Molecular and Cellular Neurobiology of Spreading Depolarization/Depression and Migraine: A Narrative Review

Abstract

Migraine is a prevalent neurological disorder, particularly among individuals aged 20-50 years, with significant social and economic impacts. Despite its high prevalence, the pathogenesis of migraine remains unclear. In this review, we provide a comprehensive overview of cortical spreading depolarization/depression (CSD) and its close association with migraine aura, focusing on its role in understanding migraine pathogenesis and therapeutic interventions. We discuss historical studies that have demonstrated the role of CSD in the visual phenomenon of migraine aura, along with modern imaging techniques confirming its propagation across the occipital cortex. Animal studies are examined to indicate that CSD is not exclusive to migraines; it also occurs in other neurological conditions. At the cellular level, we review how CSD is characterized by ionic changes and excitotoxicity, leading to neuronal and glial responses. We explore how CSD activates the trigeminal nervous system and upregulates the expression of calcitonin gene-related peptides (CGRP), thereby contributing to migraine pain. Factors such as genetics, obesity, and environmental conditions that influence the CSD threshold are discussed, suggesting potential therapeutic targets. Current treatments for migraine, including prophylactic agents and CGRP-targeting drugs, are evaluated in the context of their expected effects on suppressing CSD activity. Additionally, we highlight emerging therapies such as intranasal insulin-like growth factor 1 and vagus nerve stimulation, which have shown promise in reducing CSD susceptibility and frequency. By elucidating the molecular and cellular mechanisms of CSD, this review aims to enhance the understanding of migraine pathogenesis and support the development of targeted therapeutic strategies.

Keywords: CGRP; CSD; intranasal insulin-like growth factor 1; migraine; trigeminal nervous system; vagus nerve stimulation.

Figure 1

Microglial activation and proinflammatory cytokines. Microglia in the TNC release inflammatory factors and neuromodulators through receptors [32].

Figure 2

KCl-induced rat CSD model. In each rat, a tracheostomy is performed with controlled ventilation and under intraperitoneal anesthesia. After catheterization of the right femoral artery, the heart rate and mean arterial blood pressure are measured through a pressure transducer. A laser-Doppler probe is placed in the cerebral cortex through a left bone fenestration located 2 mm posterior and 2 mm left to the bregma to measure the CBF. A platinum electrode coated with chloroplatinic acid is used to measure the direct current (DC) potential, which is inserted through a left bone fenestration located 2 mm posterior and 4 mm lateral (left) to the bregma. The Ag/AgCl reference electrode is inserted into the temporal muscle. The potential between a platinum electrode and an Ag/AgCl electrode placed in the temporal muscle is recorded during the experiment. One bone fenestration is opened at a site 7 mm posterior and 3 mm lateral (left) to the bregma to apply the KCl solution. Thirty minutes to an hour of stable potential is allowed after insertion of the DC potential electrode, and then a 1.0 M KCl solution is applied through the bone fenestration to the cortical surface to induce CSD.

Figure 3

Changes in CSD due to constitutional factors (obesity). Zucker fatty rats (ZF rats) are homozygous for a mutated leptin receptor gene (fa gene) and show signs of obesity at 4 weeks of age, presenting a clear obese phenotype compared to normal rats (photo left: Sprague-Dawley rats; SD rats) (A). The number of CSDs in the ZF rat is significantly higher than in the Zucker lean rat, which does not have the gene mutation (B). * p < 0.01. Open circles represent lean rats, and closed circles represent fatty rats. Data from Kitamura et al. [41].

Figure 4

Changes in CSD due to environmental factors (temperature). When CSD is induced in rats whose body temperature (BT) has increased in a high-temperature (y) environment, the frequency of CSD increases significantly after the BT has increased (average BT, 40.4 °C) compared to before the BT increased (average BT, 36.4 °C). ** p < 0.001. Data from Kitamura et al. [45].