Renovis Talk 1 25 05final


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  • Renovis Talk 1 25 05final

    1. 1. Renovis Presentation (January 2005) HO-BVR Pathway Offers Reliable Neuroprotection In Stroke and Traumatic Spinal Cord Injury. Dr. Nariman Panahian
    2. 2. Epidemiology & Registries Report (PMID: 15253917) <ul><ul><li>Cardiovascular disease (including stroke), </li></ul></ul><ul><ul><li>cancer, and diabetes account for approximately </li></ul></ul><ul><ul><li>two-thirds of all deaths in the United States and </li></ul></ul><ul><ul><li>about 700 billion US dollars in direct and indirect </li></ul></ul><ul><ul><li>economic costs each year. </li></ul></ul><ul><ul><li>incidence of stroke accounts for 500,000 new </li></ul></ul><ul><ul><li>clinical cases each year. US population is about 300 mln. </li></ul></ul><ul><ul><li>Stroke, depression, heart disease and motor vehicle trauma </li></ul></ul><ul><ul><li>are projected to become the worldwide burden. </li></ul></ul>
    3. 3. Pipeline Drugs Targeting the Subtypes of the Glutamate Receptor (32 of 49 neuroprotective agents were tested during the “Decade of the Brain”) <ul><li>Competitive NMDA antagonists: CGS 19755 (Ciba-Geigy); LY 233053 (Lilly); MDL-100,453 HHY (Marion Merrel D.); SDZEAA494 (Sandoz) </li></ul><ul><li>Noncompetitive NMDA antagonists: DX and DM, Levorphanol (Hoffman LaRoche); CNS1102 (Cambridge Neuroscience); Memantine (Merz); Eliprodil (Synthelabo); Ramacemide (Fisons); MK-801 (Merck); </li></ul><ul><li>Polyamine site antagonists : Ifenprodil (Pfizer) </li></ul><ul><li>Glycine antogonists : ACEA 1031; ACEA 1021; Felbamate (Carter-Wallace) </li></ul><ul><li>AMPA Receptor Antagonists: CNQX, NBQX, DNQX </li></ul>
    4. 4. Why stroke studies failed: poor choice of a model? <ul><li>Ischemic thresholds are higher in primates than in rodents, residual circulation may remain leading to continuous intraischemic oxidative bursts; </li></ul><ul><li>Energy needs and oxygen consumption are higher in the rodent at least by a factor of 3 (Moskowitz); </li></ul><ul><li>Difference in penumbral “metabolism/ flow coupling ratio” in rodents higher than in humans 4-5 fold (Ginsberg); </li></ul><ul><li>Glia in rodents requires more energy proportionally to the greater number of neurons per glia-neuron unit; </li></ul>
    5. 5. Why stroke studies failed: wrong target? <ul><li>NMDA receptors are found at synapses rather than on axons or myelin. NMDA antagonists are ineffective against axonal damage (Steinberg); </li></ul><ul><li>Cortical neuronal density is threefold higher in rats. Primates have more glial cells, so neurons should not have been the prime target for neuroprotection (Stys). </li></ul><ul><li>No emphasis on regeneration and repair (Finklestein) : Axonal sprouting, formation of new synapses, dendritic spines, stimulation of expression of growth factors in peri-infarct regions and neuroplasticity (neuregulins, oncostatins). </li></ul>
    6. 6. Will Future Neuroprotection Drugs Demonstrate Multiple Mechanisms of Action? <ul><li>NXY-059 and PBN </li></ul><ul><li>2 nd Gen. Azulenyl nitrone (STAZN)? (70-90%  Crtx infarct volume) </li></ul><ul><li>Nicotinamide (K. I. Maynard) </li></ul><ul><li>Human albumin </li></ul><ul><li>Atrial and brain natriuretic peptides (cGMP stimulators) </li></ul><ul><ul><li>Caspase inhibitor  (z-VAD) </li></ul></ul><ul><li>t-PA vs mechanical clotbusting? </li></ul><ul><li>PDE-4 inhibitor (Merck, Decode Genomics) </li></ul><ul><li>Activated protein C (Xigris [Lilly]) </li></ul><ul><li>Phosphokinase inhibitor (MLX105 [Millenium]) </li></ul>
    7. 7. Free radical scavengers or caspase inhibitors?
    8. 10. Disease Morbidity and Literature Findings
    9. 11. “ Neuroprotective potency of bilirubin is striking as 10 nM bilirubin prevent neurotoxicity induced by 10,000 times higher concentration of hydrogen peroxide”. 1 International Symposium on HO/CO, 7/14/2000
    10. 12. NOS and HO-1: friends or foes?
