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THE BASICS OF ASICS

THE BASICS OF ASICS. Dr. P.M. van Zyl Department of Pharmacology UFS 4 th June 2010. NSAIDS. Anti-inflammatory. Anti-pyretic. Analgesic. TWO WILD ASSUMPTIONS. NSAIDs cause analgesia via elimination of inflammation. COX-1 and -2 inhibition only mechanism of action. OBSERVATION.

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THE BASICS OF ASICS

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  1. THE BASICS OF ASICS Dr. P.M. van Zyl Department of Pharmacology UFS 4th June 2010

  2. NSAIDS Anti-inflammatory Anti-pyretic Analgesic

  3. TWO WILD ASSUMPTIONS • NSAIDs cause analgesia via elimination of inflammation. • COX-1 and -2 inhibition only mechanism of action.

  4. OBSERVATION • NSAIDs reduces cutaneous and corneal pain induced by acidic pH in absence of inflammation.

  5. THE TRUTH IS • Analgesic effects of NSAIDs are not necessarily consequence of anti-inflammatory action

  6. Known Analgesic Mechanisms on NSAIDs • Inhibition of inflammatory mediator release from neutrophils • Central neuromodulatory effect • ?Via NMDA receptors Nitric Oxide release PG release • Inhibition of acid-sensing ion channels (ASICs)

  7. Acidosis and Pain • Stable pH critical for normal cellular function. • Physiologic pH (extracellular: 7.3, intracellular: 7.0) • Tissue acidosis occurs in acute and chronic pain conditions: • Inflammation:extracellular pH (< pH=6) • Angina • Stroke • Ischaemic heart disease • Arthritis • Cancer • Trauma • Infection, hematomas and exercise. • Maintaining pH critical for neuronal functioning • Mild acidosisexcitatory injury of neurons because of proton inhibition of NMDA channels. • Severe acidosisneuronal injury.

  8. Acid Sensing • Elaborate pH surveillance system: Various types of acid sensors activated under various conditions INCLUDE: • Acid-sensing ion channels (ASICs): moderate  in extracellular pH • Transient receptor potential vanilloid-1 (TRPV1) ion channels: severe acidosis pH < 6. • Two-pore-domain K(+) (K(2P)) channels: small deviations in pH. • Expressed by primary sensory neurons •  acid sensing, acid-induced pain and acid-evoked feedback regulation of homeostatic reactions. • Upregulation and overactivity of acid sensors contribute to chronic pain

  9. ASICs • Best studied class of pH-detecting receptors. • H+-gated subgroup of degenerin/epithelial Na+ channel (DEG/ENaC) family of cation channels sensitive to amiloride*. • Preferentially permeable to Na+, to a lesser extent also conduct other cations (Ca2+, K+, Li+ and H+).

  10. ASICs • Expressed principally in NOCICEPTIVE sensory neurons • Able to induce action potential triggering on sensory neurons after moderate  extracellular pH. • Proton-gating of ASICs activate nociceptive sensory neurons depolarizing currents Significant source of pain and hyperalgesia.

  11. Inflammation and ASICs • Inflammatory mediators enhance ASIC activity and expression • Transcriptional induction and post-translational regulation of ASICs: participate in hypersensitization of nociceptive system.

  12. ASIC Isoforms Permeable to Na+ and Ca2+. No Ca2+ permeability. Dorsal Root Ganglia Pituitary

  13. ISOFORMS OF ASIC CHANNELS • ASIC1 (1a/1b) and ASIC3 widely distributed in primary sensory neurons: attractive targets for pain treatment. • ASIC3 and ASIC1a activated in acidity range pH 7,0 – 6,0, seen in several acute and chronic pain conditions. • ASIC3 • senses lactic acidosis  anaerobic metabolism: important in cardiac, muscle ischaemia. • contributes to hyperalgesia and allodynia in inflammation • more widely distributed in humans than in mice, ?more extensive role in human nociception.

  14. ASIC in Peripheral Nervous System • Dorsal root ganglion and trigeminal ganglion; subunit composition varies among DRG neurons of different sizes. • Neurons innervating skin, heart, gut and muscle. Detected in the eye, ear, taste buds and bone. • Localization characterized most thoroughly: ASIC2 and ASIC3 in specialized cutaneousnerve endings.

  15. The physiological significance of ASICs in the PNS • Location and properties make ASIC subunits attractive candidates to serve as H+-gated nociceptors. • Acidosis activate nociceptors and produce pain that can be attenuated by DEG/ENaC inhibitor amiloride. • Inflammatory mediators such as nerve growth factor (NGF), 5-hydroxytryptamine (5-HT or serotonin), interleukin- 1, bradykinin and brain-derived neurotrophic factor (BDNF) can stimulate ASIC transcription, ? contributes to pain-enhancing effects of these mediators.

