Tiziana Ruggiero (238561) & Francesca Bar (239273)
Clinical data suggest that being female, and having high levels of estrogens, increase the probability of having migraine. But paradoxically the sudden decreases in estrogen leves during menstruation increase the probability of having an attack. This paradox is probably explicated by two indipendent mechanism: one mechanism increases the likelihood of migraine when there are high estrogens level, while another mechanism is activated when there is a sudden decrease in estrogens.
Now we study the first mechanis, whereby high estrogen levels may increase the probability of having migraine.
The trigeminal ganglia contain neurons innervating the head and face that carry pain information into the brain. These neurons also secrete neuropeptides capable of regulating blood flow and local inflammation in peripheral tissues such as meninges.
Estrogen has direct effects on gene expression and intracellular signalling. Physiological doses of estrogen up-regulate genes involved in synaptic transmission and intracellular signalling and down-regulate bradykinin and IL receptors.
Up-regulated genes
ERK
(ERK's pathway)
Cytoplasmic ERs function by activating transcription at AP-1 sites in response to 17β-oestradiol, by inducing activation of STAT related promoters, and by inducing phorphorylation of ERK.
ER-α in neurites mediates rapid effects of estrogen, including local activation of ERK.
(All of these mechanisms are potentially involved in regulating expression of the genes.)
An estrogen treatment up-regulates expression of ERK-2 mRNA and increases ERK activation.
ERKs are MAPKs that are activated by membrane depolarization,calcium influx, mitogens and, in the central nervous system, by neurotrophins and neurotransmitters. Mitogen-activated protein kinases (MAPKs) are a family of intracellular signalling molecules that mediate signalling between extracellular events and cellular responses. The MAPK family includes extracellular signal-regulated protein kinase (ERK). Chronic ERK activation of sensory neurons occurs in experimental models of neuropathicand inflammatory pain.
ERK activation contributes to nociception as activation of nociceptive fibres induces phosphoERK (pERK) in sensory neurons in an intensity-dependent manner, and ERK antagonists inhibit capsaicin-induced hyperalgesia. ERK activation also contributes to inflammatory pain. The ERK pathway is necessary for capsaicinandNGF-induced heat hyperalgesia.
Inflammation increases pERK in nociceptive DRG neurons, and treatment with the MAPK kinase inhibitor U0126 decreases thermal hyperalgesia after capsaicin treatment. ERK activation has been used as a marker for the functional activation of neurons in a model of peripheral inflammation. Axotomy,a model of neuropathic pain, induces ERK in medium and large DRG neurons and satellite cells.Inhibiting ERK activation with U0126 also decreasespain related-behaviour after axotomy. ERK activation increases neuron excitability by phosphorylating the Kv4.2 channel, which mediates a transient outward potassium current. Phosphorylation inhibits that channel, resulting in increased excitation of the neuron.
Thus, activation of nociceptors activates ERK, as do inflammatory and neuropathic pain, and ERK activation increases neuron excitability.
Physiological levels of estrogen regulate the Raf1 → MEK1/2→ ERK1/2 signalling pathway in trigeminal ganglia.
Class 1 MHC
Estrogen treatment up-regulated class 1b MHC mRNA in trigeminal neurons. Class I MHC is a glycoprotein, expressed by most cells, that is involved in antigen presentation.
Adult neurons express little class I MHC, but injury and inflammation up-regulate it.
MHC-I is up-regulated in motor neurons after axotomy and in hypothalamic neurons in both chronic and acute inflammation models.
(Increased class I MHC expression in response to chronic infection and acute inflammation may be involved in antigen presentation of infiltrating T cells, in presentation of self antigens, and possibly to mark injured neurons and damaged axons.)
Sensory neurons normally do not express class I MHC because they express high levels of suppressor of cytokine signalling-1 (SOCS1), which down-regulates class I MHC. The mechanism whereby estrogen up-regulates class I MHC is unknown, but one possibility is that estrogen down-regulates SOCS1 expression.
Endothelin receptor B and Synapsin 2
Estrogen treatment up-regulated endothelin receptor B and synapsin 2, which may be involved in increased excitability after injury.
● Endothelin is involved in nociceptive signalling independently of its vasoconstrictive effects.
Tissue endothelin levels increase after cutaneous injury, where it is thought to contribute to local inflammation and pain. Activation of the endothelin B receptor inhibits endothelin-induced nociceptive behaviour. Thus, estrogen treatment also up-regulates a gene that may be antinociceptive. Up-regulation of synapsin 2 suggests that estrogen treatment may alter excitability by increasing neurotransmitter release.
● Synapsin 2 is a major phosphoprotein found in nerve terminals, where it is shown to be associated with maintenance of synaptic vesicle contact with actin filaments. Physiological stimuli, including pregnancy and lactation, up-regulate synapsin 2 expression in the hypothalamus.
Down-regulated genes
Estrogen treatment down-regulated several genes which are potentially relevant to calcitoningene-related peptide (CGRP) release from nociceptors.
Bradykinin B2 receptor
Down-regulation of bradykinin B2 receptor suggests that this receptor is expressed at highest levels during low estrogen phases of the cycle. Bradykinin induces release of CGRP from sensory neurons, which should be greatest when estrogen levels are low. Bradykinin B2 receptor
IL-1b receptor
Down-regulation of the IL- 1b receptor may have similar effects of bradykinin, as IL-1 receptor is expressed in sensory neurons and IL-1b also induces release of CGRP from sensory neurons.
Other genes
Estrogen down-regulated several other genes with potential relevance to migraine, including zinc finger protein 36, fetal intestinal lactase-phlorizin hydrolase, N-tropomodulin, epsin 1 and cysteine string protein.
● Zinc finger protein 36 has an antiinflammatory function achieved by binding-3 untranslated regions of the mRNAs encoding tumour necrosis factor (TNF) leading to accelerated mRNA degradation.
● Estrogen down-regulates fetal intestinal lactase-phlorizin hydrolase (LPH), which is involved in vitamin B6 release. Interestingly, vitamin B6 pyridoxine deficiency causes a sensory neuropathy, while pyridoxine overdoses are neurotoxic to large fibre sensory neurons.
● N-tropomodulin is a neuron-specific form of tropomyosin binding protein. Tropomodulins regulate the length of actin filaments and play a role in synaptic function, providing another potential mechanism for hormones to alter excitability.
● Cysteine string protein (CSP) is an abundant synaptic vesicle protein demonstrated to be necessary for continued synaptic function. Epsin 1 is also involved in synaptic function. Down-regulation of CSP and epsin 1 provide additional potential mechanisms for estrogen to regulate neuronal excitability.
● Estrogen treatment down-regulated other genes involved in inflammation and excitability.
CCL20/ MIP3a/ST38 is a member of the CC chemokine family that attracts immature dendritic cells, effector/memory T cells and B cells to injury sites. CCL20 is up-regulated in ischaemic brain and in models of brain inflammation.
● Estrogen treatment also down-regulated GABA transporter GAT3. GABA immunoreactive neurons are present in trigeminal ganglia. GABA B receptor agonists reduce excitability of trigeminal neurons, suggesting that trigeminal GABA may regulate trigeminal excitability.
Reports
Cairns BE. The influence of gender and sex steroids on craniofacial nociception.Headache. 2007 Feb;47(2):319-24.
Brandes JL.The influence of estrogen on migraine: a systematic review.JAMA. 2006 Apr 19;295(15):1824-30. Review.
