Abstract
BackgroundHydrocephalus is a neurological disease with an incidence of 80–125 per 100,000 births in the United States. Neuropathology comprises ventriculomegaly, periventricular white matter (PVWM) alterations, inflammation, and gliosis. We hypothesized that hydrocephalus in a pig model is associated with subventricular and PVWM cellular alterations and neuroinflammation that could mimic the neuropathology described in hydrocephalic infants.MethodsHydrocephalus was induced by intracisternal kaolin injections in 35-day old female pigs (n = 7 for tissue analysis, n = 10 for CSF analysis). Age-matched sham controls received saline injections (n = 6). After 19–40 days, MRI scanning was performed to measure the ventricular volume. Stem cell proliferation was studied in the Subventricular Zone (SVZ), and cell death and oligodendrocytes were examined in the PVWM. The neuroinflammatory reaction was studied by quantifying astrocytes and microglial cells in the PVWM, and inflammatory cytokines in the CSF.ResultsThe expansion of the ventricles was especially pronounced in the body of the lateral ventricle, where ependymal disruption occurred. PVWM showed a 44% increase in cell death and a 67% reduction of oligodendrocytes. In the SVZ, the number of proliferative cells and oligodendrocyte decreased by 75% and 57% respectively. The decrease of the SVZ area correlated significantly with ventricular volume increase. Neuroinflammation occurred in the hydrocephalic pigs with a significant increase of astrocytes and microglia in the PVWM, and high levels of inflammatory interleukins IL-6 and IL-8 in the CSF.ConclusionThe induction of acquired hydrocephalus produced alterations in the PVWM, reduced cell proliferation in the SVZ, and neuroinflammation.
Highlights
Hydrocephalus is a neurologic condition resulting from cerebrospinal fluid (CSF) flow impairment that promotes the expansion of the brain ventricles [1,2,3]
The levels of pro-inflammatory molecules, such as interleukins IL1α, interleukin 4 (IL4), interleukin 6 (IL6), interleukin 12 (IL12), Tumor Necrosis Factor-alpha (TNF-α), or Transforming Growth Factor-beta, some of them activated by the Toll Like Receptor 4 downstream pathway [15], in the CSF correlate with the severity of the disease [8, 12, 16,17,18,19,20,21,22,23]
The pathology associated with hydrocephalus in the pigs was studied by analyzing the Subventricular Zone (SVZ), the neuroinflammatory reaction in the brain parenchyma and CSF, and alterations in the periventricular white matter (PVWM) adjacent to both frontal horn and body of the lateral ventricles
Summary
Hydrocephalus is a neurologic condition resulting from cerebrospinal fluid (CSF) flow impairment that promotes the expansion of the brain ventricles [1,2,3]. Ischemia/hypoxia and alterations in the periventricular white matter (PVWM), including myelin destruction and loss of oligodendrocytes progenitors, have been described in human and experimental models [8,9,10,11]. Hydrocephalus is a neurological disease with an incidence of 80–125 per 100,000 births in the United States. Neuropathology comprises ventriculomegaly, periventricular white matter (PVWM) alterations, inflammation, and gliosis. We hypothesized that hydrocephalus in a pig model is associated with subventricular and PVWM cellular alterations and neuroinflammation that could mimic the neuropathology described in hydrocephalic infants
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