  16. ASICs in the CNS • ASIC1a is the predominant functional ASIC subunit in CNS neurons. • Important role in • Ischaemic brain injury • Epilepsy • ?Fear-related conditions • ?Learning

  17. ASIC1a activation in acidosis-mediated and ischemic neuronal injury • Ischemia  anaerobic glycolysis lactic acid accumulation acidosis. • Severe cerebral ischemia: pH may drop to 6.3 and belowimportant role in ischemic brain injury. • Ca2+ overload causes toxicity in the ischemic brain, ASIC1a homomultimers conduct Ca2+: ASIC1a activation could contribute to cell damage and death in cerebral ischemia.

  18. Evidence for relevance to Ischemic stroke • Neurons lacking ASIC1a and cells treated with amiloride or PcTX-1 resisted acidosis-induced injury. • PcTX-1  effects of NMDA-induced cell death. • Disrupting ASIC1a reduced infarct volume by 60% in a mouse model of cerebral infarction. • ASIC1a blockade protectsup to 5hr, persists for 7+ days. • Intracerebroventricular NaHCO3 also protective. • NMDA + ASIC blockade  additional neuroprotection, prolongs effectiveness of NMDA blockade.

  19. ASIC1a activation in ischemic neuronal injury and neuroprotection by ASIC1a blocker.

  20. ASIC activation and epileptic seizure activity • Significant  brain pH during intense neuronal excitation or seizure activity • ASIC blockade by amiloride and selective ASIC1a blocker PcTX1 significantly inhibits increase of neuronal firing and neuronal damage caused by noxious stimuli. • = activation of ASIC1a channels involved in generation or maintenance of seizure activity and resultant seizure-mediated neuronal injury.

  21. Function of ASIC1a • Loss of ASIC1a •  disrupt hippocampal-dependent LTP and spatial memory (modest effect) • considerably impair cerebellum-dependent learning

  22. Function of ASIC1a • Substantial expression in amygdala: important in fear-related behavior. • Mice with a disruption of the gene encoding ASIC1a: fear response • Implication: risk-taking behavior (personality trait might be associated with loss of ASIC1a function.)

  23. Function of ASIC1a • Over-expressing ASIC1a in amygdala and elsewhere in the brainH+- evoked currents and enhanced context fear conditioning. • Implication: • provide animal model of acquired anxiety • ? prone to fearful behavior, • ? Also supersensitive to acidosis.: • ?Explain why many pts with panic disorder have panic attacks when breathing CO2. (that lowers brain pH).

  24. Pharmacological Modulation of ASICs: Amiloride • Diuretic block Na+/H+, Na+/ Ca2+ exchangers and ENaC • Non-specific reversible blocker for ASICs. • Inhibits acid-induced increase of [Ca2+]i and membrane depolarization. • Peripheral sensory system: acid-induced pain • CNS:  acid-mediated and ischemic neuronal injury. • Problems: • Nonspecificity for various ion channels and ion exchange systems • Na+/Ca2+ exchanger critical for maintaining cellular Ca2+ homeostasis and the survival of neurons against delayed calcium deregulation and injury caused by glutamate receptor activation. • NOT a future analgesic or neuroprotective agent in humans.

  25. Pharmacological Modulation of ASICs: • A-317567: non-selective ASIC blocker, 10-fold potency of amiloride, no diuresis or nutriuretic effect. Neuroprotection unknown • Psalmotoxin 1 (PcTX1) specifically inhibits ASIC1a current. Gating modulater, Neuroprotective, yet not practical • APETx2: inhibits ASIC3, fails to cover sustained currents

  26. NSAIDs • Various NSAIDs inhibit ASICs at therapeutic doses for analgesic effects. • Ibuprofen and flurbiprofen inhibit ASIC1a. • Aspirin, salicylate and diclofenac inhibit ASIC3. • Ideal for a large spectrum of pain conditions, particularly pain caused by tissue inflammation. • In acute phase of tissue inflammation: rapid inhibition of ASIC currents by NSAIDs blocks activation of pain-sensing neurons by inflammatory acidosis. • Later, NSAIDs suppress inflammation and pain via effect on COXs, limiting the production of PGs. • In chronic phase: reduce sensitization to pain by combined inhibition of COXs, ASIC currents, and ASIC expression.

  27. Concluding remarks • ASICs a novel target for intervention in acute and chronic pain • Ca2+-permeable ASIC1a a novel pharmacological target for ischemic brain injury. • NSAIDs worthy analgesics, on their own and as adjuvants.

  28. References • Wemmie, J.A., Price M.P. and Welsh, M. J. 2006. Acid-sensing ion channels: advances, questions and therapeutic opportunities TRENDS in Neurosciences 29(10). • Odendaal CL. 2010 Refresher Course: Are NSAIDs inferior to other analgesics? S Afr J AnaesthesiolAnalg16(1). • Sluka, K.A., Winter, O.C. and Wemmie, J.A. 2009. Acid-sensing ion channels: A new target for pain and CNS diseases. CurrOpin Drug DiscovDevel. 12(5):693-704. • Xiong, Z-G., Pignataro, G., Li, M., Chang, S-y and Simon, R.P. 2008. Acid-sensing ion channels (ASICs) as pharmacological targets for neurodegenerative diseases. Current Opinion in Pharmacology 8:25–32.

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