The use of the anti-inflammatory agent bindarit to treat neonatal hydrocephalus may reduce neuroinflammation and improve white matter and neuronal maturation, say two Cincinnati Children’s researchers.  

Francesco Mangano, DO, and June Goto, Ph.D., study neonatal hydrocephalus in the progressive hydrocephalus (prh) mutant mouse model. They found the use of bindarit significantly supports healthy postnatal cerebral cortical development, as reported in the Journal of Neuroscience in March 2022. This opens the potential for the therapeutic use of using anti-inflammatory reagents like bindarit. Neonatal hydrocephalus presents with various degrees of neuroinflammation caused by a build-up of cerebrospinal fluid (CSF). This recent study goes beyond what’s commonly known about neonatal hydrocephalus—that neuroinflammation and glial cell activation occur as a reaction to pressure, Goto says.

“It’s not been studied whether it’s also related to cognitive or motor dysfunction in those patients,” she says. “We thought we could find a new target to help improve neural cell development and brain function.”

Inflammation, Mutations, and Impaired Neural Cell Development

Mangano and Goto are learning more about delayed myelination in surgically treated hydrocephalus and the impact of neuroinflammation on long-term neurologic deficits.  In an earlier study, Mangano and Goto found elevated neuroinflammation with pro-inflammatory microglia and severe periventricular white matter damage in mouse brains with robust neonatal hydrocephalus. The prh mutant mice harbor a mutation in the Ccdc39 gene, which causes loss of cilia-mediated unidirectional CSF flow. 

In the current bindarit study, Mangano and Goto identified more cortical neuropil maturation defects in early postnatal prh mutant mice, such as:

• Impaired excitatory synapse maturation 

• Dendritic arborization of inhibitory neurons  

• Loss of homeostatic microglia 

• Hindlimb locomotor defects 

“The hydrocephalus mice showed spastic hind limb movements in the swim test,” Goto says. “The bindarit treatment supported both neuronal and glial cell development and improved those movements.” 

In essence, hydrocephalus prevents proper myelination and development of cortical neuronal cells. This study, Mangano says, further evaluates the inflammatory response in microglial cells. Bindarit blocks nuclear factor (NF)-kB activation and pro-inflammatory microglial activation. This restores the cortical neuropil thinning and synaptic maturation defects in the prh mutant mouse brains. 

“It’s not simply a matter of CSF building up and shunting it away,” Mangano says. “What we want to study is the downstream effect of intracranial pressure and the abnormal environment that causes the long-term neurocognitive deficits in neonatal hydrocephalus.” 

More Basic Science Studies to Come

Once researchers understand the mechanistic actions of neuroinflammation in the developing brain and their negative results in neural cell development, they can look for ways to interrupt that detrimental pathway, Mangano says. There may be opportunities to prevent microglial activations or turn off damaging responses. 

For example, Goto wants to test the appropriate timing for administering anti-inflammatory agents like bindarit to get the best results. Is it needed for the long term or just during particular ties in brain development? 

Future studies of bindarit treatment combined with CSF diversion surgery may provide long-term benefits supporting neuronal development in neonatal hydrocephalus. Research on the horizon for Mangano and Goto includes:

• Microglia activation. Studying how microglia are activated and what specific types of microglia are involved in neonatal hydrocephalus.

• Microglial medicine. Tests of a drug to moderate microglial behavior and understand when microglia become involved in neonatal hydrocephalus neural disfunction.

Several studies of inflammation in neonatal hydrocephalus are underway by researchers across the nation. Each lab uses different models and techniques. Everyone is interested in improving outcomes for children, Goto says. 

“Our overarching goal is to find the most optimal treatment for individual patients,” Mangano says. “More than likely that will be a combination of some medical and surgical intervention.”