The Anti-Inflammatory Agent Bindarit Attenuates the Impairment of Neural Development through Suppression of Microglial Activation in a Neonatal Hydrocephalus Mouse Model

• Published in: The Journal of neuroscience 2022-03, Vol.42 (9), p.1820-1844
• Main Authors: Iwasawa, Eri, Brown, Farrah N, Shula, Crystal, Kahn, Fatima, Lee, Sang Hoon, Berta, Temugin, Ladle, David R, Campbell, Kenneth, Mangano, Francesco T, Goto, June
• Format: Article
• Language: English
• Subjects: Animals; Animals, Newborn; Anti-inflammatory agents; Anti-Inflammatory Agents - pharmacology; Anti-Inflammatory Agents - therapeutic use; Cell death; Cerebrospinal fluid; Cilia; Corpus callosum; Cytokines; Defects; Disease Models, Animal; Female; Humans; Hydrocephalus; Hydrocephalus - drug therapy; Indazoles; Inflammation; Maturation; Medical treatment; Mice; Microglia; Monocyte chemoattractant protein; Monocyte chemoattractant protein 1; Monocytes; Morphogenesis; Mutants; Mutation; Myelination; Myeloid cells; Neonates; Neuropil; Phenotypes; Point mutation; Pregnancy; Propionates; Substantia alba; Swimming; Synaptogenesis; Ventricle
• ISSN: 0270-6474; 1529-2401; 1529-2401
• DOI: 10.1523/JNEUROSCI.1160-21.2021

Neonatal hydrocephalus presents with various degrees of neuroinflammation and long-term neurologic deficits in surgically treated patients, provoking a need for additional medical treatment. We previously reported elevated neuroinflammation and severe periventricular white matter damage in the ( ) mutant which contains a point mutation in the gene, causing loss of cilia-mediated unidirectional CSF flow. In this study, we identified cortical neuropil maturation defects such as impaired excitatory synapse maturation and loss of homeostatic microglia, and swimming locomotor defects in early postnatal mutant mice. Strikingly, systemic application of the anti-inflammatory small molecule bindarit significantly supports healthy postnatal cerebral cortical development in the mutant. While bindarit only mildly reduced the ventricular volume, it significantly improved the edematous appearance and myelination of the corpus callosum. Moreover, the treatment attenuated thinning in cortical Layers II-IV, excitatory synapse formation, and interneuron morphogenesis, by supporting the ramified-shaped homeostatic microglia from excessive cell death. Also, the therapeutic effect led to the alleviation of a spastic locomotor phenotype of the mutant. We found that microglia, but not peripheral monocytes, contribute to amoeboid-shaped activated myeloid cells in mutants' corpus callosum and the proinflammatory cytokines expression. Bindarit blocks nuclear factor (NF)-kB activation and its downstream proinflammatory cytokines, including monocyte chemoattractant protein-1, in the mutant. Collectively, we revealed that amelioration of neuroinflammation is crucial for white matter and neuronal maturation in neonatal hydrocephalus. Future studies of bindarit treatment combined with CSF diversion surgery may provide long-term benefits supporting neuronal development in neonatal hydrocephalus. In neonatal hydrocephalus, little is known about the signaling cascades of neuroinflammation or the impact of such inflammatory insults on neural cell development within the perinatal cerebral cortex. Here, we report that proinflammatory activation of myeloid cells, the majority of which are derived from microglia, impairs periventricular myelination and cortical neuronal maturation using the mouse genetic model of neonatal hydrocephalus. Administration of bindarit, an anti-inflammatory small molecule that blocks nuclear factor (NF)-kB activation, restored the cortical thinning and synaptic matur