A Preliminary Study of Effect of Melatonin on Inflammation and Hypoxia‐Related Factors in a Mouse Model of Elastase‐Induced Intracranial Aneurysm

TL;DR

This study explores how melatonin may reduce inflammation and hypoxia in a mouse model of intracranial aneurysms, suggesting potential therapeutic benefits.

Contribution

The study is the first to investigate melatonin's effects on inflammation and hypoxia-related factors in an elastase-induced intracranial aneurysm mouse model.

Findings

Melatonin reduced inflammation markers like IL-1β, IL-6, and TNF-α in aneurysm mice.

Melatonin improved vascular wall integrity and reduced apoptosis in the aneurysm model.

Melatonin modulated hypoxia-related genes and immune cell activity in intracranial aneurysms.

Abstract

Intracranial aneurysms (IAs) are relatively common cerebrovascular anomalies. Melatonin could modulate inflammatory and offers neuroprotective effects, and its role in IA has not been fully elucidated.

An elastase‐induced IA mouse model was constructed and melatonin (150 mg/kg) was administered to investigate its therapeutic effects on IA. Aneurysm formation was observed by bromophenol blue gelatin perfusion, and the pathology changes in IA mice were examined using hematoxylin‐eosin (HE) staining. The potential mechanisms of melatonin treatment of IA were explored using western blot, enzyme‐linked immunosorbent, real‐time qPCR, immunohistochemistry, and flow cytometry. An H2O2‐reduced human brain vascular smooth muscle cells (HBVSMC) injury model was also constructed.

The formation of aneurysms was observed in the circle of Willis in the IA mice. Melatonin treatment alleviated the thinning of blood vessel walls and disruption of the internal elastic lamina in IA mice. The levels of Bcl‐2 were significantly increased and Bax and cleaved caspase‐3 were decreased in IA mice with melatonin treatment, suggesting reduced apoptosis. Furthermore, melatonin reduced levels of interleukin (IL)‐1β, IL‐6, and tumor necrosis factor‐alpha (TNF‐α) in IA mice. The H2O2‐reduced HBVSMCs model showed consistent results. Melatonin reduced levels of krüppel‐like factor 6 (KLF6) in IA mice. Importantly, melatonin significantly reduced levels of regulatory T cells (Treg), hypoxia‐inducible factor (HIF)‐1α, nuclear factor interleukin 3‐regulated (NFIL3), TCDD‐inducible poly‐ADP‐ribose polymerase (TIPARP), and increased levels of monocytes in IA mice.

Melatonin mitigates IA injury by modulating immune cells and hypoxia‐related factors. These findings provide an exploratory foundation for therapeutic strategies in IA.

We established a mouse model of elastase‐induced intracranial aneurysms (IAs) to investigate the therapeutic potential of melatonin. Our findings suggest that melatonin may influence the formation and progression of IA by improving IA‐associated histological changes, regulating immune and inflammatory responses, and modulating the expression of hypoxia‐related genes. However, further studies are needed to optimize dosing, determine the ideal treatment timing, and assess specificity for clinical translation. Some images were obtained from SciDraw (https://doi.org/10.5281/zenodo.3925901, https://doi.org/10.5281/zenodo.3926245).

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