Module 1 Flashcards
(41 cards)
1
Q
Migraine attack symptoms
A
- moderate to severe headache
- unilateral and/or pulsating
- aggravated by routine physical activity
- nausea/vomiting
- photophobia and/or phonophobia
- allodynia
- aura
2
Q
Phases of a migraine attack
A
- Prodrome
- Aura
- Headache
- Postdrome
3
Q
Prodrome phase
A
- 3hr-days after initiation
- marks the beginning of a migraine attack
- irritability, fatigue, nausea
4
Q
Aura phase
A
- 5-60min
- visual disturbances, temporary loss of sight, numbness and tingling
5
Q
Headache phase
A
- 4-72hr
- throbbing, nausea, vomiting, insomnia and anxiety
6
Q
Postdrome phase
A
- 1-2 days
- inability to concentrate, fatigue, depressed mood and lack of comprehension
7
Q
What causes a migraine
A
- inheritable
- diverse SNPs associated with ion channel/transport proteins and those regulating neurotransmitters
- triggers = stress, auditory stimuli, fatigue, fasting, weather, sleep, alcohol
8
Q
Migraine physiology
A
- considered to be a neurovascular disorder
- vascular models are commonly used to study migraines so there is a lack of neurone models
- evidence suggests there is inappropriate activation of the trigeminovascular system
- aura is correlated with cortical spreading depression
9
Q
What is the trigeminovascular system
A
a network of neurones originating in the trigeminal ganglion that innervate the cerebral vasculature
10
Q
Trigeminal ganglion
A
- sensory ganglion of the trigeminal nerve
- peripheral of the brain
- highly vascularised
- contains several cell types
11
Q
Cell types in the trigeminal ganglion
A
- cell bdies of pseudounipolar sensory neurones
- myelinated or unmyelinated C-fibres
- satellite glia and schwann cells
12
Q
Ganglionic signalling
A
- trigeminal nerve cells release neuropeptides to act directly on adjacent cells (neurones or satellite glial cells) in the gangli peripheral tissues and the brain stem
- act autocrine or paracrine
- factors required for peptide release are reportedly expressed in cell bodies
13
Q
Current acute treatment options
A
- Anti-inflammatory agents
- triptans
- gepants
14
Q
Current preventative options
A
- anticonvulsants
- anti-depressants
- beta-blockers
- depants
- monoclonal antibodies that target CGRP
15
Q
Neuropeptides
A
- peptides <50aa released by neurones
- may have a role in migraine pathophysiology or treatment
- have GPCR receptors that are typically GaS coupled
16
Q
Questions to ask whether a neuropeptide is involved in migraines
A
- does it have access to a potential site of action
- it its receptor expressed at a potential site of action
- does the neuropeptide have roles in related biological processes
- is the concentration altered during a migraine
- does administration of the peptide effect migraines
- does blocking the neuropeptide effect migraines
17
Q
Experimental models to study migraines
A
- cell/primary culture
- antagonist response curve
- agonist response curve
- expression studies
- animal models
- human studies
18
Q
Cell/primary culture models
A
- looks at receptor pharmacology and signaling
- in vitro/ex vivo
19
Q
Agonist response curve
A
- used for receptor phenotyping
- measures potency
20
Q
Antagonist response curve
A
- single or multiple concentration administration
- single = single concentration of an agonist is used which is then gradually blocked by increasing concentrations of the drug to test for potency, cannot be used to compare between studies
- multiple = different concentrations of the drug are administered and signalling changes are measured, can be compared
21
Q
Animal models
A
- assess trigeminal/downstream neural activation relevant to headache typically involving some form of stimulation
- mechanical allodynia
- thermal allodynia
22
Q
Human studies
A
- provocation studies = a substance given to a migraine patient and the induction of a migraine-like attack is recorder
- Observational studies = measurement taken during an induced or natural migraine attack, measures blood of CSF factors
- Clinical trials
23
Q
CGRP
A
- member of the calcitonin peptide family
- 2 isoforms = alpha and beta
- 37aa neuropeptide expressed throughout the central and peripheral nervous systems
- have an N-terminal domain with disulfide linked cysteines and a C-terminal amide domain
- has a wide range of potential roles such as pain sensitivity
- larger than most small molecules so drug development is difficult
- vasodilator
24
Q
CGRP receptor family
A
- heterodimer
- formed via a GPCR and an accessory protein
