Global neuroinflammation patterns in experimental neonatal hydrocephalus
Authors: James P. (Pat) McAllister II, Jennifer Forsyth, Kelley E. Deren
Background
Hydrocephalus causes reactive astrocytosis and microgliosis
throughout the brain but the global response of pro-inflammatory
cytokines is not known. Thus we sought to characterize common
inflammatory markers in a neonatal model of obstructive
hydrocephalus. Our main hypothesis was that neuroinflammation would
progress in neonatal hydrocephalus proportional to
ventriculomegaly. In addition, the long-standing uncertainty
about the possible global inflammatory effects of kaolin could also
be addressed.
Materials and Methods
Intraventricular (obstructive) hydrocephalus was induced in
one-day old Sprague-Dawley rats by intracisternal injections of 25%
kaolin (n=6-7 per tissue sample); aged-matched controls received
similar injections of saline (n=3-6 per tissue sample). MRI was
employed to characterize ventriculomegaly, and animals were
sacrificed on post-natal day 21. Tissue from the frontal cortex,
parietal cortex, hippocampus, midbrain (tectum and tegmentum), and
medulla was analyzed. Quantitative real time reverse transcriptase
polymerase chain reaction (qRT-PCR) was performed to determine
changes in mRNA expression of interleukin 6 (IL-6), tumour necrosis
factor alpha (TNF-alpha), glial fibrillary acidic protein (GFAP),
and major histocompatibility complex class II (MHC-II). Protein
expression was also examined in these animals by Western blotting.
Correlative immunocytochemistry was also performed.
Results
All portions of the cerebral ventricles expanded, especially in
the lateral ventricles where ventriculomegaly was severe and in the
cerebral aqueduct where the posterior recess was separated from the
overlying subarachnoid space (which also expanded) by only a thin
membrane. Both the frontal and parietal cortices exhibited
significant (p<0.05) increases in IL-6, TNF-alpha, GFAP and
MHC-II. Likewise, the midbrain exhibited statistically significant
increases in IL-6, TNF-alpha, GFAP and MHC-II. In contrast, the
medulla, which was the only region adjacent to kaolin deposits,
showed no change in IL-6, TNF-alpha and GFAP, and only a modest
non-significant increase in MHC-II.
Conclusions
These results suggest that severe hydrocephalus causes
inflammatory changes in the cerebral cortex and midbrain of the
developing brain which are probably a direct consequence of
ventriculomegaly. Data from the medulla suggest that kaolin itself
is not directly involved in a wide-spread inflammatory response.
Characterizing the time course and association with ventricular
volume will provide baseline data for future studies on
pharmacological interventions. In this regard, our previous
findings of significant decreases in the number of reactive
astrocytes and microglia with minocycline treatment suggest that
this agent may also reduce neuroinflammation in hydrocephalus.
Department of Neurosurgery, Primary Children's Medical
Center, Salt Lake City, Utah
Email: pat.mcallister@hsc.utah.edu
