Effect of methotrexate on cerebellar development in infant rats

Sugiyama, Akihiko; Sun, Jinyuan; Ueda, Kazutoshi; Furukawa, Satoshi; Takeuchi, Takashi

doi:10.1292/jvms.14-0475

Cited by 7 publications

(6 citation statements)

References 46 publications

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“…It was assumed that these histopathological changes participate largely in the recovery and increase of cell proliferation in VZ/SVZ of the telencephalic wall on GD 19, and they were the compensatory changes for preceding apoptosis and cell proliferation inhibition. These results are in agreement with the previous studies [ 1 , 48 ]. The MTX exposure on PD 6 in infant rats inhibited cell proliferation in the external granular layer of the cerebellum on PD 7, however, mitotic- and phospho-Histone H3-indices showed a tendency to increase compensatorily on PDs 8–10 [ 48 ].…”

Section: Discussionsupporting

confidence: 94%

“…These results are in agreement with the previous studies [ 1 , 48 ]. The MTX exposure on PD 6 in infant rats inhibited cell proliferation in the external granular layer of the cerebellum on PD 7, however, mitotic- and phospho-Histone H3-indices showed a tendency to increase compensatorily on PDs 8–10 [ 48 ]. Bálentová’s study demonstrated that the prenatal exposure of the single whole-body dose of 3 Gy of gamma rays induced the increase in cell proliferation in the rostral migratory stream (RMS) in neonatal and young rats [ 1 ].…”

Section: Discussionsupporting

confidence: 94%

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Effect of methotrexate exposure at late gestation on development of telencephalon in rat fetal brain

Hirako

Furukawa

Takeuchi

et al. 2016

The Journal of Veterinary Medical Science

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ABSTRACT. Pregnant rats were treated with 30 mg/kg of methotrexate (MTX) on gestation day (GD) 16, and fetal brains were examined time-dependently. On GD 20, the appearance of the telencephalon in the MTX group was different from that in the control group, and the major axis of the telencephalon of the MTX group was shortened, compared to that of the control group. In the sagittal section of the telencephalon in the MTX group on GD 20, histopathological findings of deformation and narrowing of the cerebral ventricle, the disturbance of the arrangement of the marginal cell layer of subventricular zone (SVZ) and thickening of telencephalic wall, cortical plate and ventricular zone (VZ)/SVZ were possibly attributable to neuronal migration disorders by MTX. Through all the experimental period, few pyknotic cells or TUNEL-positive cells were observed in the VZ/SVZ of the telencephalic wall and striatum in the control group. On the other hand, in the VZ/SVZ of the telencephalic wall and striatum in the MTX group, pyknotic cells or TUNEL-positive cells were observed on GD 17, and they increased significantly on GD18 and then decreased to the control levels from GD 19 onward. The phospho-Histone H3-positive rate decreased remarkedly in the VZ/SVZ of the telencephalic wall and striatum of the MTX group on GDs 17 and 18, compared to the control group, but they recovered on and after GD 19. These results suggested that there was a high possibility that development of the telencephalon in this period required strong folic acid. Folate is a water-soluble B-complex vitamin which functions as a coenzyme in single-carbon transfers in the metabolism of nucleic acid and amino acids [11,47]. Folate plays an important part in the brain development in the prenatal periods [11,40]. Folate deficiency during pregnancy is one of several well-established factors that can increase the risk of neural-tube defects, especially spina bifida and anencephaly [11,40]. Folic acid deficiency during late gestation decreased the number of progenitor cells undergoing cell proliferation in the ventricular zones (VZ) of the septum, striatum (caudate putamen) and neocortex and increased apoptosis in the septum of fetal mouse brain [6]. Prenatal folate deficiency manifested later with increased anxiety 9-12 weeks after birth in mice [12]. As stated above, there have been several reports demonstrating the relation between folate deficiency in the prenatal period and abnormal development of brain. However, studies of the consequences of inadequate prenatal folate status on brain development of fetuses are scarce; detailed histopathological findings of fetal brains of folatedeficient animals have not been reported. Folate deficiency occurs in various pathophysiological conditions including impairment in intestinal absorption and renal tubular reabsorption induced by alcohol consumption, and intestinal diseases, such as celiac disease and renal malfunctioning [53]. Folate deficiency is also induced by chronic use of anticonvulsants, such as phenobarbital, pr...

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Section: Discussionsupporting

confidence: 94%

Section: Discussionsupporting

confidence: 94%

Effect of methotrexate exposure at late gestation on development of telencephalon in rat fetal brain

Hirako

Furukawa

Takeuchi

et al. 2016

The Journal of Veterinary Medical Science

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“…There is also evidence of pro-regenerative effects of folate in the adult CNS [51], as well as on peripheral neurons [52] which depend essentially on DHFR [53]. Blocking DHFR function by administration of the folate analogue and DHFR antagonist methotrexate (MTX) leads to neurotoxic effects in the cerebellum of newborn rats [54] as well as to the degeneration of PCs in guinea pigs, which could be rescued by application of the tetrahydrofolate derivative leucovorin [55]. This rescue effect of folate is also apparent in newborn rats, in which PC atrophy and cerebellar degenerative changes induced by treatment with valproic acid in the mothers could be markedly reduced by an additional treatment with folic acid [56].…”

Section: Discussionmentioning

confidence: 99%

A Variation in FGF14 Is Associated with Downbeat Nystagmus in a Genome-Wide Association Study

et al. 2020

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Downbeat nystagmus (DBN) is a frequent form of acquired persisting central fixation nystagmus, often associated with other cerebellar ocular signs, such as saccadic smooth pursuit or gaze-holding deficits. Despite its distinct clinical features, the underlying etiology of DBN often remains unclear. Therefore, a genome-wide association study (GWAS) was conducted in 106 patients and 2609 healthy controls of European ancestry to identify genetic variants associated with DBN. A genome-wide significant association (p < 5 × 10 −8 ) with DBN was found for a variation on chromosome 13 located within the fibroblast growth factor 14 gene (FGF14). FGF14 is expressed in Purkinje cells (PCs) and a reduction leads to a decreased spontaneous firing rate and excitability of PCs, compatible with the pathophysiology of DBN. In addition, mutations in the FGF14 gene cause spinocerebellar ataxia type 27. Suggestive associations (p < 1 × 10 −05 ) could be detected for 15 additional LD-independent loci, one of which is also located in the FGF14 gene. An association of a region containing the dihydrofolate reductase (DHFR) and MutS Homolog 3 (MSH3) genes on chromosome 5 was slightly below the genome-wide significance threshold. DHFR is relevant for neuronal regulation, and a dysfunction is known to induce cerebellar damage. Among the remaining twelve suggestive associations, four genes (MAST4, TPPP, FTMT, and IDS) seem to be involved in cerebral pathological processes. Thus, this GWAS analysis has identified a potential genetic contribution to idiopathic DBN, including suggestive associations to several genes involved in postulated pathological mechanisms of DBN (i.e., impaired function of cerebellar PCs).

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“…Although several DNA-damaging agents have demonstrated toxic effects on the developing brains of fetuses and newborns of rats and mice 11 , 5-FU has not been adequately investigated for its toxic effects on the developing central nervous system (CNS). Few detailed reports have been published examining the effects and mechanism of DNA-damaging agents 12 , 13 , 14 , 15 , 16 , 17 , including 5-FU 18 , in the developing cerebellum; however, the timings of administration of such agents were disparate in the aforementioned studies.…”

Section: Introductionmentioning

confidence: 99%

Changes in 5-Fluorouracil-induced external granular cell damage during the time-course of the developing cerebellum of infant rats

et al. 2022

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5-Fluorouracil (5-FU) is widely used as a chemotherapeutic agent that blocks DNA synthesis and replication by inhibiting thymidylate synthetase. This study aimed to elucidate 5-FU-induced changes in the external granular cells (EGCs) in the cerebellum of infant rats and the possible underlying mechanism. Six-day-old infant rats were injected subcutaneously with 40 mg/kg of 5-FU, and their cerebellums were examined at 6, 9, 12, and 24 h after treatment (HAT), and 2, 4, and 10 d after treatment (DAT).The width of the external granular layer (EGL) decreased from 24 HAT to 4 DAT in the 5-FU group compared to that in the control group. However, the width in the 5-FU group was comparable to that of the control group at 10 DAT. The number of apoptotic cells, cleaved caspase 3-labeling index (LI%), p21 cip1 -LI%, and expression levels of p53, p21 cip1 , and Fas mRNAs increased at 24 HAT. However, no changes were detected in the expression levels of Puma and Bax mRNAs at any time point. BrdU-LI% increased at 6 and 12 HAT but decreased at 24 HAT. The phospho-histone H3-LI% decreased from 6 HAT to 2 DAT. The width of the molecular layer decreased compared to that of the control group at 10 DAT. No differences were observed in Purkinje cell development. These results indicate that 5-FU inhibited cell proliferation by inducing apoptosis of EGCs via activation of Fas and caspase-3 without the involvement of the mitochondrial pathway and induced p53-dependent G1-S and G2-M phase arrest.

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Effect of methotrexate on cerebellar development in infant rats

Cited by 7 publications

References 46 publications

Effect of methotrexate exposure at late gestation on development of telencephalon in rat fetal brain

Effect of methotrexate exposure at late gestation on development of telencephalon in rat fetal brain

A Variation in FGF14 Is Associated with Downbeat Nystagmus in a Genome-Wide Association Study

Changes in 5-Fluorouracil-induced external granular cell damage during the time-course of the developing cerebellum of infant rats

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