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Updated: Mar 15, 2026
Early Pathological and Magnetic Resonance Detection of Cerebral Injury Using a Rat Model of Neonatal Hypoxic Ischemic Encephalopathy
Published on: October 28, 2022
Developmental Injury to the Cerebellar Cortex Following Hydroxyurea Treatment in Early Postnatal Life: An
Joaquín Martí1, Vanesa Molina2, M C Santa-Cruz2
1Unidad de Citología e Histología, Facultad de Biociencias, Universidad Autónoma de Barcelona, Bellaterra, 08193, Barcelona, Spain. joaquim.marti.clua@uab.es.
Insights
Hydroxyurea (HU) exposure in early life harms cerebellar cortex development in rats, causing external granular layer cell death and cytoarchitectural abnormalities. These findings highlight the neurodevelopmental toxicity of HU.
Area of Science:
- Neuroscience
- Developmental Biology
- Toxicology
Background:
- The cerebellar cortex undergoes significant postnatal development.
- Hydroxyurea (HU) is a cytotoxic agent with potential developmental effects.
Purpose of the Study:
- To investigate the effects of a single dose of hydroxyurea (HU) on postnatal cerebellar cortex development in rats.
- To characterize the cellular and cytoarchitectural alterations induced by HU exposure.
Main Methods:
- Rats were administered a single dose of HU (2 mg/g) on postnatal day 9.
- Cellular parameters (pyknotic, mitotic, BrdU-positive, vimentin-stained cells) were quantified.
- Apoptosis was assessed using TUNEL staining and electron microscopy.
- Cerebellar cortex cytoarchitecture was analyzed in adulthood.
Main Results:
- HU significantly compromised external granular layer (EGL) cell survival and induced apoptosis.
- Vimentin immunocytochemistry showed glial process alterations.
- Adult rats exposed to HU exhibited ectopic Purkinje cells, abnormal dendritic arbors, and ectopic granule cells.
- Observed anomalies were less pronounced in adulthood compared to earlier time points.
Conclusions:
- Hydroxyurea exposure during early postnatal life induces significant neurodevelopmental toxicity in the rat cerebellar cortex.
- HU disrupts EGL cell survival and leads to lasting cytoarchitectural abnormalities.
- The study underscores the importance of considering the adverse effects of HU during critical developmental periods.
Abstract:
Postnatal development of the cerebellar cortex was studied in rats administered with a single dose (2 mg/g) of the cytotoxic agent hydroxyurea (HU) on postnatal day (P) 9 and collected at appropriate times ranging from 6 h to 45 days. Quantification of several parameters such as the density of pyknotic, mitotic, BrdU-positive, and vimentin-stained cells revealed that HU compromises the survival of the external granular layer (EGL) cells. Moreover, vimentin immunocytochemistry revealed overexpression and thicker immunoreactive glial processes in HU-treated rats. On the other hand, we also show that HU leads to the activation of apoptotic cellular events, resulting in a substantial number of dying EGL cells, as revealed by TUNEL staining and at the electron microscope level. Additionally, we quantified several features of the cerebellar cortex of rats exposed to HU in early postnatal life and collected in adulthood. Data analysis indicated that the analyzed parameters were less pronounced in rats administered with this agent. Moreover, we observed several alterations in the cerebellar cortex cytoarchitecture of rats injected with HU. Anomalies included ectopic placement of Purkinje cells and abnormities in the dendritic arbor of these macroneurons. Ectopic granule cells were also found in the molecular layer. These findings provide a clue for investigating the mechanisms of HU-induced toxicity during the development of the central nervous system. Our results also suggest that it is essential to avoid underestimating the adverse effects of this hydroxylated analog of urea when administered during early postnatal life.
