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Dysfunction of Sodium Homeostasis in Migraine

Award Number: R01NS072497
ORGANIZATION: NATIONAL INSTITUTE OF NEUROLOGICAL DISORDERS AND STROKE
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 08/01/2011
PERIOD OF PERFORMANCE END DATE: 06/30/2024

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Dysfunction of Sodium Homeostasis in Migraine - From 1990-2016, migraine was in the top 5 leading causes of “years lived with disability”. Even with good diagnosis and treatment (triptans, gepants, ditans, and glurants), many remain disabled. The prevailing trigeminovascular theory points to a combination of neuronal and vascular components, but the fundamental mechanism for why and when a migraine starts is still unclear. Our broad premise is that the varied triggers that initiate migraine, or medications that suppress it, act through a common pathway; finding this mechanism will offer a more cohesive strategy to treat migraine, complimentary to the empirical approach. We proposed a common pathway of altered cerebrospinal fluid (CSF) sodium concentration [Na+] in our recent RO1 NS072497 project: “Dysfunction of sodium homeostasis in a rat migraine model.” In this nitroglycerin (NTG) triggered model, we demonstrated [Na+] increased mainly in the ventricular CSF, using 23Na MRI. In humans, we found higher CSF [Na+] during migraine, which has been validated in an independent study of migraine, recently reported and also using 23Na MRI. To explore the relationship of increased [Na+] and hypersensitivity in migraine, we demonstrated that higher extracellular [Na+] increases neuronal excitability in simulations, in neural cells, and in vivo; that the effects can be mimicked by increasing [Na+] directly in the ventricles; and that NTG effects can be prevented by Na,K-ATPase inhibition targeted to the choroid plexus (CP) epithelium. These results suggest nociception arises from neurons exposed to higher extracellular [Na+] along the path of ventricular and subdural CSF. Our central hypothesis is that triggers of migraine alter CP Na,K-ATPase activity and CSF [Na+] homeostasis, which changes neuronal excitability and initiates migraine. Our hypothesis predicts that the most successful treatments will correct the altered Na,K-ATPase homeostasis. We will validate and examine the CP Na,K-ATPase activity and change in CSF [Na+] in the rat NTG model (Aim 1a), examine how the CP is altered (Aim 1b), and map how the CSF and brain tissue [Na+] change (Aims 1c & d). We will measure metabolic and trigemonovascular changes in brain tissue (Aim 1e) and examine how these features relate to CSF [Na+] and CP Na,K-ATPase activity. Aim 2 will test if typical migraine medications (sumatriptan and telcagepant) rescue the NTG-triggered nociception. These studies have the potential to support repurposing of digoxin at a low and safe dose (1/100 the dose currently used in cardiology) to inhibit the CP Na, K-ATPase and prevent surges in CSF [Na+]. These experiments will justify future efforts to optimize new modulators to regulate the CP Na,K-ATPase and CSF [Na+] biomarkers. The potential to improve brain homeostasis by adjusting CP and CSF [Na+] biomarkers may extend to other fluctuating disorders, such as migraine comorbid pain and mood conditions.


Issue Date FY	Funding FY	Legal Entity Name	Legal Entity Address	Legal Entity City	Legal Entity State	Legal Entity Zip Code	Legal Entity COUNTY	Legal Entity COUNTRY	Assistance Listing	Award Code	Budget Year	Action Date	Action Type	Action Amount

Issue Date FY: 2023 ( Subtotal = $596,921 )
2023	2023	HUNTINGTON MEDICAL RESEARCH INSTITUTES	686 S FAIR OAKS AVE	PASADENA	CA	91105	LOS ANGELES	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	10	7/5/2023	NON-COMPETING CONTINUATION	$596,921
														Subtotal = $596,921

Issue Date FY: 2022 ( Subtotal = $609,180 )
2022	2022	HUNTINGTON MEDICAL RESEARCH INSTITUTES	686 S FAIR OAKS AVE	PASADENA	CA	91105	LOS ANGELES	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	9	8/17/2022	NON-COMPETING CONTINUATION	$609,180
														Subtotal = $609,180