- have overlapping affinity such as CGRP can activate both the CGRPR and AMY1R
- as they are heterodimers it can make problems when using antagonist
25
CGRP receptor
CLR and RAMP1
26
Evidence for CGRP in migraines
- overlapping expression of CLR and RAMP1 suggests the expression of the CGRPR in the trigeminal nerve and cranial vasculature
- induces facial allodynia and photophobia when administered to mice
- CGRP is elevated in both episodic and chronic migraine patients
- CGRP infusion can provoke a migraine-like attack in migraine patients
- pain signal in the head
27
Triptans targeting CGRP
- rizatriptan and sumatriptan causes vasoconstriction to oppose CGRP vasodilation
- Lasmiditan inhibits CGRP release at the trigeminal ganglia neurones
28
Gepants
- designed to fix the problem of an antagonist targeting both parts of the receptor
- larger than typical GPCR drugs
- block CGRP induced facial allodynia
- block dermal vasodilation in humans
29
Telcagepants
- antagonist that works at the RAMP1/CLR interface of the CGRP receptor
- interacts with tryptophan 74 residue on CLR which is crucial for RAMP1 binding
- tests in mice revealed importance of W74 as it was weaker due to the absence of this residue
- safe for acute treatment but prophylaxis was terminated due to liver toxicity concerns
30
Amylin
- 37aa peptide hormone part of the calcitonin peptide family
- closely related to CGRP
- primarily expressed by pancreatic B-cells
- functions in glucose regulation, feeding, body weight, adiposity, nociception
31
How does amylin work
- acts principally at sensory circumventricular organs of the brain
- it is released into the circulation following nutrient influx
- circulating amylin activates neurones in the circumventricular orans of the central nervous system
- might be expressed by some neurones and act locally at the spinal cord and hypothalamus
32
AMY1 receptor
- CTR + RAMP1
- senses both amylin and CGRP
33
AMY2
- CTR and RAMP2
- senses amylin only
34
AMY3
- CTR and RAMP3
- senses amylin only
35
Irimeia et al 2020 - Interictal amylin levels in chronic migraine patients
- compared the levels of amylin and CGRP in peripheral blood between controls and chronic and episodic migraines
- Increased interictal (between attacks) peripheral blood amylin levels in CM than EM
- CGRP levels in CM and EM both elevated
- Activation of trigemino-vascular system could be induced by amylin
- amylin is a better diagnostic tool than CGRP in differentiating CM from HC
- Strengths = large sample, good thorough parameters
- Limitations = selective population, majority were using prophylaxis, most female
36
Walker et al 2015 - function and expression of the AMY1 receptor
- aimed to look at the expression of the CGRPR and AMY1R in the trigeminal system
- both CGRP and AMY1 receptors expressed in the trigeminal system
- amylin is a selective agonist for AMY1 so activity of amylin must occur in neurones
- Rat TG neurones were potent for both CGRP and amylin to stimulate cAMP
- CTR and RAMP1 co-localise in the TG and in the brain stem - shows AMY1 in these 2 areas
- Strengths = large amount of techniques used, animal and humans, multi-centre
- Limitations = gepants used cannot distinguish between CGRP and AMY1, doesnt directly provide evidence for migraines, advanced age of human donors
37
Ghanizada et al 2021 - Amylin Analog Pramlintide Induces Migraine-like Attacks in Patients
- aimed to look at if amylin analogue plays a role in migraine pathophysiology
- pramlintide induces migraine like attacks
- pramlintide acts mainly via AMY1
- CGRP has stronger arterial dilation and facial flushing but dilation is likely not the main driver of migraines
- mice with amylin had increased light aversion and hypersensitivity which is reflective of migraine symptoms
- little or no amylin expressed in the TG
- strengths = humans and mice, multi-centre
- limitations = almost all patients were female, no control, binding compromised due to facial flushing, advanced age of human tissue donors
38
Action of Triptans
agonistically bind 5HT1B/D receptors in the trigeminal vessels preventing vasoconstriction
39
Action of Lasmiditan
agonist for 5HT1F on trigeminal nerve inhibiting CGRP release without vasoconstriiction
40
Action of gepants
CGRP receptor antagonists preventing its downstream signalling
41
Action of Monoclonal antibodies
can either bind free CGRP (Fremanezumab) or bind the CGRP receptor (Erenumab) preventing receptor activation
