倍他司汀通过诱导多种 CTRP 家族成员的产生和激活 ERK1/2-AKT/PPARγ 通路来缓解良性阵发性位置性眩晕（BPPV）。
Betahistine alleviates benign paroxysmal positional vertigo (BPPV) through inducing production of multiple CTRP family members and activating the ERK1/2-AKT/PPARy pathway.
机构信息
Department of Neurology, The Second Affiliated Hospital of Xi'an Medical College, Xi'an, 710038, China.
Shaanxi Normal University Hospital, Xi'an, 710119, China.
出版信息
Biol Res. 2022 Apr 4;55(1):16. doi: 10.1186/s40659-022-00385-3.
BACKGROUND
Betahistine is a clinical medication for the treatment of benign paroxysmal positional vertigo (BPPV). Otolin, a secreted glycoprotein with a C-terminal globular domain homologous to the immune complement C1q, has been identified as a biomarker for BPPV. However, the role of complement C1q/TNF-related proteins (CTRPs) with a C-terminal globular domain in BPPV is unclear, so we explored the change of CTRPs in betahistine treated BPPV.
METHODS
We treated BPPV patients with Betahistine (12 mg/time, 3 times/day) for 4 weeks and observed the clinical efficacy and the expression of CTRP family members in BPPV patients. Then, we constructed a vertigo mice model of vestibular dysfunction with gentamicin (150 mg/Kg) and a BPPV model of Slc26a4 mutant mice. Adenoviral vectors for CTRP expression vector and small interfering RNA were injected via the intratympanic injection into mice and detected the expression of CTRP family members, phosphorylation levels of ERK and AKT and the expression of PPARγ. In addition, we treated mice of vestibular dysfunction with Betahistine (10 mg/Kg) and/or ERK inhibitor of SCH772984 (12 mg/Kg) and/or and PPARγ antagonist GW9662 (1 mg/Kg) for 15 days, and evaluated the accuracy of air righting reflex, the time of contact righting reflex and the scores of head tilt and swimming behavior.
RESULTS
After treatment with Betahistine, the residual dizziness duration and the score of the evaluation were reduced, and the expression of CTRP1, 3, 6, 9 and 12 were significantly increased in BPPV patients. We also found that Betahistine improved the accuracy of air righting reflex, reduced the time of contact righting reflex and the scores of head tilt and swimming behavior in gentamicin-treated mice and Slc26a4 mutant mice. The expression levels of CTRP1, 3, 6, 9 and 12, phosphorylation levels of ERK and AKT, and PPARγ expression were significantly increased, and the scores of head tilt and swimming behavior were decreased in vestibular dysfunction mice with overexpression of CTRPs. Silencing CTRPs has the opposite effect. SCH772984 reversed the effect of Betahistine in mice with vestibular dysfunction.
CONCLUSION
Betahistine alleviates BPPV through inducing production of multiple CTRP family members and activating the ERK1/2-AKT/PPARy pathway.
背景
倍他司汀是一种治疗良性阵发性位置性眩晕（BPPV）的临床药物。Otolin 是一种分泌性糖蛋白，其 C 端球状结构域与免疫补体 C1q 同源，已被鉴定为 BPPV 的生物标志物。然而，具有 C 端球状结构域的补体 C1q/TNF 相关蛋白（CTRPs）在 BPPV 中的作用尚不清楚，因此我们探讨了倍他司汀治疗 BPPV 时 CTRPs 的变化。
方法
我们用倍他司汀（12mg/次，3 次/天）治疗 BPPV 患者 4 周，观察临床疗效和 BPPV 患者中 CTRP 家族成员的表达。然后，我们用庆大霉素（150mg/Kg）构建前庭功能障碍小鼠模型和 Slc26a4 突变小鼠的 BPPV 模型。通过鼓室内注射腺病毒载体表达载体和小干扰 RNA 转染小鼠，检测 CTRP 家族成员的表达、ERK 和 AKT 的磷酸化水平以及 PPARγ 的表达。此外，我们用倍他司汀（10mg/Kg）和/或 ERK 抑制剂 SCH772984（12mg/Kg）和/或 PPARγ 拮抗剂 GW9662（1mg/Kg）治疗前庭功能障碍小鼠 15 天，评估空气定向反射的准确性、接触定向反射的时间和头倾斜和游泳行为的评分。
结果
用倍他司汀治疗后，残余头晕持续时间和评估评分降低，BPPV 患者中 CTRP1、3、6、9 和 12 的表达明显增加。我们还发现，倍他司汀改善了庆大霉素处理小鼠和 Slc26a4 突变小鼠的空气定向反射准确性，减少了接触定向反射时间和头倾斜及游泳行为评分。在过表达 CTRPs 的前庭功能障碍小鼠中，CTRP1、3、6、9 和 12 的表达水平、ERK 和 AKT 的磷酸化水平以及 PPARγ 的表达均显著增加，头倾斜和游泳行为评分降低。沉默 CTRPs 则有相反的效果。SCH772984 逆转了前庭功能障碍小鼠中倍他司汀的作用。
结论
倍他司汀通过诱导多种 CTRP 家族成员的产生和激活 ERK1/2-AKT/PPARγ 通路来缓解 BPPV。
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