title: Maternal administration of meclozine for the treatment of foramen magnum stenosis in transgenic mice with achondroplasia.
abstract: 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 Fgfr3achmice and wild-type mice using micro-CT scanning. Meclozine was administered to the pregnant mice carrying Fgfr3achoffspring 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 Fgfr3achmice 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 Fgfr3achmice at PD 4.5. The average bony bridge score in the cranial base was 7.053 ± 1.393 in untreated Fgfr3achmice and 6.125 ± 2.029 in meclozine-treated Fgfr3achmice. 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 Fgfr3achmice, 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.
authors: Division of Neurogenetics, Center for Neurological Diseases and Cancer, and.|Department of Orthopaedic Surgery, Nagoya University Graduate School of Medicine, Nagoya, Japan.
authors: Masaki
authors: M
authors: Matsushita
authors: Division of Neurogenetics, Center for Neurological Diseases and Cancer, and.|Department of Orthopaedic Surgery, Nagoya University Graduate School of Medicine, Nagoya, Japan.
authors: Kenichi
authors: K
authors: Mishima
authors: Division of Neurogenetics, Center for Neurological Diseases and Cancer, and.|Department of Orthopaedic Surgery, Nagoya University Graduate School of Medicine, Nagoya, Japan.
authors: Ryusaku
authors: R
authors: Esaki
authors: Department of Orthopaedic Surgery, Nagoya University Graduate School of Medicine, Nagoya, Japan.
authors: Naoki
authors: N
authors: Ishiguro
authors: Division of Neurogenetics, Center for Neurological Diseases and Cancer, and.
authors: Kinji
authors: K
authors: Ohno
authors: Department of Orthopaedic Surgery, Nagoya University Graduate School of Medicine, Nagoya, Japan.
authors: Hiroshi
authors: H
authors: Kitoh
mesh_terms: D000130:Achondroplasia / Q000000981:diagnostic imaging* / Q000188:drug therapy* / Q000235:genetics; D000818:Animals; D003251:Constriction, Pathologic / Q000000981:diagnostic imaging / Q000188:drug therapy / Q000235:genetics; D005260:Female; D005539:Foramen Magnum / Q000000981:diagnostic imaging* / Q000187:drug effects; D018811:Maternal Exposure; D008431:Maternal-Fetal Exchange / Q000187:drug effects* / Q000502:physiology; D008468:Meclizine / Q000008:administration & dosage*; D051379:Mice; D008822:Mice, Transgenic; D011247:Pregnancy; D011897:Random Allocation; D051498:Receptor, Fibroblast Growth Factor, Type 3 / Q000037:antagonists & inhibitors / Q000235:genetics; D016896:Treatment Outcome
chemical_list: D008468:Meclizine; C496365:FGFR3 protein, human; D051498:Receptor, Fibroblast Growth Factor, Type 3
keywords: ACH = achondroplasia; ED = embryonic day; FGFR3; FGFR3 = fibroblast growth factor receptor 3; FMS = foramen magnum stenosis; PD = postnatal day; achondroplasia; foramen magnum; meclozine; spine