Five to twenty percent of low birth weight preterm infants manifest some form of periventricular white matter injury (PWMI), making it the most common form of brain injury affecting premature infants 1-2. PWMI includes a spectrum of brain injury ranging from diffuse white matter disease to focal necrosis 2-4. PWMI is associated with significant morbidity, as affected individuals may have profound intellectual impairment and cerebral palsy 5-7. Highlighting the magnitude of PWMI, each year in the United States more than 400,000 infants are born prematurely 8. Of these infants, 150,000 are born at risk for PWMI, and about 25,000 children per year will develop PWMI. World-wide, 1,000,000 infants will be born each year at risk for PWMI, and about 250,000 children per year will develop PWMI. It is estimated the lifetime care costs for infants who develop cerebral palsy due to PWMI exceeds $1.5 million per infant9. Thus, finding a prevention and treatment for PWMI is of major public health importance. Oligodendrocytes (OLs) are the myelinating cells of the central nervous system and play a critical role in white matter formation 10-13. It is believed that due to loss of Pre-oligodendrocytes (PreOLs), which are proliferative cells that develop into myelinating OLs, plays a major role in PWMI causation 3. Presently, we are unaware of pharmacological approaches that specifically target PreOLs, resulting in increased proliferation of these cells and increased brain myelination. Recently, we used high-throughput screening to identify compounds ("hits") that would stimulate PreOL proliferation. These studies proved to be highly successful. We identified diazoxide as a stimulator of PreOL proliferation and showed that this compound promotes myelination in a murine model of PWMI. Diazoxide acts by activating KATP channels 14-15. We also found that other KATP activators stimulate PreOL proliferation. We also identified KATP channel component in OLs. We thus hypothesize that diazoxide will be a potential novel therapeutic for PWMI, and that we have discovered a novel therapy for PWMI. We propose to extend our study of diazoxide in preclinical, proof-of-concept studies involving cell culture and animal studies. These studies have been developed with direction form the US Food and Drug Administration and experts in central nervous system (CNS) medicinal chemistry. More specifically we will: 1. Assess diazoxide neonatal toxicity. 2. Define OL-stage specific responses to diazoxide. 3. Evaluate protection against PWMI in animal models. 4. Assess long-term effects of neonatal diazoxide therapy. 5. Identify alternative diazoxide-derivative compounds These studies will focus on the lead compound diazoxide for several reasons. First, diazoxide is a generic drug that is approved by the US Food and Drug Administration (FDA) for the acute treatment of hypertension and the treatment of hyperinsulinism in infants15-16. Second, diazoxide is currently the treatment of choice for infants with hyperinsulinism, and major adverse events related to diazoxide use in infants have not been reported 17. Third, there is favorable clinical and commercial precedent for developing new use indications for generic drugs18-20. Fourth, toxicology studies show that diazoxide has a very broad therapeutic index, with an LD50 value greater than 500 mg/kg in neonatal rodents. This value compares very favorably with the effective 10 mg/kg dose used in our studies. As such, we will avoid the high costs and the lengthy time frame associated with new drug development in applying FDA-approved, generic drugs for novel clinical applications. The long-term goal of this work is to develop novel therapeutic agent for the treatment of PWMI in premature infants. Ultimately, research such as this will lead to important discoveries with significant public health benefit for treating and preventing white matter injury in the tens of thousands of premature infants born and hospitalized each year.
The goal of this work is to assess the utility of diazoxide as a therapeutic agent for the treatment of white matter injuries in premature infants. We anticipate that these studies will lead to the development of novel approaches for treating and preventing white matter injury in the tens of thousands of premature infants born and hospitalized each year.
|Zhu, Ying; Wendler, Christopher C; Shi, Olivia et al. (2014) Diazoxide promotes oligodendrocyte differentiation in neonatal brain in normoxia and chronic sublethal hypoxia. Brain Res 1586:64-72|
|Rivkees, Scott A; Wendler, Christopher C (2011) Adverse and protective influences of adenosine on the newborn and embryo: implications for preterm white matter injury and embryo protection. Pediatr Res 69:271-8|
|Fogal, Birgit; McClaskey, Carolyn; Yan, Sha et al. (2010) Diazoxide promotes oligodendrocyte precursor cell proliferation and myelination. PLoS One 5:e10906|