Suppression of microglial activation with anti-inflammatory drug bindarit enhances neural development in the shunt-treated neonatal hydrocephalus model rat.

Neonatal hydrocephalus is a prevalent neurological condition typically managed through cerebrospinal fluid (CSF) diversion procedures, such as ventriculoperitoneal shunting. Despite surgical intervention, many patients exhibit persistent hypomyelination and long-term neurocognitive deficits, and no permanent pharmacological treatments currently exist. In this study, we investigated the therapeutic potential of combining shunting with bindarit, an anti-inflammatory agent, using a shunt-treated neonatal progressive hydrocephalus (prh) rat model. Ventriculo-subcutaneous shunting was performed between postnatal days (P) 6-8 in both wild-type and prh mutant rats. In the treatment group, bindarit was administered subcutaneously from P4 to P10. MRI and histological analyses were conducted at P10/11. Shunting alone significantly reduced ventricular volume and partially suppressed activated, amoeboid microglia expressing monocyte chemoattractant protein-1 in the corpus callosum. However, activated microglia with CD68 expression persisted in both grey and white matter. Notably, bindarit treatment further attenuated microglial activation, as evidenced by reduced morphological changes and CD68 expression. This was accompanied by improved myelination, indicated by increased myelin basic protein expression in the corpus callosum-an effect not achieved by shunting alone during our follow-up. Furthermore, the population of premyelinating and myelinating oligodendrocytes, which is diminished in prh mutants, was restored only with the combined treatment. These findings suggest that adjunctive anti-inflammatory therapy with bindarit enhances the neuroprotective effects of CSF diversion surgery by mitigating microglial activation and promoting oligodendrocyte maturation and myelination. This combined approach may offer a promising strategy for supporting brain development and improving neurocognitive outcomes in neonatal hydrocephalus.