Transcript ASIC as Therapeutic Target

THE BASICS OF ASICS
Dr. P.M. van Zyl
Department of Pharmacology
UFS
4th 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.
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OBSERVATION
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NSAIDs reduces cutaneous and corneal
pain induced by acidic pH in absence of
inflammation.
THE TRUTH IS
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Analgesic effects of NSAIDs are not
necessarily consequence of antiinflammatory action
Known Analgesic Mechanisms on
NSAIDs
Inhibition of inflammatory mediator release from
neutrophils
 Central neuromodulatory effect
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?Via NMDA receptors Nitric Oxide release PG
release
Inhibition of acid-sensing ion channels (ASICs)
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:
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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.
Acid Sensing
Elaborate pH surveillance system: Various types of acid
sensors activated under various conditions
INCLUDE:
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◦ 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.
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Expressed by primary sensory neurons
◦  acid sensing, acid-induced pain and acid-evoked feedback
regulation of homeostatic reactions.
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Upregulation and overactivity of acid sensors contribute
to chronic pain
ASICs
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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+).
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.
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Inflammation and ASICs
Inflammatory mediators enhance ASIC
activity and expression
 Transcriptional induction and posttranslational regulation of ASICs: participate
in hypersensitization of nociceptive system.
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ASIC Isoforms
Permeable to Na+ and
Ca2+.
No Ca2+ permeability.
Dorsal
Root
Ganglia
Pituitary
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
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◦ 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.
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 cutaneous
nerve endings.
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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.
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ASICs in the CNS
ASIC1a is the predominant functional ASIC
subunit in CNS neurons.
 Important role in
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Ischaemic brain injury
Epilepsy
?Fear-related conditions
?Learning
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.
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Evidence for relevance to Ischemic stroke
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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 protects up to 5hr, persists for 7+
days.
Intracerebroventricular NaHCO3 also protective.
NMDA + ASIC blockade  additional
neuroprotection, prolongs effectiveness of NMDA
blockade.
ASIC1a activation in ischemic neuronal injury and neuroprotection by ASIC1a blocker.
ASIC activation and epileptic seizure
activity
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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.
Function of ASIC1a
Loss of ASIC1a
  disrupt hippocampal-dependent LTP and
spatial memory (modest effect)
 considerably impair cerebellum-dependent
learning
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Function of ASIC1a
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Substantial expression in amygdala: important
in fear-related behavior.
◦ Mice with a disruption of the gene encoding
ASIC1a:  fear response
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Implication: risk-taking behavior
(personality trait might be associated with
loss of ASIC1a function.)
Function of ASIC1a
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Over-expressing ASIC1a in amygdala and
elsewhere in the brainH+- evoked currents
and enhanced context fear conditioning.
Implication:
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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).
Pharmacological Modulation of ASICs:
Amiloride
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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.
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
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NSAIDs
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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.
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Concluding remarks
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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.
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 Anaesthesiol Analg 16(1).
 Sluka, K.A., Winter, O.C. and Wemmie, J.A. 2009. Acid-sensing ion
channels: A new target for pain and CNS diseases. Curr Opin
Drug Discov Devel. 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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