Blocking anti-inflammatory antibodies to histamine/serotonin receptors is a prospective method of medical management of Acute Radiation Disease and can inhibit pro inflammatory cascades and possible damage of internal organs of irradiated mammals.
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Molecular Mechanisms of Acute Radiation Disease - Histamine & Serotonin.
1. Molecular Mechanisms of Acute
Radiation Disease: Histamine &
Serotonin.
Dmitri Popov. PhD, Radiobiology.
MD (Russia)
Advanced Medical Technology and Systems Inc. Canada.
2. Molecular Mechanisms of ARD.
• Molecular Mechanisms of Acute Radiation Disease.
• Anti-inflammatory Specific Blocking Antibodies.
4. Radiation.
• Radiation activate the immune reactions and allergy/autoimmune cascade
presents with pro-inflammatory activation, activation of cytokine and
chemokine signaling, and multiple reactions of immune and endothelial
responses that lead to development and manifestations of
allergic/autoimmune reactions.
5. Histamine.
• Histamine, a peptide with prominent vasoactive properties, is released from
granules contained within mast cells, basophils, lymphocytes, platelets and
other reservoirs and interacts with histamine receptors to activate cellular
functions involved in allergic inflammation and immune modulation,
activation and release of proteolytic enzymes.
• http://www.waojournal.org/content/pdf/1939-4551-4-2-47.pdf
• http://www.scielo.br/pdf/abd/v85n2/en_10.pdf
6. Histamine and histamine receptors.
Histamine is important aminergic neurotransmitters, playing an important role
in the regulation of several pathophysiological processes.
Histamine is a compound C5H9N3 especially of mammalian tissues. Histamine
causes dilatation of capillaries, contraction of smooth muscle, and stimulation
of gastric acid secretion, that is released during allergic reactions, and that is
formed by decarboxylation of histidine.
• http://www.merriam-webster.com/medical/histamine
• http://www.tocris.com/pdfs/histaminrev.pdf
7. Histamine and histamine receptors.
• HR1 – Location : Nerve cells, airway and vascular smooth muscles,
endothelial cells, hepatocytes, epithelial cells, neutrophils, eosinophils,
monocytes, DC, T and B cells. Main signaling: enhanced Ca2+
• Others: PhLC, PhLD, cGMP, PhLA, NFκ B.
• HR2 – Location: Nerve cells, airway and vascular smooth muscles,
hepatocytes, chondrocytes, endothelial cells, epithelial cells, neutrophils,
eosinophils, monocytes DC, T and B cells. Main signaling: enhanced AMPc
• Others: Adenylate cyclase, c-Fos, c-Jun, PKC, p70S6K
8. Histamine and histamine receptors.
• HR3 – Location: Nerve cells, airway and vascular smooth muscles,
hepatocytes, chondrocytes, endothelial cells, epithelial cells, neutrophils,
eosinophils, monocytes DC, T and B cells.
• Main signaling: inhibition of cAMP, Others: enhanced Ca2+, MAP kinase.
9. Histamine and histamine receptors.
• HR4 – Location: high expression on bone marrow and peripheral
hematopoietic cells, eosinophils, neutrophils, DC, T cells, basophils, mast
cells, low expression in nerve cells, hepatocytes peripheral tissues, spleen,
thymus, lung, small intestine, colon and heart. It stimulates chemotaxis of
eosinophils and mast cells. Enhanced Ca2+, inhibition of cAMP.
10. Histamine and histamine receptors.
• Eos, eosinophils; B cells, B lymphocytes; T cells, T lymphocytes; PKC,
protein kinase C; cAMP, cyclic adenosine monophosphate; PhLC,
phospholipase C; PhLD, phospholipase D; PhLA, phospholipase A; NF_B,
nuclear transcription factor Kappa Adapted source: Jutel M, et al.
• http://www.scielo.br/pdf/abd/v85n2/en_10.pdf
• Maintz L, Novak N. Histamine and histamine intolerance. Am J Clin Nutr.
2007;85;1185-06.
11. Histamine and histamine receptors.
• Hill SJ, Ganelin CR, Timmerman H, Schwartz JC, Shankley NP, Young JM,
et al. International Union of Pharmacology. XIII. Classification of histamine
receptors. Pharmacol Rev. 1997;49:253-78.
12. Histamine and histamine receptors.
• Important terminology aspects: Classical models of GPCRs need histamine receptors to be
occupied by antagonist agents, which initiate the activation of signal transduction pathways.
