  17. 17. Neuro-protective effects of EPO  auto-phosphorylation of JAK-2 results in activation of several signaling pathways:  PI3K/AKT: Down-regulation of NF-ƙB: suppresses pro-inflammatory cytokines likeTNF-α and IL-6 and simultaneously increases anti-inflammatory cytokine IL-10 level. EPO+EPO-R JAK-2 NF-ƙB downregulation TNF-α IL-6 IL-10 anti- inflammatory effect 17
  18. 18. Neuro-protective effects of EPO  auto-phosphorylation of JAK-2 results in activation of several signaling pathways: PI3K/AKT: Expression of eNOS (endothelial Nitric Oxide Synthase) eNOS PI3K/AKT EPO+EPO-R JAK-2 NO &vasodilatation NADPH oxidase inhibition & ROS 18
  19. 19. Neuro-protective effects of EPO  a multicenter double blinded clinical study in Germany: EPO had no cell-protective effect or even might be hazardous in humans.  Ehrenreich H, Weissenborn K, Prange H. Recombinant Human Erythropoietin in the Treatment of Acute Ischemic Stroke. Stroke. 2009; 40: e647-e656 19
  20. 20. Neuro-protective effects of EPO the modulatory effect of EPO on the central respiratory commands:  acute (less than 1 hour) and chronic EPO administration: attenuated and abolished hypoxia-induced central respiratory depression MEK½ and PI3K pathways mediates this response Repir Physiol Neurobiol. 2015; 206: 36-40 20
  21. 21. Neuro-protective effects of EPO  The report of a phase II double blinded placebo controlled study in infants with moderate to severe hypoxic/ischemic encephalopathy:  EPO could: 1) diminish MRI brain injury, and 2) improve the motor function of the infants after 1 year, yet 3) the mortality did not differ significantly Pediatrics. 2016; 137(6): e20160191 21
  22. 22. Neuro-protective effects of EPO  EPO-R knock-out mice: Low level of neural progenitor cells Low neurogenesis 22
  23. 23. Neuro-protective effects of EPO High baseline concentration of EPO-R is expressed as an autocrine/paracrine system in:  astrocytes that surround capillaries in white matter,  purkinje neurons,  the choroid plexus  the ependymal cells  limbic system and hippocampus 23
  24. 24. Neuro-protective effects of EPO  EPO and EPO-R: Expressed in low levels in healthy brain Increase markedly following injuries 24
  25. 25. Neuro-protective effects of EPO EPO: Does it pass through BBB? cannot penetrate BBB: in hypoxia/ischemia permeability of BBB increases, and peripherally administered EPO: can be found in CSF in rats, primates and humans. through the extracellular pathways. 25
  26. 26. Neuro-protective effects of EPO  the absolute source of EPO in the CNS is not the blood.  it is produced de novo in the CNS  tissue hypoxia in the CNS increases: EPO concentration EPO-R expression 26
  27. 27. Neuro-protective effects of EPO  EPO expression in the nervous system is regulated by:  the tissue oxygen supply and via activation of the (HIF-1) pathway  In non-hypoxic circumstances: mechanical damage Infection metabolic stress (glucose , insulin?) oxidative stress elevated temperature Intense neural activity enriched environment  pro-inflammatory cytokines 27
  28. 28. Neuro-protective effects of EPO  CNS lesions:  primary injury: Necrotic core, Penumbra Infiltration of inflammatory cells  secondary injury: Propagation of necrotic core and lesion in the penumbra  Final pathway: resorption of cellular debris gliosis vs regenerating a functional tissue 28
  29. 29. Neuro-protective effects of EPO  Ischemic/hypoxic and other types of brain injuries: lack of oxygen and nutrients pro-inflammatory mediators in neurovascular unit: TNF-α, IL-6, ICAM-1 brain edema and hemorrhagic transformation neural cell apoptosis and death 29
  30. 30. Neuro-protective effects of EPO Reperfusion restoration of perfusion in the ischemic lesion  oxygen stress  free radical formation  excitotoxicity,  nitric oxide production 30
  31. 31. Neuro-protective effects of EPO  In brain injuries the leakiness of BBB  due to: inflammatory mediators, reactive oxygen species (ROS), VEGF, MMP, microRNA 31
