Pharmacological targeting of spreading depression in migraine

Abstract

Migraine, particularly with aura, is a genetically heterogeneous disorder of ion channels, pumps or transporters associated with increased cortical excitability. Spreading depression, as one reflection of hyperexcitability, is the electrophysiological event underlying aura symptoms and a trigger for headache. Endogenous (e.g., genes and hormones) and exogenous factors (e.g., drugs) modulating migraine susceptibility have also been shown to modulate spreading depression susceptibility concordantly, suggesting that spreading depression can be a relevant therapeutic target in migraine. In support of this, several migraine prophylactic drugs used in clinical practice have been shown to suppress spreading depression susceptibility as a probable mechanism of action, despite belonging to widely different pharmacological classes. Hence, susceptibility to spreading depression can be a useful preclinical model with good positive and negative predictive value for drug screening.

Progesterone Receptor Gene (PROGINS) Polymorphism Correlates with Late Onset of Migraine

“…Further genetic association studies are imperative to understand the role of PGR in migraine physiopathology that may be useful as a biomarker for detecting asymptomatic individuals at an increased risk for migraine and for developing effective treatment strategies as well (Eikermann-Haerter et al, 2012;Nappi et al, 2013).…”

“…Considering the correlation between estrogens, CSD susceptibility, and glutamate neurotransmission, it is important to note the linear correlation we found between the copy number of T allele and the age at migraine onset in female patients affected by MwA, the migraine type most clearly characterized by a glutamatedependent cortical hyperexcitability (Eikermann-Haerter et al, 2012). In addition, it is interesting to report that previous genome-wide analysis and association studies suggested a significant association between ''PROGINS'' variant and the increase of age for menarche (Guo et al, 2006;Taylor et al, 2010).…”

“…In ovariectomized animals, CSD frequency is markedly decreased compared with normal cycling rats. Estrogens can increase the susceptibility to CSD through different mechanisms encompassing effects on glutamate neurotransmission, as well as through an increase of dendritic spines and synaptic density (Eikermann-Haerter et al, 2012). Interestingly, it has been recently demonstrated that progesterone also significantly increases CSD frequency and restores the CSD inhibition by L-kynurenine (Chauvel et al, 2013).…”

Neurovascular regulation is critical for metabolic recovery from spreading depression

“…Although many investigations have been carried out into the initiation, occurrence and spread of spreading depression, the mechanisms of ionic current flow underlying depolarization, and treatment paradigms (Pietrobon and Moskowitz, 2014), it is only recently that recording and imaging techniques have been able to confirm the occurrence of spreading depression in damaged human cortex, particularly in conditions involving trauma, subarachnoid haemorrhage, stroke, and possibly migraine headache with aura Eikermann-Haerter et al, 2012;Woitzik et al, 2013). The intense depolarization and loss of ionic gradients in large volumes of brain tissue experiencing spreading depression means that significant substrate and metabolic capacity is required to generate energy for cell recovery (Somjen, 2001).…”

“…Piilgard et al (2011) have suggested additional treatment possibilities, including cyclosporin to block mitochondrial permeability transition (to maintain metabolic function) and to enhance neurovascular coupling. Further, a number of treatments aimed at migraine episodes may also act to suppress episodes of spreading depression (Eikermann-Haerter et al, 2012). From a surgical perspective, removing damaged cortical areas in traumatic brain injury outside of eloquent regions may also reduce episodes of spreading depression and brain swelling, preventing further secondary injury .…”