Effect of activated autophagy on an animal model of vestibular migraine-like attacks

Abstract

Background

Patients with vestibular migraine (VM) experience both dizziness and headache. Our team's previous pilot study has revealed a significant increase in the concentration of the autophagic marker P62 in the blood of VM patients. This finding indicates a close association between cellular autophagic function and VM pathogenesis.

Objective

In our study, our objective was to integrate the elements of dizziness and headache, thereby constructing a rat model of vestibular migraine-like attacks (VMa) that could effectively mimic the symptoms of VM. This article will conduct an in-depth exploration into the establishment of the VMa rat model and comprehensively analyze the role of autophagy within both the VMa rat model and VM patients.

Methods

We established the VMa rat model via intraperitoneal nitroglycerin injection and 2-h variable speed rotation. Assessed VMa rats' pain sensitivity by periorbital mechanical and tail thermal pain thresholds. Evaluated their vestibular function with MS index and balance beam experiments. Measured CGRP, c-fos, P62 and LC3-II/I proteins in TCC and VN by western blot. In clinical experiments, selected same-age patients without comorbidities based on CM and VM criteria. Determined P62 and LC3-II concentrations in peripheral plasma by ELISA. Explored the therapeutic significance of blocking PI3K/AKT/mTOR pathway and autophagy agonist intervention in VM disease.

Results

First, compared VMa model rats with normal SHAM group: periorbital mechanical & tail thermal pain thresholds decreased, CGRP & c-fos expression increased in TCC & VN, MS index higher, balance beam time increased, vestibular function disturbed. LC3-II/I ratio not significantly changed but P62 expression elevated. Second, compared VM patients with normal individuals: plasma P62 concentration elevated, LC3-II/I slightly increased (not statistically significant), showing autophagy dysfunction in VM patients. Finally, in VMa rats treated with rapamycin & LY294002 for prevention: periorbital mechanical & tail thermal pain thresholds increased, MS index decreased, balance beam time shortened. CGRP & c-fos expression reduced in TCC & VN, P62 expression decreased, autophagy function normal.

Conclusions

The VMa rat model can be established by mimicking VM patients' dizziness and headache symptoms. It shows similar increased pain sensitivity, disrupted vestibular function, and autophagy dysfunction as in VM patients. Activating autophagy might provide prophylactic treatment for VM disease.