Defining mechanisms and new treatments for headache in raised intracranial pressure

Grech, Olivia (2024). Defining mechanisms and new treatments for headache in raised intracranial pressure. University of Birmingham. Ph.D.

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Abstract

Headache disorders are common and debilitating neurological conditions. While treatments can alleviate pain, our understanding of the mechanisms triggering attacks is incomplete. Evidence suggests that metabolic dysfunction may play a role in headache development and susceptibility, with fasting being a suspected migraine trigger, highlighting the importance of glucose metabolism. Identifying these energy-related mechanisms could lead to targeted interventions. Elevated intracranial pressure (ICP) can also cause headaches that are migraine-like, as seen in idiopathic intracranial hypertension (IIH), which additionally features metabolic disturbances. Although migraine treatments have exhibited some efficacy for raised ICP headaches, there is a lack of targeted therapies for IIH-related headaches, and the underlying mechanisms are poorly understood.
Cortical spreading depression (CSD) is a pivotal mechanism involved in migraine and has been established as energetically demanding. This thesis explored the metabolic consequences of CSD by analysing calcium signalling, mitochondrial activity, and metabolite profiles in an ex vivo acute brain slice model. This thesis also investigated the influence of ICP on headache mechanisms including CSD using a rodent model of raised ICP. Additionally, it examined the impact of reducing ICP with glucagon-like peptide-1 (GLP-1) receptor agonism and blocking calcitonin gene-related peptide (CGRP), a key factor in migraine.
Brain slices showed astrocytic calcium movement and markers of increased aerobic and anaerobic glycolysis in response to CSD. When challenged with glucose deprivation, mitochondrial activity was downregulated, potentially indicating exhaustion. Interestingly, there was evidence of metabolic adaptability in glucose absence, suggesting the utilization alternative energetic pathways and substrates under metabolically stressful conditions. These findings enhance the understanding of the role of metabolism in CSD but also unveil altered energetic pathways, thereby identifying potential targets for therapeutic interventions.
The rodent model of raised ICP identified altered pain behaviour (indicative of changes in trigeminal sensitivity), disrupted cortical blood flow (CBF) and CSD responses. GLP-1 receptor agonism reduced ICP which was associated with prevention of pain behaviours and demonstrated restored cortical and CBF CSD responses. CGRP receptor antagonism ameliorated cranial pain behaviour, indicating a role for CGRP in driving pain responses in elevated ICP. Reduction of ICP through GLP-1R agonism and nociception attenuation via CGRP antagonism could represent potential therapeutic approaches. This pre-clinical evidence highlights the efficacy of therapeutics in managing headache behaviours and pathways, essential for guiding future clinical trials given the lack of targeted therapies for elevated ICP.

Type of Work:

Thesis (Doctorates > Ph.D.)

Award Type:

Doctorates > Ph.D.

Supervisor(s):