Cell Death, Axonal Damage, and Cell Birth in the Immature Rat Brain Following Induction of Hydrocephalus

doi:10.1006/exnr.1998.6922

Experimental Neurology

Volume 154, Issue 1, November 1998, Pages 157-169

https://doi.org/10.1006/exnr.1998.6922 Get rights and content

Abstract

We hypothesized that hydrocephalus can cause death of brain cells and that generation of new brain cells might compensate for the cell loss. Hydrocephalus was induced in 3-week-old rats by injection of kaolin into the cisterna magna. The brains were studied 1 to 4 weeks later by histochemical, immunochemical, and ultrastructural methods. The ventricles enlarged progressively. Some axons in the corpus callosum were injured as early as 1 week, but axonal damage was not prevalent until 4 weeks when ventriculomegaly became severe. Dying cells detected by DNA end labeling and often identified as oligodendrocytes by electron microscopy were evident in white matter. Late-stage hydrocephalus was associated with a significant increase in the quantity of dying cells. Hydrocephalus was associated with increased Ki67 labeling and bromodeoxyuridine incorporation in the subependymal zone. Reactive changes were identified among astrocytes, oligodendroglia, and microglia. We conclude that hydrocephalus causes, in addition to axonal injury, gradual cell death in the cerebrum, particularly the white matter. The brain response includes production of new glial cells, but whether the new cells play any beneficial role remains unknown.

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Hydrocephalus is defined as the accumulation of cerebrospinal fluid in the brain ventricles. The usual treatment of hydrocephalus is surgical (shunt), but not all patients can undergo treatment immediately after diagnosis. Thus, neuroprotective measures were tested to minimize the tissue damage involved. Memantine is a non-competitive antagonist of the N-methyl-D-aspartate (NMDA) receptor, which has shown a neuroprotective action in neurodegenerative diseases. This study aimed to evaluate the neuroprotective response of memantine in animals treated with or without a ventricular-subcutaneous shunt. Seven-day-old male Wistar rats induced by intracisternal injection of kaolin were used, divided into five groups: intact control (n = 10), hydrocephalic (n = 10), hydrocephalic treated with memantine (20 mg/kg/day) (n = 10), hydrocephalic treated with shunt (n = 10), hydrocephalic treated with shunt and memantine (20 mg/kg/day) (n = 10). Memantine administration was started on the day after hydrocephalus induction and continued until the last day of the experimental period, totaling 21 consecutive days of drug application. The CSF shunt surgery was performed seven days after hydrocephalus induction. Behavioral tests (open field, and modified Morris water maze), histological, and immunohistochemical evaluations were performed. Treatment with memantine resulted in significant improvement (p < 0.05) in sensorimotor development, preservation of spatial memory, reduction of astrocytic reaction in the corpus callosum, cortex, and germinal matrix. When associated with the shunt, it has also been shown to reduce the cell death cascade. It is concluded that memantine is a promising adjuvant drug with beneficial potential for the treatment of lesions secondary to hydrocephalus.
The association of Edaravone with shunt surgery improves behavioral performance, reduces astrocyte reaction and apoptosis, and promotes neuroprotection in young hydrocephalic rats
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The neuroprotective effect of Edaravone in young hydrocephalic rats associated with a CSF derivation system was evaluated. The drug has already been shown to be beneficial in experimental hydrocephalus, but the combination of this drug with shunt surgery has not yet been investigated. Fifty-seven-day-old Wistar rats submitted to hydrocephalus by injection of kaolin in the cisterna magna were used and divided into five groups: control (n = 10), hydrocephalic (n = 10), hydrocephalic treated with Edaravone (20 mg/kg/day) (n = 10), hydrocephalic treated with shunt (n = 10) and hydrocephalic treated with shunt and Edaravone (n = 10). Administration of the Edaravone was started 24 h after hydrocephalus induction (P1) and continued until the experimental endpoint (P21). The CSF shunt surgery was performed seven days after hydrocephalus induction (P7). Open-field tests, histological evaluation by hematoxylin and eosin, immunohistochemistry by Caspase-3 and GFAP, and ELISA biochemistry by GFAP were performed. Edaravone reduced reactive astrogliosis in the corpus callosum and germinal matrix (p < 0.05). When used alone or associated with CSF shunt surgery, the drug decreased the cell death process (p < 0.0001) and improved the morphological aspect of the astroglia (p < 0.05). The results showed that Edaravone associated with CSF bypass surgery promotes neuroprotection in young hydrocephalic rats by reducing reactive astrogliosis and decreasing cell death.
Kaolin-induced hydrocephalus causes acetylcholinesterase activity dysfunction following hypothalamic damage in infant rats
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In hydrocephalus, the progressive accumulation of cerebrospinal fluid (CSF) causes dilatation of the lateral ventricles affecting the third ventricle and diencephalic structures such as the hypothalamus. These structures play a key role in the regulation of several neurovegetative functions by the production of the hormones. Since endocrine disturbances are commonly observed in hydrocephalic children, we investigated the impact of progressive ventricular dilation on the hypothalamus of infant rats submitted to kaolin-induced hydrocephalus. Seven-day-old infant rats were submitted to hydrocephalus induction by kaolin 20% injection method. After 14 days, the animals were decapitated and brain was collected to analyze mitochondrial function, neuronal activity by acetylcholinesterase (AChE) enzyme, oxidative damage, glial activation, and, neurotransmission-related proteins and anti-apoptotic processes in the hypothalamus. The hydrocephalic animals showed reduction in respiratory rates in the States of phosphorylation (P < 0.01) and non-phosphorylation (P < 0.05); increase in AChE activity in both the cytosol (P < 0.05) and the membrane (P < 0.01); decrease in synaptophysin (P < 0.05) and Bcl-2 (P < 0.05) contents and; increase in protein carbonyl (P < 0.01), GFAP (P < 0.01) and Iba-1 (P < 0.05) levels. The results demonstrate that ventricular dilation causes hypothalamic damage characterized by cholinergic dysfunction and suggests further investigation of the synthesis and secretion of hormones to generate new approaches and to assist in the treatment of hydrocephalic patients with hormonal alterations.
Comprehensive analysis of differentially expressed profiles of long non-coding RNAs and messenger RNAs in kaolin-induced hydrocephalus
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Citation Excerpt :
Our functional enrichment analysis suggested that complement activation may be critical in the pathophysiological process of hydrocephalus, and the dysregulated lncRNAs associated with complement activation may play a role in epigenetic regulation. Astrocytes are activated during hydrocephalic brain injury, and GFAP (an intermediate filament and a key component of the astrocyte cytoskeleton) increases in white matter, especially in periventricular white matter (Del Bigio and Zhang, 1998; Lopes Lda et al., 2009; Deren et al., 2010; Olopade et al., 2012). However, whether astroglial activation is better or worse for brain injuries is controversial.
The pathophysiology of hydrocephalus induced brain damage remains unclear. Long non-coding RNAs (lncRNAs) have been demonstrated to be implicated in many central nervous system diseases. However, the roles of lncRNAs in hydrocephalus injury are poorly understood.
The present study depicted the expression profiles of lncRNAs and messenger RNAs (mRNAs) in C57BL/6 mice with kaolin-induced hydrocephalus and saline controls using high-throughput RNA sequencing. Afterward, Gene ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway analyses were performed to identify potential targets that correlated with hydrocephalus. In addition, co-expression networks and cis- and trans-regulation were predicted using bioinformatics methods. Finally, representative lncRNAs and mRNAs were further validation using quantitative real-time polymerase chain reaction.
A total of 1575 lncRNAs and 1168 mRNAs were differentially expressed (DE) in hydrocephalus. GO and KEGG analyses indicated several immune and inflammatory response-associated pathways may be important in the hydrocephalus. Besides, functional enrichment analysis based on co-expression network showed several similar pathways, such as chemokine signaling pathway, phagosome, MAPK signaling pathway and complement and coagulation cascade. Cis-regulation prediction revealed 5 novel lncRNAs might regulate their nearby coding genes, and trans-regulation revealed several lncRNAs participate in pathways regulated by transcription factors, including BPTF, FOXM1, NR5A2, P2RX5, and NR6A1.
In conclusion, our results provide candidate genes involved in hydrocephalus and suggest a new perspective on the modulation of lncRNAs in hydrocephalus.
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Regular ArticleCell Death, Axonal Damage, and Cell Birth in the Immature Rat Brain Following Induction of Hydrocephalus

