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Cerebral Protection Part 2

Cerebral Protection Part 2. http://myprofile.cos.com/eugenefox. Eugene Yevstratov MD. Pathogenesis of ischaemic brain injury. Depolarization Biochemical cascade Reperfusion injury. Depolarization. Cessation of neuronal electrical ativity Energy loss Impair ion homeostasis

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Cerebral Protection Part 2

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  1. Cerebral Protection Part 2 http://myprofile.cos.com/eugenefox Eugene Yevstratov MD

  2. Pathogenesis of ischaemic brain injury • Depolarization • Biochemical cascade • Reperfusion injury

  3. Depolarization Cessation of neuronal electrical ativity Energy loss Impair ion homeostasis Depletion of high energy phosphates Membrane ion pump failure Efflux of cellular K Influx of Na ,Cl and H2O

  4. Biochemical cascade Glutamate Glutamatergic receptors Calcium influx Nitric oxide Calpains Gelsolin Cell death/Apoptosis

  5. Evidence for a role of Glutamate in Ischemic Neuronal Injury • High concentrations of Glutamte receptors occur in seletively vulnerable neurons • High concentrations of Glutamateare released in ischemic brain regions • Lesioning of glutamergic pathways reduces ischemic injury • NMDA or AMPA receptors blockade reduces ischemic injury • Delayed Ca2+ overload occurs in selectively vulnerable neurons, which is not blocked by Ca2+ channel blockers

  6. Reperfusion injury Hallmark – Ischaemic brain leukocyte infiltration Inflamatory cascade activation Released large amounts of OFR Proinflamatory cytokine expression Neutrophils activation Cerebral oedema

  7. The Ischemic penumbra

  8. Strategies for mitigating ischaemic brain injury • Hypothermia • Biochemical intervention • Pharmacological intervention • Modification of techniques or mechanical devices

  9. Hypothermia(HCA) Mild systemic hypotermia 34Co Mild to moderade hypotermia 34 – 30 Co Moderade Hypotermia 30 – 28 Co Severe Hypotermia 28 –18 Co Profound Hypotermia 18 – 15 Co

  10. Biochemical Intervention • Ingibitors of presynaotic glutamate release • Inhibitors of postsynaptic glutamate release • Monosialogangliosides • Ca2+ channel blockers • Nitric oxide synthase inhibitors • Calpain inhibitors • Gelsolin-like chemical agents • Caspase inhibitors

  11. Pharmacological strategies • Corticosteroids • Free radical inhibition • Cytokine inhibition • Anti-adhesion molecule antibodies

  12. Presynaptic Ca2+ channels N-type ω -conotoxins SNX-111 Hypotension Na+ channels Pyramidines: Lamotrigine Licensed for epilepsy BW1003C87 In vitro and in vivo experiments BW 619C87 In vitro and in vivo experiments Lubeluzole; Studied clinically for stroke Riluzole In vitro and in vivo experiments Lifarizine Hypotension, cardiac side-effects

  13. Postsynaptic NMDA receptors Non-competitive Aptiganel CNS1102 (Cerestat) Hypotension, hallucinogenic Dizoclipine MK801 Toxicity NPS 1506 Less toxic than MK801 Ketamine Anaesthetic, blood pressure effects Dextromethorphan AHN649 Blood pressure effects Memantine Licensed for Parkinsonism Remacemide desglycine FPL 12495 Clinical study with CABG

  14. Competitive Selfotel CGS 19755 Toxicity / psychomimetic d-CPP In vitro and in vivo experiments studies Glycine site Felbamate C-W 554 Lic.for epilepsy, protects in vitro ZD9379 In vitro and in vivo experiments Licostinel ACEA-1021 In vitro and in vivo experiments ACEA-1031 In vitro and in vivo experiments ACEA-1416 In vitro and in vivo experiments

  15. AMPA receptors NBQX In vitro and in vivo experiments GYKI 52466 In vitro and in vivo experiments YM 90 K In vitro and in vivo experiments Monosialogangliosides GM1 In vitro and in vivo experiments Ca2+-channels Nimodipine Intracerebral haemorrhage AT 877 In vitro and in vivo experiments

  16. Gelsolin Microfilaments Cytochalalacin D In vitro and in vivo experiments Calpain Cbz-Val-Phe-H In vitro and in vivo experiments MDL 28,170 In vitro and in vivo experiments NO NO synthase 7- nitroin dazole In vitro and in vivo experiments TRIM In vitro and in vivo experiments 1400 W In vitro and in vivo experiments BN 80933 In vitro and in vivo experiments

  17. Reperfusion Cytokine inhibition Soluble TNF reseptor I In vitro and in vivo experiments TNFα Mab In vitro and in vivo experiments Endo thelium Anti-adhesionmolecules In vitro and in vivo experiments Free radicals Lazeroids Tirilazad 74006F In clinical trials U-101033E In vitro and in vivo experiments PBN In vitro and in vivo experiments studies

  18. Apoptosis Caspases z-VAD-FMK In vitro and in vivo experiments z-DEVD.FMK In vitro and in vivo experiments

  19. Modification of techniques or mechanical devices SCP Selective Cerebral Perfusion RCP Retrograde Cerebral Perfusion

  20. The End ostlandfox@yahoo.de ostlandfox@medscape.com Eugene Yevstratov MD ICCC Anesthesiology Division BsAs.Argentina

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