# Blood Brain Barrier and Migraine: Effect on Therapy

> **NIH NIH R01** · UNIVERSITY OF ARIZONA · 2020 · $325,134

## Abstract

Project Summary/Abstract
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 b...

## Key facts

- **NIH application ID:** 9997708
- **Project number:** 5R01NS099292-04
- **Recipient organization:** UNIVERSITY OF ARIZONA
- **Principal Investigator:** Tally Marie Milnes
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $325,134
- **Award type:** 5
- **Project period:** 2017-09-29 → 2022-06-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9997708

## Citation

> US National Institutes of Health, RePORTER application 9997708, Blood Brain Barrier and Migraine: Effect on Therapy (5R01NS099292-04). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/9997708. Licensed CC0.

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