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. 2024 May 21:15:1307319.
doi: 10.3389/fneur.2024.1307319. eCollection 2024.

A role of NLRP3 and MMP9 in migraine progression: a systematic review of translational study

Rapuru Rushendran  1 , Anuragh Singh  1 , S Ankul Singh  1 , Vellapandian Chitra  1 , Kaliappan Ilango  2
Affiliations

A role of NLRP3 and MMP9 in migraine progression: a systematic review of translational study

Rapuru Rushendran et al. Front Neurol. .

Abstract

Background: Migraines affect one billion individuals globally, with a higher occurrence among young adults and women. A significant survey in the United States indicated that 17.1% of women and 5.6% of men suffer from migraines. This study seeks to investigate the potential connection between NLRP3 and MMP9 in migraine pathology.

Methods: The research involved searching databases such as PubMed, Scopus, Science Direct, Google Scholar, and Proquest, with the search concluding on March 31, 2024. Following PRISMA guidelines, PICO data were collected, focusing exclusively on animal models induced by Nitroglycerine (10 mg/kg), while excluding clinical studies.

Results: The study, originally registered in Prospero Reg. No. CRD42022355893, conducted bias analysis using SYRCLE's RoB tool and evaluated author consensus using GraphPad v9.5.1. Out of 7,359 search results, 22 papers met the inclusion criteria. Inter-rater reliability among reviewers was assessed using Cohen's kappa statistics.

Conclusion: This review summarizes 22 preclinical studies on Nitroglycerin (NTG), NLRP3, MMP9, and related biomarkers in migraine. They reveal that NTG, especially at 10 mg/kg, consistently induces migraine-like symptoms in rodents by activating NLRP3 inflammasome and stimulating proinflammatory molecule production.

Systematic review registration: https://www.crd.york.ac.uk/prospero/, CRD42022355893.

Keywords: IL-18; IL1-β; IL1β; MMP9; NLRP3; P2X4; P2X7R; migraine.

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Conflict of interest statement

The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

Figures

Figure 1
Figure 1
Schematic representation of article screening.
Figure 2
Figure 2
The risk of bias was analysed for all the authors. The proportion of studies with a high risk of bias categorised as ‘Yes’ is indicated in orange. The blue colour represents the proportion of studies with a low risk of bias labelled as ‘No,’ while the purple colour represents the proportion of study with an unclear response to the stated issue.
Figure 3
Figure 3
Quantify agreement by kappa value of all authors. RR-KI and VC-SA reported perfect agreement and rest others showed substantial agreement.
Figure 4
Figure 4
The significance of NLRP3 and MMP9 in the context of a migraine episode involves the generation and refinement of proinflammatory signaling molecules through various receptors, including P2X7R, P2X4, PAMPs or DAMP, TLR4, IL-1β, and IL-18 receptor activation. This process triggers the release of CGRP, leading to vasoconstriction by enhancing the maturation of IL-1β. Simultaneously, an elevation in MMP9 levels results in blood–brain barrier permeability and the leakage of proteins due to vasoconstriction. This phenomenon contributes to the further production of proinflammatory molecules. Additionally, astrocyte activation plays a pivotal role in the release of excitatory neurotransmitters and other neuroinflammatory substances within the brain, collectively contributing to the onset of a migraine attack. The figure was created with BioRender.com.
Figure 5
Figure 5
Networking of migraine targets. The figure illustrating that the different proteins interlinked with NLRP3 and MMP9 in migraine attack. There are different connecting targets of NLRP3 and MMP9 are analysed by protein–protein interaction in string database that NOX4, IL1B, P2RX4, NOS2, IL18, CCL2, TRPA1, CALCA, MAP 3 K5, TXNIP etc. are connected to migraine progression.
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