However, it has been recently shown that GPCRs may show spontaneous activation, which
does not depend upon the occupation of the receptor by an antagonist. 4 This is
denominated constitutional (physiological) activity of the receptor, which has led to a
reclassification of the drugs that act on GPRCs. (Ligand) drugs traditionally considered
antagonists, are now called inverse agonists, that is, substances capable of reducing the
constitutional activity of GPCRs, or neutral antagonists, when ligands do not alter the basal
activity of these receptors (GPCRs), but interfere with the binding of their agonists. Since
antihistamines can theoretically be both inverse agonists and neutral antagonists, it is not yet
clear whether the term “H1 receptor antagonist” is accurate. Thus, the adoption of the term
“H1 antihistamines” has been suggested
13. Histamine and histamine receptors.
• http://www.scielo.br/pdf/abd/v85n2/en_10.pdf
• Maintz L, Novak N. Histamine and histamine intolerance. Am J Clin Nutr. 2007;85;1185-06.
• Leurs R, Church MK, Taglialatela M. H1-antihistamines: inverse agonism, anti-inflammatory
actions and cardiac effects. Clin Exp Allergy. 2002;32489-98.
• Hill SJ, Ganelin CR, Timmerman H, Schwartz JC, Shankley NP, Young JM, et al.
International Union of Pharmacology. XIII. Classification of histamine receptors.
Pharmacol Rev. 1997;49:253-78.
• Milligan G, Bond RA, Lee M. Inverse agonism: pharmacological curiosity or potential
therapeutic strategy? Trends Pharmacol Sci. 1995;16:10-3.
14. Serotonin and serotonin receptors.
• Serotonin plays a variety of roles in normal physiology, including
developmental, cardiovascular, gastrointestinal, and endocrine function,
sensory perception, behaviors, etc.
• http://bitnest.ca/Silo42/10.1021/cr078224o.pdf
15. Serotonin and serotonin receptors.
• Serotonin (5-hydroxytryptamine, 5HT)
• Serotonin is synthesized from the amino acid l-tryptophan by hydroxylation
and decarboxylation.
• 90% of serotonin located in the enterochromaffin cells of the
gastrointestinal tract. Other serotonin is found in the platelets and brain.
Serotonin is stored in granules as a complex with adenosine triphosphate –
ATP.
16. Serotonin and serotonin receptors.
• 5-HT1 Inhibitory. Gi/G0-protein coupled. Decreasing intracellular concentration of cAMP.
Stimulation contract arterial smooth muscle especially in gastrointestinal and cranial
circulaation – hypoxia.
• 5-HT2 Excitatory. Gq11-protein coupled. Increasing intracellular concentration of IP3 and
DAG. Increase phospholipase C activity. Stimulation causes contraction of vascular and
intestinal smooth muscle and increases microcirculation and vascular permeability.
Stimulation of this receptors caused platelet aggregation and in thee CNS mediates
hallucinogenic effects.
• 5-HT3 Excitatory. Ligand-gated Na+ /K+ channel Depolarization of cell plasma
membrane . Stimulation of these receptors in the area postrema causes nausea and vomiting.
17. Serotonin and serotonin receptors.
• 5-HT4 Excitatory Gs-protein coupled. Increasing intracellular concentration
of cAMP. Located in gastrointestinal tract. Stimulation of these receptors
after radiation ( or other) mediate increase in secretion and peristalsis.
• 5-HT5 Inhibitory Gi/G0-protein coupled. Decreasing intracellular
concentration of cAMP.
18. Serotonin and serotonin receptors.
• 5-HT6. Excitatory Gs-protein coupled. Increasing intracellular concentration
of cAMP.
• 5-HT7. Excitatory Gs-protein coupled. Increasing intracellular concentration
of cAMP.
19. Serotonin and serotonin receptors.
• Serotonin antagonists.
• ONDACETRON ( Zofran) – is a 5 HT3 receptor antagonist.
• Ondacetron – very effective in therapy the diarrhea and vomiting after
radiation therapy or radiation injury.
20. Experimental medical management of Acute Radiation
Disease and associated Acute Radiation Syndromes.
• IgG blocking specific antibodies are the basis of effective and specific of the
most effective therapeutics developed for medical management and
treatment of Acute Radiation Disease and associated syndromes: Acute
Radiation Cerebrovascular Syndrome, Acute Cardiovascular Syndrome,
Acute Gastrointestinal Syndrome . These blocking inhibitory ( antagonists)
antibodies are highly specific, have long serum-half lives, making those
antibodies ideal drugs for immunotherapy of Acute Radiation Disease.
21. Experimental medical management of Acute Radiation
Disease and associated Acute Radiation Syndromes.
• Pro inflammatory and anti inflammatory antibodies.
