Abstract
BackgroundReactive astrocytosis and microgliosis are important features of the pathophysiology of hydrocephalus, and persistent glial "scars" that form could exacerbate neuroinflammation, impair cerebral perfusion, impede neuronal regeneration, and alter biomechanical properties. The purpose of this study was to determine the efficacy of minocycline, an antibiotic known for its anti-inflammatory properties, to reduce gliosis in the H-Tx rat model of congenital hydrocephalus.MethodsMinocycline (45 mg/kg/day i.p. in 5% sucrose at a concentration of 5-10 mg/ml) was administered to hydrocephalic H-Tx rats from postnatal day 15 to day 21, when ventriculomegaly had reached moderate to severe stages. Treated animals were compared to age-matched non-hydrocephalic and untreated hydrocephalic littermates. The cerebral cortex (both gray matter laminae and white matter) was processed for immunohistochemistry (glial fibrillary acidic protein, GFAP, for astrocytes and ionized calcium binding adaptor molecule, Iba-1, for microglia) and analyzed by qualitative and quantitative light microscopy.ResultsThe mean number of GFAP-immunoreactive astrocytes was significantly higher in untreated hydrocephalic animals compared to both types of controls (p < 0.001). Minocycline treatment of hydrocephalic animals reduced the number of GFAP immunoreactive cells significantly (p < 0.001). Likewise, the mean number of Iba-1 immunoreactive microglia was significantly higher in untreated hydrocephalic animals compared to both types of controls (p < 0.001). Furthermore, no differences in the numbers of GFAP-positive astrocytes or Iba-1-positive microglia were noted between control animals receiving no minocycline and control animals receiving minocycline, suggesting that minocycline does not produce an effect under non-injury conditions. Additionally, in six out of nine regions sampled, hydrocephalic animals that received minocycline injections had significantly thicker cortices when compared to their untreated hydrocephalic littermates.ConclusionsOverall, these data suggest that minocycline treatment is effective in reducing the gliosis that accompanies hydrocephalus, and thus may provide an added benefit when used as a supplement to ventricular shunting.
Highlights
Reactive astrocytosis and microgliosis are important features of the pathophysiology of hydrocephalus, and persistent glial "scars" that form could exacerbate neuroinflammation, impair cerebral perfusion, impede neuronal regeneration, and alter biomechanical properties
We have shown previously that gliosis in the form of reactive astrocytosis and microgliosis increases significantly in the H-Tx rat model of congenital hydrocephalus [9,10]
glial fibrillary acidic protein (GFAP)- immunoreactive astrocyte number The number of GFAP-immunoreactive astrocytes was significantly increased in untreated hydrocephalic animals, but minocycline treatment significantly reduced this number (Figure 1)
Summary
Reactive astrocytosis and microgliosis are important features of the pathophysiology of hydrocephalus, and persistent glial "scars" that form could exacerbate neuroinflammation, impair cerebral perfusion, impede neuronal regeneration, and alter biomechanical properties. Shunts fail for numerous reasons; one likely cause is failure of the shunt valve to actuate properly due to the changing hydrostatic properties of a stiff, Gliosis is an important feature of the pathophysiology of hydrocephalus [3,4,5,6,7,8,9,10], and persistent glial "scars" that form in the shunted brain could promote neuroinflammation, impair cerebral perfusion, alter the blood-brain barrier, prevent repair of damaged neural tissue and impede neuronal plasticity, and change intracranial compliance which poses additional problems for optimal shunt function. This study is the first investigation of minocycline treatment in hydrocephalus-induced gliosis and represents a promising new approach in the treatment of this condition
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