    11. 13. NOS and HO together: close interaction between the systems
    12. 16. Inducers of Heme Oxygenase 1 <ul><li>Metal Ions (Cobalt Chloride, CdCl2, HgCl2) </li></ul><ul><li>Cobalt Protoporphyrin (CoPP) </li></ul><ul><li>Heme </li></ul><ul><li>Chemical Oxidants (Hydrogen peroxide) </li></ul><ul><li>GSH Depletors (Buthione sulfoximine, sodium arsenite and iodoacetamide) </li></ul><ul><li>Inflammatory Cytokines </li></ul><ul><li>LPS </li></ul><ul><li>X-rays, UV radiation </li></ul><ul><li>Kainic acid </li></ul><ul><li>Heat Shock </li></ul><ul><li>Ischemia, diseases </li></ul><ul><li>Oxidative Stress </li></ul><ul><li>Toxins: cobra venom, </li></ul><ul><li>Industrial toxins: </li></ul><ul><li>(Carbon tetrachloride, Bromobenzine) </li></ul><ul><li>Medication: Cyclosporine </li></ul><ul><li>Anti-CD40L antibody </li></ul><ul><li>Δ12- Prostaglandin J2 </li></ul><ul><li>SNP, SNAP, SIN-1 </li></ul>
    13. 17. Inducers of Heme Oxygenase 2 <ul><li>Adrenal Glucocorticoids </li></ul><ul><li>Opiates </li></ul><ul><li>Free Radicals bound to “heme regulatory motifs” </li></ul>
    14. 18. Blockers of HO-1 and HO-2 <ul><li>HO-1 selective inhibitor </li></ul><ul><li>D2702 (SangStat) </li></ul><ul><li>D2 peptide is derived from a region of HLA class I heavy chain (Iyer, 1997). </li></ul><ul><li>HO-2 inhibitors </li></ul><ul><li>NO donors: Sin-1; SNP </li></ul><ul><li>HO-1 & HO-2 inhibitors </li></ul><ul><li>Zn-PP </li></ul><ul><li>Sn-PP </li></ul>
    15. 19. Circle of Willis and Watershed cortical areas in the mouse
    16. 20. <ul><li>Example 1: HO protects against ischemic stroke </li></ul><ul><li>Distribution of Ischemic Neuronal Damage After MCA Occlusion in HO-1 Tg and WT Mice </li></ul>
    17. 21. Example 2: ICH model induced by collagenase injection
    18. 22. Loss of labeling of processes of NADPH diaphorase (+) neurons in the ischemic penumbra
    19. 23. Multiple Molecular Penumbra after MCAo HO-2 Infarct Core-denatured proteins with lipid peroxidation rim HO-1, p53, Nf-kB, transferrin Bcl-2, BVR
    20. 24. Persephin, IL6 and TGF pathway is considered neuroprotective and capable of (+) modulating HMOX1. Pspn is a recently cloned TGF- ß/GDNF family member.
    21. 26. Ferritin and Transferrin staining at the ischemia borderline
    22. 27. “ Iron wasting” and lipid peroxidation in ischemic caudate Ipsi, at a distance Ipsilateral, penumbra Core Contralateral LP
    23. 28. Enhanced Iron Staining in Olfactories, Purkinje neurons and Bergman glia Contralateral Ipsilateral
    24. 29. HO-2 immunostaining in distant areas of the brain RN, contr RN, isch CIC, contr CIC, isch
    25. 30. Changes in n.Trigeminalis, HO-2 ICC cont ipsi
    26. 31. CIC and Purkinje neurons after MCAo, BVR ICC ipsi contra
    27. 32. Red nucleus, BVR ICC contra ipsi
    28. 33. Example 3: HO-1, HO-2 and BVR protect against SCI
    29. 34. Tissue changes in HO-2 and HO-1 after SCI HO-2 above HO-2 below HO-1 above HO-1 below
    30. 35. Double-labeling of HO-1 with cGMP or bcl2 above the level of Spinal Cord Injury HO1-cGMP above HO1-bcl2 above BVR above
    31. 36. β -COP and GR ICC above the level of spinal cord injury β -COP above SCI Glucocorticoid Receptor, below SCI
    32. 37. GFAP labeling above and below injury GFAP-above GFAP-below
    33. 38. Ependyma and Blood Vessels in HO-1 Tg mouse
