Migraine and mast cell degranulation

Theoharis C. Theoharides, and collegues pointed out that neurogenic inflammation continues to be considered a key pathological process and stated that activation of meningeal sensory neurons is the primary mechanism in the origin of headaches in migraine. ^[1]

The authors explained that the pathogenesis of migraine has been associated with “cortical spreading depression” (CSD) as well as with meningeal and cerebral vasodilation. But neither the vascular nor the CSD theory sufficiently explain the full pathogenesis of migraine attacks.

Harvard scientists Levy et al stated one year after the paper discussed above:

Epidemiologic findings, clinical data, and observations on anatomical and physiological characteristics of mast cells converge to suggest an important role of these immune cells in the pathogenesis of migraine.^[2]

In the fotopgraph after Levy (2007) mast cells in the dural space.

The link between mast cells and migraine is currently gaining much interest, as the triptanes on the market still seem not optimally fit to treat migraine sufficiently. Therefore more attention is flowing into the direction of the meningeal mast cell:

A particular class of inflammatory cells residing within the intracranial milieu, known as meningeal mast cells, was suggested to play a role in migraine pathophysiology more than five decades ago, but until recently the exact nature of their involvement remained largely unexplored. This review examines the evidence linking meningeal mast cells to migraine and highlights current experimental data implicating these immune cells as potent modulators of meningeal nociceptors' activity and the genesis of migraine pain.  ^[3]

Recently a new chapeter was openend understanding the relation between mastcells and glia:

 The brain-derived neurotrophic factor (BDNF) plays a critical role in pain hypersensitivity. BDNF is the ligand of P2X4 receptors (P2X4R) in the microglia. The causative factors involving the P2X4R over expression in the microglia remains unclear. Mast cell activation has a close relation with pain hypersensitivity. However, the underlying mechanism between mast cell activation and pain hypersensitivity is unknown.

Mast cell activation is markedly promoted the expression of P2X4R and BDNF in microglial cells, which significantly enhanced the release of BDNF from microglial cells upon exposure to adenosine triphosphate. Mast cell-derived tryptase activated PAR2 that resulted in promoting the expression of P2X4R in microglial cells. Pretreatment with antibodies against tryptase or PAR2, or using tryptase-deficient HMC-1 cells or PAR2-deficient microglial cells abolished the increase in P2X4R expression and BDNF release. Increase in mitogen activated protein kinase phosphorylation was observed in the processes of mast cell-induced BDNF release and P2X4R expression

The conclusion was that mast cell activation has the capacity to promote the expression of P2X4R and BDNF in microglial cells. ^[4]

Mast cell: a new target in migraine 

The mast cell is already a clear target for a variety of drugs, and new principles to stabilize mast cells, with a good safety profile are needed. Palmitoylethanolamide (PEA) is such a mast cell stabilizer, and has been demonstrated to be safe and effective in a variety of chronic pain states. Therefore PEA might become a new safe alternative to treat certain migraine states.^[5][6][7][8]

October 2010, Jan M. Keppel Hesselink, MD 

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