New Research Reveals the Mechanism of Atogepant in Migraine Prevention

Background

Migraine is a common and highly disruptive neurological disorder affecting millions of people worldwide. Calcitonin Gene-Related Peptide (CGRP) is believed to play a key role in the pathophysiology of migraine. CGRP released from sensory trigeminal ganglia neurons in areas such as the dura mater and choroid plexus can induce migraine-like headaches. Furthermore, middle meningeal artery dilation is one of the hallmark manifestations of CGRP-triggered migraines (Hansen et al., 2010). In recent years, drugs that inhibit CGRP signaling, such as CGRP monoclonal antibodies and CGRP receptor antagonists, have shown effective results in preventing migraines (Goadsby et al., 2017; Lipton et al., 2019).

Research Introduction

This study was conducted by Agustin Melo-Carrillo and colleagues from the research team at Beth Israel Deaconess Medical Center and Harvard Medical School, in collaboration with Allergan, an Abbvie Company. The research paper was published on February 27, 2024, in the Oxford University Press journal “Brain”. The study aimed to explore the mechanism of action of the small molecule CGRP receptor antagonist atogepant in migraine prevention, particularly its effect on the activation and sensitization of high-threshold (HT) and wide-dynamic-range (WDR) central dura-sensitive trigeminal neurons induced by cortical spreading depression (CSD).

Research Methods

The experiment used 40 male Sprague-Dawley rats and was approved by the Animal Care Committee of Beth Israel Deaconess Medical Center and Harvard Medical School. The experimental design was as follows:

1. Preoperative preparation: Rats were intravenously injected and anesthetized, then underwent craniotomy to expose the left transverse sinus and specific areas of the spinal cord for electrophysiological recording.
2. Atogepant injection: Atogepant or vehicle was administered intravenously 1 hour before CSD induction.
3. Neuronal recording: Tungsten microelectrodes were used to record single-unit activity in the spinal trigeminal nucleus. The recording period included a baseline period, 1 hour after drug injection, and 2 hours after CSD induction.
4. CSD induction: CSD was induced by needle prick while recording brain electrical activity. CSD is a cortical event associated with migraine attacks.
5. Data analysis: Statistical analysis of neuronal responses to CSD and mechanical stimulation, including HT and WDR neurons. Non-parametric repeated measures and Fisher’s exact test were used for statistical analysis.

Research Results

The results showed that atogepant pretreatment significantly inhibited the activation and sensitization of high-threshold (HT) neurons but had no significant inhibitory effect on the activation of wide-dynamic-range (WDR) neurons.

• High-threshold (HT) neurons: In the control group, CSD triggered activation in 80% (⁸⁄₁₀) of HT neurons, while in the treatment group, only 10% (¹⁄₁₀) of HT neurons were activated (p = 0.005). Further analysis showed that the spontaneous firing rate of HT neurons in the control group significantly increased at 1 and 2 hours post-CSD, while there was no significant change in the treatment group.
• Wide-dynamic-range (WDR) neurons: In the control group, CSD triggered activation in 70% (⁷⁄₁₀) of WDR neurons, compared to 50% (⁵⁄₁₀) in the treatment group (p = 0.64). Although atogepant could not completely prevent WDR neuron activation, it significantly suppressed their mechanical stimulation response.

Discussion and Conclusion

This study demonstrates that atogepant can prevent the activation and sensitization of high-threshold (HT) neurons by selectively inhibiting thinly myelinated Aδ fibers. This selective inhibitory effect may be attributed to the high expression of CGRP receptors on thinly myelinated Aδ fibers and HT neurons. Additionally, atogepant weakens central sensitization induced by anti-CGRP drugs in the trigeminal nucleus by inhibiting CGRP-mediated slow synaptic transmission.

Atogepant has a lower inhibitory effect on wide-dynamic-range (WDR) neurons, possibly due to its lesser impact on unmyelinated C fibers. However, atogepant can prevent central sensitization of WDR neurons by reducing slow transmission input from dural C fibers.

Research Highlights

• High selectivity: Atogepant significantly inhibits HT neuron activation through selective action on thinly myelinated Aδ fibers, which is a key mechanism in migraine prevention.
• Prevention of central sensitization: Although atogepant has no significant effect on WDR neuron activation, it effectively prevents central sensitization by inhibiting slow transmission input mediated by C fibers.
• Clinical application prospects: These findings expand our understanding of atogepant’s mechanism of action in migraine, highlighting its potential value in preventing migraine attacks and central sensitization.

This study, through detailed experimental design and analysis, reveals the complex mechanism of action of atogepant in migraine prevention, providing strong support for future clinical applications.

Research Limitations and Future Directions

Although the current study was conducted only in male rats, future research should validate the current results in female rats. Additionally, more clinical trials are needed to confirm the actual efficacy of atogepant in human migraine patients.