    34. 39. ALAS HAP-1 Catalase NOS c-FOS Lipooxygenase Cyclooxygenase VEGF HIF-1A Transferrin Ferritin c-Jun ATF2 ATF4 c-MYC IFN- γ TGF-B1 RIP, BAX, TRAIL, FADD PECAM1 CDKN1 CDKN2 P38 MAP-kinase AP-1 NF-kB NRF2* STAT-3 Erk-1,2 CREB1 *HO-1 not inducible in NRF2 Null mice HO-1 may participate in regulation of the following: IL-10 IL-13 IL-6 IL1B STAT3 GH-1 IGF1R IGF2R angiotensin II Leptin IGF-1 EGFR GADD45 P53
    35. 40. Autism Crohn’s disease Ulcerative Colitis Early diagnosis of Sepsis Schizophrenia & Tardive Dyskinesia Early diagnosis of Multipe Sclerosis Early Diagnosis of Alzheimer’s disease Prostate & Ovarian Cancers Acute indicators of outcome in stroke Acute indicators of outcome in MI Future Directions: Active projects for Biomarker Discovery WorldWide
    36. 41. Tool: Development of Clinical Diagnostic Microarrays <ul><li>Therapy Without Biomarkers </li></ul><ul><ul><li>Traditional Clinical classifications of disease </li></ul></ul><ul><ul><li>Clinical staging </li></ul></ul><ul><ul><li>Empiric drug treatment </li></ul></ul><ul><ul><li>Uncertain drug response </li></ul></ul><ul><li>Therapy With Biomarkers </li></ul><ul><ul><li>Molecular classification of diseases </li></ul></ul><ul><ul><li>Molecular Staging of diseases </li></ul></ul><ul><ul><li>Treatment based on Biomarker profile </li></ul></ul><ul><ul><li>Predicted drug response, personalized approach </li></ul></ul>
    37. 42. Automated RCAT TM Protein Chips Proteomics Workstation Protein Chip Production
    38. 43. Array Content (185 features) AFP ALCAM ANG Antithrombin III ATIII/Thrombin AR BDNF BLC BTC 6Ckine VE-Cadherin CCL28 CNTF CNTF R  CT-1 CTACK CTLA-4 CD27 CD30 CD31 CD40 CRF CRP  Defensin 1 DR6 EGF Elastase ENA-78 Eot Eot2 Eot3 Factor V Fas Fas Lig FGF-1 FGF-2 FGF-4 FGF-6 FGF-7 FGF-9 Flt-3 Lig Follistatin Fractalkine GCP-2 G-CSF GDNF GM-CSF GRO-  GRO-  GRO-   EGF HCC-1 HCC-4 HCG HGF HVEM I-309 ICAM-1 ICAM-3 IFN-  IFN-  IFN-  IFN-omega IGF-I IGF-I R IGFBP-1 IGFBP-2 IGFBP-3 IGFBP-4 IGFBP-6 IGF-II IL-10 IL-10 R  IL-11 IL-12 p70 IL-12 p40 IL-13 IL-15 IL-16 IL-17 IL-18 IL-1  MCP-3 MCP-4 M-CSF M-CSF R MDC Midkine MIF MIG MIP-1  MIP-1  MIP-1  MIP-3  MIP-3  MMP-1 MMP-10 MMP-1 MMP-13 MMP-2 MMP-3 MMP-7 MMP-8 MMP-9 MPIF-1 MSP NAP-2  -NGF NT-3 NT-4 OSM PAI-I PAI-II PAPP-A PARC PDGF R  PF4 PlGF Pleiotrophin Prolactin Protein C Protein S RANK RANTES SCF SCF R sCD23 SDF-1  SDF-1  E-Selectin L-Selectin P-Selectin sgp130 ST2 TARC TECK TGF-  TGF-  1 TGF-  3 TGF-  RIII TIMP-1 TIMP-2 Tissue factor TNF-  TNF-  TNF-RI TNF-RII TRAIL TRAIL R1 TRAIL R4 TRANCE TSH uPAR sVAP-1 VCAM-1 VEGF VEGF-D VEGF R2 IL-1  IL-1ra IL-1 sRI IL-1 sRII IL-2 IL-2 sR  IL-2 sR  IL-2 sR  IL-21 IL-3 IL-4 IL-5 IL-5 sR  IL-6 IL-6 sR IL-7 IL-8 IL-9 IP-10 I-TAC Leptin LIF sLIF R Lymphotactin Lymphotoxin  R MCP-1 MCP-2
    39. 44. <ul><li>HO-1 overexpression offers neuroprotection in models of pMCAo and ICH; increased distal ipsilateral immunoreactivity for BVR and HO-2 may play a role in recovery from injury; </li></ul><ul><li>HO-1 and HO-2 play differential roles in SCI: HO-1 stimulates proapoptotic gene expression below the level of trauma, while HO-2 helps regeneration above the level of injury by stimulating ependymal cells and suppressing generation of ROS during the inflammation phase; </li></ul><ul><li>cGMP/bcl2/HO-1 expression offers neuroprotection by preventing apoptosis in the spinal cord above the level of traumatic injury; </li></ul>Conclusion: