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Changes in the thickness of the external granular layer (A) and molecular layer (B). Control group, MTX-treated group. Values are expressed as means ± SE. *, ***: Significantly different from control at P<0.05, P<0.001 (Student's t-test). † † †: Significantly different from control at P<0.001, respectively (Welch's t-test).
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Six-day-old rats were treated intraperitoneal injections with methotrexate 1 mg/kg, and the cerebellum was examined. Both the length and width of the vermis decreased in the methotrexate-treated group instead of the control from 4 day after treatment (DAT) onward. A significant reduction in the width of the external granular layer was detected on 2...
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Granule cells (GCs) are the most numerous cell type in the cerebellum and indeed, in the brain: at least 99% of all cerebellar neurons are granule cells. In this review article, we first consider the formation of the upper rhombic lip, from which all granule cell precursors arise, and the way by which the upper rhombic lip generates the external gr...
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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. ...
... As the next step, the present study was carried out to clarify the effects and mechanisms of 5-FU on neural progenitor cells during the development of the external granule cells (EGCs) of the cerebellum as well as the cerebrum. Cerebellar granule cells have been widely used as in vitro models to elucidate the mechanisms of action of various therapeutic agents [14][15][16][17][18] . Since granule cells continue to develop after birth 20 21 , it is inferred that neonatal granule cells are highly sensitive to 5-FU. ...
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.
... Neuronal cell death was assessed by increased dark-brown caspase 3 immunohistochemistry. Similar findings of deformed of external granular and thinner of molecular layer of cerebellum were reported in 6 day-old rat treated with methotrexate (0.1mg/kg) [24]. ...
There is no research published in literature concerning the dramatic changes in the offspring of fathers treated with cisplatin. The present research focused on toxicity of cisplatin on cerebellum and testis of offspring that are paternally subjected to cisplatin treatment and therapeutic potential of quercetin. Thirty-two male and female rats weighing approximately 150 gram body weight were used. They were classified into four groups (n=8); control, quercetin, cisplatin, and cisplatin and quercetin. Males were only treated and females were used only for mating and investigated their newly progeny for histopathological abnormalities in testis and cerebellum. Offspring paternally treated with cisplatin exhibited deformation of seminiferous tubules associated with massive degeneration of gonocytes. Widespread of cellular debris was detected within the lumina of the tubules. Early sign of sclerotic tubules were ensheathed by dense aggregation of fibroblast cells around the tubules. Also, the treated cerebellar cortex developed different grades of neurotoxicity. Vacuolar degeneration and fragility are common in both external granular and molecular layer. The internal granular cells were sparsely widely separated and angiogenesis was detected in between the cerebellar folia. Hypoplasia of cerebellar cortex was clarified by reduced migration of granular cell to the inner one. Neuronal cell death was measured by increased dark-brown caspase 3 immunohistochemistry. The mentioned drastic effects were improved in offspring testis and brain paternally received co-administration of quercetin plus cisplatin-treatment. The improvement of both organs was attributed to the quercetin antioxidant activity plus its cytological inclusion of micromolecules which activate cell defense. Citation: Hasan El-Sayyad. (2020). Therapeutic potential of quercetin in rat offspring cerebellum and testis of father subjected to Cisplatin treatment, Current Research in Cytology and Histology, 1(1) 36-41. http://dx.
... In the current study, one of the evidences of cellular degeneration was the decreased thickness of the ML that also contained many vacuolations dispersed within the neuropil. Degeneration and collapse of nerve fibers of necrotic Purkinje cells result in irregular vacuolation and decreased thickness of the ML (Kaufmann et al., 2012) in addition incomplete development of the parallel fiber contributes to thinning of the ML (Sugiyama et al., 2015). ...
The central neurotoxicity of cisplatin (CisPt) has always raised questions especially during development, but few studies are available. Hence, this work was designed to assess the CisPt’s impacts on the postnatal rat cerebellum via evaluation of locomotor activity, histological and immunohistochemical studies, and to focus on cerebellar oxidative stress-related alterations. Eighty newborn pups were divided into 2 equal experimental groups: the control group was kept without any treatment and CisPt-treated group received a single subcutaneous injection of CisPt (5 μg /g b.w.) in their nape at PD10. Ten rats at PD11, PD17, and PD30 ages were weighed, then deeply anesthetized and sacrificed. For locomotor assessment, 20 pups were divided equally into control and CisPt-treated groups and tested at PD11-13, PD15-17, and PD28-30 ages. CisPt-treated rats suffered from decreased motor activity and showed decreased body and cerebellar weights, reduced levels of enzymatic antioxidants (SOD and CAT), and non-enzymatic antioxidant defense (GSH), and increase of lipid peroxidation marker (MDA). Histopathologically, CisPt sowed deleterious changes within cerebellar cortical layers in the form of vacuolations, decreased thickness, and hemorrhage (in PD17), while Purkinje cells exhibited profound degenerative changes in the form of swelling, disrupted arrangement, distortion, and nuclear shrinkage. In CisPt-treated rats, GFAP demonstrated upregulated, hypertrophied, and branched Bergmann glial fibers and reactive astrogliosis. Immuno-localization of Ki-67-positive cells revealed defective migration associated with decreased proliferation in early ages in addition to glial proliferation in PD30. In conclusion, CisPt causes oxidative stress-related deleterious effects on structure of developing cerebellar cortex and affects locomotor activity.
