Matsushita Masaki, Mishima Kenichi, Esaki Ryusaku, Ishiguro Naoki, Ohno Kinji, Kitoh Hiroshi
Division of Neurogenetics, Center for Neurological Diseases and Cancer, and.
Department of Orthopaedic Surgery, Nagoya University Graduate School of Medicine, Nagoya, Japan.
J Neurosurg Pediatr. 2017 Jan;19(1):91-95. doi: 10.3171/2016.7.PEDS16199. Epub 2016 Oct 21.
OBJECTIVE Achondroplasia (ACH) is the most common short-limbed skeletal dysplasia caused by gain-of-function mutations in the fibroblast growth factor receptor 3 (FGFR3) gene. Foramen magnum stenosis (FMS) is one of the serious neurological complications in ACH. Through comprehensive drug screening, the authors identified that meclozine, an over-the-counter drug for motion sickness, inhibited activation of FGFR3 signaling. Oral administration of meclozine to the growing ACH mice promoted longitudinal bone growth, but it did not prevent FMS. In the current study, the authors evaluated the effects of maternal administration of meclozine on FMS in ACH mice. METHODS The area of the foramen magnum was measured in 17-day-old Fgfr3 mice and wild-type mice using micro-CT scanning. Meclozine was administered to the pregnant mice carrying Fgfr3 offspring from embryonic Day (ED) 14.5 to postnatal Day (PD) 4.5. Spheno-occipital and anterior intraoccipital synchondroses were histologically examined, and the bony bridges were scored on PD 4.5. In wild-type mice, tissue concentrations of meclozine in ED 17.5 fetuses and PD 6.5 pups were investigated. RESULTS The area of the foramen magnum was significantly smaller in 17-day-old Fgfr3 mice than in wild-type mice (p < 0.005). There were no bony bridges in the spheno-occipital and anterior intraoccipital synchondroses in wild-type mice, while some of the synchondroses prematurely closed in untreated Fgfr3 mice at PD 4.5. The average bony bridge score in the cranial base was 7.053 ± 1.393 in untreated Fgfr3 mice and 6.125 ± 2.029 in meclozine-treated Fgfr3 mice. The scores were not statistically significant between mice with and those without meclozine treatment (p = 0.12). The average tissue concentration of meclozine was significantly higher (508.88 ± 205.16 ng/g) in PD 6.5 mice than in ED 17.5 mice (56.91 ± 20.05 ng/g) (p < 0.005). CONCLUSIONS Maternal administration of meclozine postponed premature closure of synchondroses in some Fgfr3 mice, but the effect on preventing bony bridge formation was not significant, probably due to low placental transmission of the drug. Meclozine is likely to exhibit a marginal effect on premature closure of synchondroses at the cranial base in ACH.
目的 软骨发育不全（ACH）是由成纤维细胞生长因子受体3（FGFR3）基因功能获得性突变引起的最常见的短肢型骨骼发育不良。枕大孔狭窄（FMS）是ACH的严重神经并发症之一。通过全面的药物筛选，作者发现茶苯海明，一种用于晕动病的非处方药，可抑制FGFR3信号的激活。对生长中的ACH小鼠口服茶苯海明可促进纵向骨生长，但不能预防FMS。在本研究中，作者评估了母体给予茶苯海明对ACH小鼠FMS的影响。
方法 使用微型计算机断层扫描（micro-CT）测量17日龄Fgfr3小鼠和野生型小鼠的枕大孔面积。从胚胎第（ED）14.5天至出生后第（PD）4.5天，对携带Fgfr3后代的怀孕小鼠给予茶苯海明。对蝶枕和枕骨内前软骨联合进行组织学检查，并在出生后第4.5天对骨桥进行评分。在野生型小鼠中，研究了胚胎第17.5天胎儿和出生后第6.5天幼崽体内茶苯海明的组织浓度。
结果 17日龄Fgfr3小鼠的枕大孔面积显著小于野生型小鼠（p < 0.005）。野生型小鼠的蝶枕和枕骨内前软骨联合处没有骨桥，而在未治疗的Fgfr3小鼠出生后第4.5天，一些软骨联合过早闭合。未治疗的Fgfr3小鼠颅底的平均骨桥评分为7.053 ± 1.393，茶苯海明治疗的Fgfr3小鼠为6.125 ± 2.029。接受和未接受茶苯海明治疗的小鼠之间的评分无统计学意义（p = 0.12）。出生后第6.5天小鼠体内茶苯海明的平均组织浓度（508.88 ± 205.16 ng/g）显著高于胚胎第17.5天小鼠（56.91 ± 20.05 ng/g）（p < 0.005）。
结论 母体给予茶苯海明可使一些Fgfr3小鼠软骨联合的过早闭合推迟，但对预防骨桥形成的效果不显著，可能是由于药物的胎盘转运率较低。茶苯海明可能对ACH颅底软骨联合的过早闭合产生轻微影响。