Abstract

Prog. Neurobiol.

Anal. Biochem.

Dev. Brain Res.

Exp. Neurol.

Brain Res.

Neuron

Exp. Neurol.

Neurosurg. Clin. North Am.

Brain Res.

Neuron

Prog. Neurobiol.

Brain Res.

J. Neurol. Sci.

Neuroscience

Cellular and molecular pathogenesis of periventricular white matter injury

Ment. Retard. Dev. Disabil. Res. Rev.

Protease antigen recovery decreases the specificity of bromodeoxyuridine detection in formalin-fixed tissue

J. Histochem. Cytochem.

Multiple extracellular signals are required for long-term oligodendrocyte survival

Development

Ferritin, transferrin, and iron in selected regions of the adult and aged rat brain

J. Comp. Neurol.

Mitotic activity in the brain of the adult rat

Anat. Rec.

A cautionary note on the use of the TUNEL stain to determine apoptosis

NeuroReport

A rapid method to determine proliferation patterns of normal and malignant tissues by H3 mRNAin situ

Am. J. Pathol.

Anaerobic glycolysis preceding white-matter destruction in experimental neonatal hydrocephalus

J. Neurosurg.

Reactive astrocytes express the embryonic intermediate filament nestin

Neuroreport

The chronology of oligodendrocyte differentiation in the rat optic nerve: Evidence for a signaling step initiating myelination in the CNS

J. Neurosci.

Subependymal cells provide a faster response to ependymal injury than astrocytes in the hydrocephalic brain

Neuropathol. Appl. Neurobiol.

In vivo

J. Neurosci.

Neuropathological changes caused by hydrocephalus

Acta Neuropathol.

Periventricular pathology in hydrocephalic rabbits before and after shunting

Acta Neuropathol.

Neuropathological changes in chronic adult hydrocephalus: Cortical biopsies and autopsy findings

Can. J. Neurol. Sci.

Acute and chronic cerebral white matter damage in neonatal hydrocephalus

Can. J. Neurol. Sci.

Regular Article
Cell Death, Axonal Damage, and Cell Birth in the Immature Rat Brain Following Induction of Hydrocephalus