超声介导血脊髓屏障开放对肌萎缩侧索硬化症模型雌性小鼠生存和运动功能的影响。

Effect of ultrasound-mediated blood-spinal cord barrier opening on survival and motor function in females in an amyotrophic lateral sclerosis mouse model.

机构信息

Sorbonne Université, Neurosurgery Department, AP-HP, Pitié-Salpêtrière Hospital, Paris, France; Advanced Surgical Research Technology Laboratory, Paris, France; Sorbonne Université, GRC 23, Brain Machine Interface, AP-HP, Pitié-Salpêtrière Hospital, Paris, France; Sorbonne Université, Institut du Cerveau - Paris Brain Institute - ICM, Inserm, CNRS, AP-HP, Hôpital de la Pitié-Salpêtrière, Paris, France.

Sorbonne Université, Institut du Cerveau - Paris Brain Institute - ICM, Inserm, CNRS, AP-HP, Hôpital de la Pitié-Salpêtrière, Paris, France.

出版信息

EBioMedicine. 2024 Aug;106:105235. doi: 10.1016/j.ebiom.2024.105235. Epub 2024 Jul 13.

DOI:10.1016/j.ebiom.2024.105235

PMID:38996764

原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC11284947/

Abstract

BACKGROUND

Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease characterized by a progressive loss of motor neurons. The limited efficacy of recent therapies in clinical development may be linked to lack of drug penetration to the affected motor neurons due to the blood-brain barrier (BBB) and blood-spinal cord barrier (BSCB).

METHODS

In this work, the safety and efficacy of repeated short transient opening of the BSCB by low intensity pulsed ultrasound (US, sonication) was studied in females of an ALS mouse model (B6.Cg-Tg(SOD1∗G93A)1Gur/J). The BSCB was disrupted using a 1 MHz ultrasound transducer coupled to the spinal cord, with and without injection of insulin-like growth factor 1 (IGF1), a neurotrophic factor that has previously shown efficacy in ALS models.

FINDINGS

Results in wild-type (WT) animals demonstrated that the BSCB can be safely disrupted and IGF1 concentrations significantly enhanced after a single session of transient BSCB disruption (176 ± 32 μg/g vs. 0.16 ± 0.008 μg/g, p < 0.0001). Five repeated weekly US sessions performed in female ALS mice demonstrated a survival advantage in mice treated with IGF1 and US (US IGF1) compared to treatment with IGF1 alone (176 vs. 166 days, p = 0.0038). Surprisingly, this survival advantage was also present in mice treated with US alone vs. untreated mice (178.5 vs. 166.5 days, p = 0.0061). Muscle strength did not show difference among the groups. Analysis of glial cell immunoreactivity and microglial transcriptome showing reduced cell proliferation pathways, in addition to lymphocyte infiltration, suggested that the beneficial effect of US or US IGF1 could act through immune cell modulation.

INTERPRETATION

These results show the first step towards a possible beneficial impact of transient BSCB opening for ALS therapy and suggest implication of immune cells.

FUNDING

Fondation pour la Recherche Médicale (FRM). Investissements d'avenirANR-10-IAIHU-06, Société Française de Neurochirurgie (SFNC), Fond d'étude et de Recherche du Corps Medical (FERCM), Aide à la Recherche des Maladies du Cerveau (ARMC), SLA Fondation Recherche (SLAFR), French Ministry for High Education and Research (MENR), Carthera, Laboratoire de Recherche en Technologies Chirurgicales Avancées (LRTCA).

摘要

背景

肌萎缩侧索硬化症（ALS）是一种致命的神经退行性疾病，其特征是运动神经元逐渐丧失。最近在临床开发中的治疗方法效果有限，这可能与由于血脑屏障（BBB）和血脊髓屏障（BSCB）导致药物无法渗透到受影响的运动神经元有关。

方法

在这项工作中，通过低强度脉冲超声（US，声处理）反复短暂打开 BSCB 来研究雌性 ALS 小鼠模型（B6.Cg-Tg（SOD1*G93A）1Gur / J）的安全性和有效性。使用与脊髓耦合的 1MHz 超声换能器破坏 BSCB，同时和不注射胰岛素样生长因子 1（IGF1），IGF1 是一种先前在 ALS 模型中显示出疗效的神经营养因子。

结果

在野生型（WT）动物中的结果表明，BSCB 可以安全破坏，单次短暂 BSCB 破坏后 IGF1 浓度显著增加（176±32μg/g 与 0.16±0.008μg/g，p<0.0001）。在雌性 ALS 小鼠中进行的五次重复每周 US 治疗显示，与单独使用 IGF1 相比，用 IGF1 和 US 治疗（US IGF1）的小鼠具有生存优势（US IGF1 为 176 天，而单独使用 IGF1 为 166 天，p=0.0038）。令人惊讶的是，与未治疗的小鼠相比，单独使用 US 的小鼠也具有生存优势（178.5 天与 166.5 天，p=0.0061）。各组肌肉力量没有差异。对神经胶质细胞免疫反应性和小胶质细胞转录组的分析显示，细胞增殖途径减少，淋巴细胞浸润，这表明 US 或 US IGF1 的有益作用可能通过免疫细胞调节起作用。