• Pro inflammatory antibodies.
• http://physio.ucsf.edu/GEMS/courses/Immunology/materials/fa12_essent
ial_immunology/september_4/anthongy_background_reading.pdf
• Anti inflammatory antibodies.
• http://physio.ucsf.edu/GEMS/courses/Immunology/materials/fa12_essent
ial_immunology/september_4/anthongy_background_reading.pdf
22. Experimental medical management of Acute Radiation
Disease and associated Acute Radiation Syndromes.
• Intravenous immunoglobulin (IVIG) is a therapeutic preparation of highly purified,
polyclonal IgG antibodies. Originally designed as an antibody replacement therapy, IVIG
exhibits general anti-inflammatory properties when given at high doses (1–2 g/kg). This
dose requirement is 50 to 200 times higher than what is recommended for therapeutic
monoclonal antibodies, including the anti-CD20 therapeutic antibody rituximab, and three
to six times higher than IVIG antibody replacement doses . As a result of this
antiinflammatory activity, IVIG has been approved by regulatory agencies for the treatment
of a number of autoimmune diseases, including immune thrombocytopenic purpura (ITP),
Kawasaki’s disease, Guillain–Barré syndrome, and chronic inflammatory demyelinating
neuropathy (CIDP).
http://physio.ucsf.edu/GEMS/courses/Immunology/materials/fa12_essential_immunolog
y/september_4/anthongy_background_reading.pdf
23. Experimental medical management of Acute Radiation
Disease and associated Acute Radiation Syndromes.
• In specific circumstances, the high doses of IgG antibodies might neutralize harmful toxins or inflammatory
compounds or block pro-inflammatory receptors . However, the general anti-inflammatory activity is
contained within the effector Fc portion. Experimental models have shown IVIG-derived Fc fragments are
sufficient to suppress inflammation, and these findings have been clinically validated: children suffering from
ITP were successfully treated by infusion with Fc fragments from IVIG.
• Nimmerjahn F, Ravetch JV. Anti-inflammatory actions of intravenous immunoglobulin. Annu Rev Immunol.
2008;26:513–33.
• Debré M, Bonnet MC, Fridman WH, Carosella E, Philippe N, Reinert P, et al. Infusion of Fc gamma
fragments for treatment of children with acute immune thrombocytopenic purpura. Lancet. 1993;342:945–9.
• Samuelsson A, Towers TL, Ravetch JV. Anti-inflammatory activity of IVIG mediated through the inhibitory
Fc receptor. Science. 2001;291:484–6.
24. Experimental medical management of Acute Radiation
Disease and associated Acute Radiation Syndromes.
• Specific blocking antibodies to pro inflammatory receptors.
• J Immunol. 1993 Jul 1;151(1):377-88.
• Experimental medical management of Acute Radiation Disease and
associated Acute Radiation Syndromes.. Characterization of neutralizing
antibodies specific for a peptide, C5aR-(9-29), derived from the
predicted amino-terminal sequence of the human C5a receptor.
• Morgan EL1, Ember JA, Sanderson SD, Scholz W, Buchner R, Ye RD, Hugli
TE.
25. Experimental medical management of Acute Radiation
Disease and associated Acute Radiation Syndromes.
• An H3-receptor antagonist is a classification of drugs used to block the action
of histamine at the H3 receptor. Unlike the H1 and H2 receptors which have
primarily peripheral actions, but cause sedation if they are blocked in the brain,
H3 receptors are primarily found in the brain and are inhibitory autoreceptors
located on histaminergic nerve terminals, which modulate the release of histamine.
Histamine release in the brain triggers secondary release of excitatory
neurotransmitters such as glutamate and acetylcholine via stimulation of
H1 receptors in the cerebral cortex.
https://en.wikipedia.org/wiki/Histamine_antagonist#H3-receptor_antagonists
26. Experimental medical management of Acute Radiation
Disease and associated Acute Radiation Syndromes.
• Anti inflammatory antibodies to H3 receptors - H3-receptor antagonist.
• Anti inflammatory antibodies to H2 receptors – H2 – receptor antagonist.
• Anti inflammatory antibodies to H1 receptors – H1 – receptor antagonist.
27. Experimental medical management of Acute Radiation
Disease and associated Acute Radiation Syndromes.
• 1. Blocking anti-inflammatory antibodies to histamine/serotonin receptors
is a prospective method of medical management of Acute Radiation Disease
and can inhibit pro inflammatory cascades and possible damage of internal
organs of irradiated mammals.
• 2. Blocking neutralizing antibodies specific for a peptide, C5aR-(9-29),
can inhibit cell membrane damage.