  32. 32. Neuro-protective effects of EPO  HIF-1α in hypoxic brain insult:   expression ofVEGF, VEGFR and MMP-9, AQP-4:   BBB hyer-permeability   Brain edema  inhibition of HIF-1α:   cerebral edema through:   MMP-9 and AQP-4 32
  33. 33. Neuro-protective effects of EPO  Neural stem cells in mammals:  SGZ, SVZ, OB  In cortical injuries:  neuroblasts originating from SVZ stem/progenitor cells migrates to the penumbra: VEGF, IGF-1, SDF-1/CXCR-4 and Ang-1/Tie-2 signals 33
  34. 34. Neuro-protective effects of EPO  MMPs:  With several significant physiological potentials involved in:  growth,  development,  tissue repair and wound healing  synaptic plasticity  neurite growth  myelinogenesis. 34
  35. 35. Neuro-protective effects of EPO  MMPs:  up-regulated and activated in ischemic and other brain injuries,  Its latent form is activated by:  Endogenous and exogenous plasminogen activator  Furin  free radicals 35
  36. 36. Neuro-protective effects of EPO  Angiogenesis:  proliferation of mature endothelial and endothelial progenitor cells (EPC) located in the penumbra in the first 12-24 hour after the insult  VEGF leads the process 36
  37. 37. Neuro-protective effects of EPO  VEGF:  a family of cytokines,  induce angiogenesis through proliferation, sprouting, migration of the endothelial cells and  New vascular tube formation by these cells.  Found in pericytes in the border of brain lesions 37
  38. 38. Neuro-protective effects of EPO  VEGF:  After binding withVEGFR-2 increases vascular permeability through activating cGMP and a NO-dependent pathway 38
  39. 39. Neuro-protective effects of EPO  AQP-4  integral membrane proteins plays important roles in: mediating water homeostasis bidirectional passive trans- cellular water transfer in response to osmotic gradient  the expression of this channel is modulated by HIF-1 and VEGF 39
  40. 40. Neuro-protective effects of EPO AQP-4 expression has an impact on BBB integrity 40
  41. 41. Neuro-protective effects of EPO  Strategy against CNS insults: Decrease apoptosis and supporting the cells restore delivery of oxygen and nutrients (angiogenesis) suppressing edema and saving the integrity of BBB, {ASAP} supporting neurogenesis and synaptogenesis (ECM) 41
  42. 42. Neuro-protective effects of EPO  hypoxia dose-dependently makes astrocytes secret EPO EPO has a trophic paracrine effect on: Neurons, Astrocytes, Microglia. 42
  43. 43. Neuro-protective effects of EPO EPO: Protects the neural cells against reduced oxygen tension, ecitotoxicity and ROS or other free radicals 43
  44. 44. Neuro-protective effects of EPO  EPO facilitates energy production in mitochondria: stabilizing mitochondrial membrane potential Inhibiting free radical production in mitochondria 44
  45. 45. Neuro-protective effects of EPO EPO in the nervous system:  apoptosis,  inflammatory responses  re-establishment of compromised functions by support of : 1) proliferation, 2) Migration, and 3) differentiation of progenitor cells to compensate for the lost or injured cells 45
  46. 46. Neuro-protective effects of EPO  rhEPO could protect BBB:  By up-regulating theTJ proteins   MMP   glial cell inflammatory reactions,  TNF-α levels and   NF–кβ activation 46
  47. 47. Neuro-protective effects of EPO  EPO protects BBB:  againstVEGF-induced injury and the resulting hyper- permeability in early phases of brain insults  have cytoprotective effect on endothelial cells in ischemic insults  inhibit AQP-4-induced astrocyte swelling through activating JNK and MAPK 47
  48. 48. Neuro-protective effects of EPO  Endogenous EPO was attributed to:  Induce neural stem/progenitor cells to proliferate, migrate and differentiate in addition to survive  in rats, EPO-R is more concentrated on neural progenitor cells (NPCs) than on the mature ones 48
