The Blood-Brain Barrier (BBB) comprises a physical and enzymatic interface between the CNS and the peripheral circulation. Communication between the CNS and vasculature is mediated through what has been termed the neurovascular unit (NVU), a highly dynamic structure. Migraine with aura is a multiphase, neurological disorder that affects 32 million Americans (14.2% of US adults), with an estimated annual cost of 17 billion dollars in the United States, that is characterized by excruciating pain and cortical dysfunction (i.e. cortical spreading depression, CSD). Both CSD and pain weaken the integrity of the BBB. A clear comprehension of biological mechanisms regulating migraine-induced alterations of the BBB is vital to understand the efficacy of antimigraine drugs during migraine. In response to PA-14-068 (Neurobiology of Migraine), investigating changes in BBB permeability (i.e. blood to CNS uptake of brain impermeant compounds) and tight junction composition (i.e., occludin, claudins, etc.) will enable an improved understanding of the role of the BBB in the development of episodic migraine. Disruption of the BBB by pain and CSD may alter analgesic efficacy or CNS toxicity of anti-migraine therapeutics, including first-line therapies like triptan compounds. Elucidating how these migraine features (i.e., pain, CSD) contribute to the functional expression of drug transporters (i.e., organic anion transporting polypeptides (OATPs) and Na+-H+ exchangers (NHEs)) may uncover mechanisms required for triptan analgesia at varying stages of migraine (prodromal, headache and postdrome phases) and lead to the identification of novel therapeutic strategies to treat migraine. Completion of these studies will advance our understanding of BBB integrity during episodic migraine and determine how CNS uptake of antimigraine therapeutics is regulated during attacks. Our preliminary data strongly suggest that the BBB integrity is dynamically compromised with migraine progression which, in turn, alters antimigraine medication blood to CNS uptake. We demonstrate that dural pinprick cortical KCl in freely moving, non-anesthetized female rats: 1) induces CSD and 2) induces long-lasting periorbital allodynia and head-tucking behavior. Moreover, we show evidence supporting that BBB integrity changes after dural pinprick KCl including: 3) enhanced whole brain uptake of 14C-sucrose, Evans? Blue Albumin and 3H- sumatriptan; 4) increased protein expression of OATP1A4, a transporter implicated in CNS uptake of numerous medications; and 5) decreased levels of NHE1 protein, a proton exchanger, as compared to controls; these may alter sumatriptan uptake kinetics. These preliminary findings led to our hypothesis that dysregulation of BBB integrity is driven by the different migraine phases increasing the severity and duration of headache while regulating anti-migraine medication blood-to-CNS uptake to mitigate the disorder.
The aims of this grant will be investigated using a combination of electrophysiological, behavioral measurements, in situ perfusion, and molecular techniques established and working in our laboratories. Specifically Aim 1 proposes studies to determine the BBB integrity, including permeability and molecular composition, during the three phases of migraine (prodromal, headache and postdrome phases), while Aim 2 studies will elucidate the CNS uptake of antimigraine agents during migraine. Completed studies will address significant gaps in our knowledge regarding BBB integrity during episodic migraine and CNS uptake of antimigraine therapeutics to aid in the treatment of patients suffering from migraine.
The Blood-Brain Barrier (BBB) comprises a physical and enzymatic interface between the CNS and the peripheral circulation. Migraine with aura is a multiphase, neurological disorder that affects 32 million Americans. Two features of migraine, CSD and pain, weaken the integrity of the BBB. This grant proposal will advance our understanding of BBB integrity during episodic migraine and determine how CNS uptake of antimigraine therapeutics is regulated during attacks. These findings will directly impact nearly 14.2 % of the US population by determining BBB mechanisms essential to headache analgesia at varying stages of migraine (prodrome, headache and postdrome phases) and lead to the identification of novel therapeutic strategies to optimally treat migraine.
| Sandweiss, Alexander J; Cottier, Karissa E; McIntosh, Mary I et al. (2017) 17-?-Estradiol induces spreading depression and pain behavior in alert female rats. Oncotarget 8:114109-114122 |
