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Abstract Details

Raised Intracranial Pressure Alters Cortical Vascular Function And Cephalic Allodynia.
Headache
S35 - Hot Topics in Headache (2:00 PM-2:12 PM)
006
Cortical vascular changes, particularly spreading depolarization, signal altered excitability in neurological conditions with raised ICP. While raised ICP is linked to cephalic pain, the relationship between ICP, cortical neurovascular changes, and allodynia remains unclear.
To evaluate the relationship between cephalic pain and altered cerebral hemodynamics in raised intracranial pressure (ICP). We investigated whether reducing ICP with a glucagon-like peptide-1 receptor agonist (GLP-1RA) could alleviate the cephalic pain and examined the role of calcitonin gene-related peptide (CGRP) associated with elevated ICP.
In a rat model of raised ICP, mechanical thresholds were measured alongside steady-state potential and cerebral blood flow (CBF) responses to spreading depolarisation. Ex-vivo nuclear magnetic resonance spectroscopy evaluated energetic substrates. Daily injection of GLP-1RA and CGRP receptor antagonist were administered, and measurements were repeated.

Kaolin increased ICP [median (range) 15.96mmHg(8.97) n=8, controls:6.02mmHg(1.79) n=6 p=0.0007] and reduced mechanical thresholds (mean (SD) hind paw baseline:5.78g(2.81), day 7:3.34g(2.22) p<0.001, periorbital baseline:6.13g(2.07), day 7:2.35g(1.91) n=12 p<0.001). Spreading depolarisation responses were altered [repolarisation duration raised ICP:1824.26s(3499.54) n=12, controls:86.96s(140.05) n=9 p<0.0001] and CBF change was reduced (raised ICP:85.55%(30.84) n=9, controls:217.64%(37.70) n=8 p<0.0001). Substrates for cellular energetics were depleted in animals with raised ICP (ADP p=0.009, ATP p=0.018, NAD+ p=0.011).

GLP-1RA lowered ICP (GLP-1RA: 9.74mmHg(6.09) n=19, vehicle: 18.27mmHg(6.67) n=16 p=0.004) and rescued changes in mechanical thresholds. GLP-1RA recovered spreading depolarisation responses [repolarisation duration GLP-1RA: 177.55s(562.88) n=7, vehicle: 800.85s(1988.67) n=6 p=0.002]. In the setting of raised ICP, CGRP receptor antagonism prevented changes in periorbital mechanical thresholds.
Animals with raised ICP showed disrupted neurovascular responses, lower pain thresholds, and depleted energy substrates. GLP-1RA reduced ICP, improving these measures, while CGRP receptor antagonism alleviated cephalic pain. These findings suggest that reducing ICP may relieve cephalic pain and targeting the CGRP pathway could be a therapeutic strategy for headache in raised ICP conditions.
Authors/Disclosures
Olivia Grech, PhD
PRESENTER 		Dr. Grech has received research support from Sir Jules Thorn.
Eloisa Rubio Beltran, PhD Dr. Rubio Beltran has nothing to disclose.
Emily C. Stanyer, PhD Dr. Stanyer has received personal compensation in the range of $500-$4,999 for serving as a Consultant for Lindus Health Ltd.
Alejandro Labastida Ramirez, MD, PhD Dr. Labastida Ramirez has nothing to disclose.
Gareth Lavery, PhD Prof. Lavery has nothing to disclose.
Lisa Hill, PhD Dr. Hill has nothing to disclose.
Philip R. Holland, PhD Dr. Holland has received personal compensation in the range of $500-$4,999 for serving on a Speakers Bureau for Pfizer. Dr. Holland has received personal compensation in the range of $500-$4,999 for serving on a Speakers Bureau for Pfizer. Dr. Holland has received personal compensation in the range of $500-$4,999 for serving on a Speakers Bureau for Abbvie. The institution of Dr. Holland has received research support from Eli lilly and Co. The institution of Dr. Holland has received research support from Kallyope.
Alexandra J. Sinclair, MD Dr. Sinclair has received personal compensation for serving as an employee of Invex Therapeutics. Dr. Sinclair has received personal compensation in the range of $500-$4,999 for serving as a Consultant for Vertex. Dr. Sinclair has received personal compensation in the range of $500-$4,999 for serving as a Consultant for Orion Pharma. Dr. Sinclair has stock in Invex Therapeutics (unclear what the company is developing but no longer working in the field of Idiopathic Intracranial Hypertension). The institution of Dr. Sinclair has received research support from DOD. The institution of Dr. Sinclair has received research support from MOD.