Issue Date FY: 2021 ( Subtotal = $620,431 )
2021	2021	HUNTINGTON MEDICAL RESEARCH INSTITUTES	686 S FAIR OAKS AVE	PASADENA	CA	91105	LOS ANGELES	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	8	7/16/2021	NON-COMPETING CONTINUATION	$620,431
2021	2021	HUNTINGTON MEDICAL RESEARCH INSTITUTES	686 S FAIR OAKS AVE	PASADENA	CA	91105	LOS ANGELES	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	001	8	8/27/2021	NON-COMPETING CONTINUATION	$0
														Subtotal = $620,431

Issue Date FY: 2020 ( Subtotal = $632,090 )
2020	2020	HUNTINGTON MEDICAL RESEARCH INSTITUTES	686 S FAIR OAKS AVE	PASADENA	CA	91105	LOS ANGELES	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	7	6/25/2020	NON-COMPETING CONTINUATION	$632,090
														Subtotal = $632,090

Issue Date FY: 2019 ( Subtotal = $675,437 )
2019	2019	HUNTINGTON MEDICAL RESEARCH INSTITUTES	686 S FAIR OAKS AVE	PASADENA	CA	91105	LOS ANGELES	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	001	6	6/13/2019	COMPETING CONTINUATION	$10,680
2019	2019	HUNTINGTON MEDICAL RESEARCH INSTITUTES	686 S FAIR OAKS AVE	PASADENA	CA	91105	LOS ANGELES	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	6	6/3/2019	COMPETING CONTINUATION	$664,757
														Subtotal = $675,437

Issue Date FY: 2018 ( Subtotal = -$10 )
2018	2015	HUNTINGTON MEDICAL RESEARCH INSTITUTES	686 S FAIR OAKS AVE	PASADENA	CA	91105	LOS ANGELES	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	5	12/19/2017	NON-COMPETING CONTINUATION	-$10
														Subtotal = -$10

Issue Date FY: 2015 ( Subtotal = $338,625 )
2015	2015	PASADENA FOUNDATION FOR MEDICAL RESEARCH	99 NORTH EL MOLINO AVENUE	PASADENA	CA	91101	LOS ANGELES	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	5	7/10/2015	NON-COMPETING CONTINUATION	$338,625
														Subtotal = $338,625

Issue Date FY: 2014 ( Subtotal = $335,238 )
2014	2014	PASADENA FOUNDATION FOR MEDICAL RESEARCH	99 NORTH EL MOLINO AVENUE	PASADENA	CA	91101	LOS ANGELES	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	4	9/5/2014	NON-COMPETING CONTINUATION	$335,238
														Subtotal = $335,238

Issue Date FY: 2013 ( Subtotal = $326,774 )
2013	2013	PASADENA FOUNDATION FOR MEDICAL RESEARCH	99 NORTH EL MOLINO AVENUE	PASADENA	CA	91101	LOS ANGELES	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	3	8/15/2013	NON-COMPETING CONTINUATION	$326,774
														Subtotal = $326,774

Issue Date FY: 2012 ( Subtotal = $338,625 )
2012	2012	PASADENA FOUNDATION FOR MEDICAL RESEARCH	99 NORTH EL MOLINO AVENUE	PASADENA	CA	91101	LOS ANGELES	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	2	7/24/2012	NON-COMPETING CONTINUATION	$338,625
														Subtotal = $338,625

Issue Date FY: 2011 ( Subtotal = $338,625 )
2011	2011	PASADENA FOUNDATION FOR MEDICAL RESEARCH	99 NORTH EL MOLINO AVENUE	PASADENA	CA	91101	LOS ANGELES	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	1	6/28/2011	NEW	$338,625
														Subtotal = $338,625

Grand Total All Awards = $4,811,936

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Dysfunction of Sodium Homeostasis in Migraine

Award Number: R01NS072497

ORGANIZATION: NATIONAL INSTITUTE OF NEUROLOGICAL DISORDERS AND STROKE

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)

PERIOD OF PERFORMANCE START DATE: 08/01/2011

PERIOD OF PERFORMANCE END DATE: 06/30/2024

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