  49. 49. Neuro-protective effects of EPO  astrocyte-derived EPO  anti-apoptotic factor for microglia: without having any influence on pro-inflammatory potentials  dose-dependent proliferative effect on microglia   Bcl/Bax ratio in the microglia  prevents activation of caspase- 3 and -9 49
  50. 50. Neuro-protective effects of EPO  EPO completes the loop of a physiological feedback pathway by:  inducing MMP-2 and -9 which promotes angiogenesis and migration of neuronal progenitor cells  limiting MMPs activity to a restricted area throughTIMPs expression by astrocytes 50
  51. 51. Neuro-protective effects of EPO  EPO through activating PI3K/Akt pathway regulates: TIMP-1 gene transcription, TIMP-1 mRNA induction and TIMP-1 expression 51
  52. 52. Neuro-protective effects of EPO  EPO supports regenerating neurons and astroglial cells by: regulating MMP-2, MMP-9 andVEGF increasingVEGF receptors 1, 2 and 3 in hypoxia 52
  53. 53. Neuro-protective effects of EPO  EPO increases survival of cultured endothelial cells through:  activating Akt1 pathway,  stabilizing mitochondrial membrane potentials and  inhibiting caspase 3 and-9 53
  54. 54. Neuro-protective effects of EPO  EPO has pro-angiogenic property:  Induces endothelial cell to:  proliferate,  migrate,  produce nitric oxide (NO),  degrade ECM delicately,  differentiate  Mobilizes the endothelial progenitor cells, 54
  55. 55. Neuro-protective effects of EPO  Effective synaptogenesis needs high degree of plasticity through regulating the consistency of perineural net and ECM remodeling:  Role of MMPs in cognition, memory, learning 55
  56. 56. Neuro-protective effects of EPO  activation of EPOR in cultured young rat cerebellar and hippocampal neurons: reduces glutamate release  by inhibiting calcium- dependent exocytosis of this excitatory amino acid 56
  57. 57. Neuro-protective effects of EPO  rhEPO in reperfusion injury:   up-regulation of IL-1β and IL-18, MMP-2 and MMP-9  protects against oxygen toxicity and free radicals (ROS, RNS) through:   pro-inflammatory mediators 57
  58. 58. Neuro-protective effects of EPO  rhEPO attenuates ischemia- induced inflammation by:  reducing neuronal death rather than by direct effects upon EPO-R–expressing inflammatory cells.  rhEPO rescues neurons within the penumbra from apoptosis 58
  59. 59. Neuro-protective effects of EPO  EPO : TNF-α, IL-6, and monocyte chemo-attractant protein-1 (MCP-1)  TNF-α, IL-1: Inhibits EPO production 59
  60. 60. Neuro-protective effects of EPO  EPO, in neonatal rats:  after hypoxic/ischemic injury stimulated:  oligodendrogenesis  attenuated white matter damage  EPO, in adult rats:  after stroke  amplified myelinating oligodendrocytes  increased myelinated axons in peri-infarct white matter and  improved functional outcome 60
  61. 61. Neuro-protective effects of EPO  EPO, in MCAO in adult mice brains:  reduced demyelination  astrocyte activation, and  decreased the protein level of β-APP.  inhibited Nogo-A and MAG protein levels after cerebral ischemia:  attenuating axonal injury 61
  62. 62. Neuro-protective effects of EPO 62
  63. 63. Neuro-protective effects of EPO EPO:  increased water permeability of astrocyte AQP-4 induced by group I mGluR agonists 63
  64. 64. Neuro-protective effects of EPO 64
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  67. 67. Neuro-protective effects of EPO May 29, 2018 June 3, 2018 67
  68. 68. Neuro-protective effects of EPO June 14, 2018 June 21, 2018 68
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  72. 72. Neuro-protective effects of EPO 72
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  77. 77. Neuro-protective effects of EPO  Now, we have a new vision of EPO’s effect in the nervous system: anti-apoptotic, anti-oxidant, anti-inflammatory neuro-protective by stimulation of : Angiogenesis Neurogenesis 77
  78. 78. Fundamentals of EKG Thanks for your patience Rezanejat.com Icuaticu.com 2icuedu.com 78

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