... MTX'in sinir sistemine olan toksik etkileri histopatolojik olarak da önceki pek çok çalışmada değerlendirilmiştir [2,32,36,37]. Vardi ve ark. [32], çalışmasında MTX uygulamasının ratlarda purkinje hücrelerinin şekillerini kaybedip küçülmesine ve Nissl cisimciklerinin yoğunluğunun azalmasına neden olduğu rapor edilmiştir. ...
... MTX shows its effect on cells by inhibiting dihydrofolate reductase, indirectly inhibiting purine synthesis, by inhibiting both DNA synthesis and cell proliferation [18]. Because MTX is a folate antagonist. ...
... III (Methotrexate-treated group) composed of 20 rats, received single intraperitoneal injection of methotrexate at a dose of 20mg/kg [8,17] (4mg/rat= 0.2 ml/solution/rat)on the 14th day of the experiment, then left without any remedy till the end of the experiment (4 weeks). ...
... In the present study, the cerebelli obtained from rats treated with methotrexate were apparently much smaller in size than those of the control group I, this is in harmony with the results of Sugiyma et al. [17] in their study on the effect of methotrexate on cerebellar development in infant rats. They reported a decrease in length and width of cerebrum and cerebellum of rats. ...
... The histological examination of methotrexate treated group revealed marked destructive changes in Purkinje cells and most of cells of the molecular layer. These results were in accordance with the results of Sugiyama et al. [17] who reported that methotrexate caused pyknotic changes in external granular cells of cerebellum of developing infants. Also, Vardi et al. [16] detected severely Purkinje cell loss and damage in the cerebellum by the effect of methotrexate. ...
... In the current study, the transverse diameter and anteroposterior diameter of the fetal telencephalon in the MTX treated group at embryonic age 17 dpc were markedly decreased. This supported what previously mentioned by Sugiyama et al [18] who observed significant decrease in cerebellum dimensions after methotrexate injection of 1 mg/kg body weight on postnatal day 6. ...
... In the current study, the transverse diameter and anteroposterior diameter of the fetal telencephalon in the MTX treated group at embryonic age 17 dpc were markedly decreased. This supported what previously mentioned by Sugiyama et al [18] who observed significant decrease in cerebellum dimensions after methotrexate injection of 1 mg/kg body weight on postnatal day 6. ...
Reproductive aging is associated with altered stress response and many other menopausal symptoms. Little is known about the adrenal expression of the anti-aging protein Klotho or how it is modulated by estrogen in ovariectomized stressed rats. Fifty-six Wistar female rats were assigned into seven equal groups. Sham-operated (Sham), sham stressed (Sham/STS), ovariectomized (OVR), ovariectomized stressed (OVR/STS), ovariectomized stressed rosiglitazone-treated (OVR/STS/R), ovariectomized stressed estrogen-treated (OVR/STS/E), and ovariectomized stressed estrogen/GW9662 co-treated (OVR/STS/E/GW) groups. All stressed rats were subjected daily to a one-hour restraint stress test for 19 days. At the end of the experiment, blood was collected for serum corticosterone (CORT) analysis. Adrenal tissues were obtained and prepared for polymerase chain reaction (PCR) assay, hematoxylin and eosin (H&E), immunohistochemistry-based identification of Klotho and PPAR-γ, and Oil Red O (ORO) staining. The rise in serum CORT was negligible in the OVR/STS group, in contrast to the Sham/STS group. The limited CORT response in the former group was restored by estrogen and rosiglitazone and blocked by estrogen/GW9226 co-administration. ORO-staining revealed a more evident reduction in the adrenal fat in the OVR/STS group, which was reversed by estrogen and counteracted by GW. Also, there was a comparable expression pattern of Klotho and PPAR-γ in the adrenals. The adrenal Klotho decreased in the OVR/STS group, but was reversed by estrogen treatment. GW9226/estrogen co-treatment interfered with the regulatory effect of estrogen on Klotho. The study suggested modulation of the adrenal Kotho expression by estrogen, in the ovariectomized rats subjected to a restraint stress test. This estrogen-provided adrenal protection might be mediated by PPAR-γ activation.
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).
