Treatment of Neonatal Hypoxic Ischemic Injury with Echogenic Noble Gas Microbubbles

The major health significance of this proposal is the delivery and local release of therapeutic gases from echogenic microbubbles using ultrasound as a novel treatment for neonatal hypoxic-ischemic (HI) encephalopathy. Hypoxic-ischemic encephalopathy (HIE) is a major cause of mortality and long-term neurological disabilities in children including cerebral palsy, seizure and behavioral disorders. Remarkably, there are no clinically approved drugs to directly treat HIE, with therapeutic hypothermia being the only major approved treatment. In recent years, noble gases like xenon (Xe) and argon (Ar) have shown great promise as cytoprotective agents that can treat HI injuries via inhalation. Whereas Xe has been researched in greater detail, including in early clinical trials, Ar treatment has been limited to animal studies. Xe is considered more effective in its treatment, while Ar is a hundred times cheaper and more widely available, while still providing excellent cytoprotective efficacy. The mechanism of Xe action depends on its interaction with glutamate receptors on cell membranes, while Ar is thought to stimulate various intracellular protection signaling pathways, independent of glutamate receptor binding. Therefore, we aim to test the hypothesis that synergistic treatment with both Xe and Ar will be a versatile and highly effective therapeutic platform. Importantly, both Xe and Ar can freely diffuse through the blood brain barrier (BBB), overcoming a major hurdle for current HIE candidate drugs. However, currently Xe and Ar are delivered systemically, (thus non-targeted) which for xenon, is highly expensive. As a solution, we propose to use microbubbles (MBs) containing pure Xe or Ar that can be ruptured via clinical ultrasound to release the gas into the cerebral arteries where it can traverse the BBB to reduce secondary injury. MBs are inherently echogenic due to the non-linear oscillations induced by clinical ultrasound. The PI has previously developed MBs containing hard-to-stabilize noble gases that are echogenic in vivo. These MBs have successfully treated other forms of brain injury. The PI has also shown that Xe and Ar can reduce damage to the BBB itself post-injury. Based on these prior studies, we hypothesize that both individual and combination therapy with Xe MBs and Ar MBs will be highly effective in treating neonatal HI, as measured using an in vitro HI model with human neurons and glia as well as using a highly translational in vivo model with histological and behavioral readouts. The proposed research has the following specific aims. (1) Test the hypothesis that Xe and Ar MBs will reduce the extent of injury when delivered a) after HI in rats alone or in combination with therapeutic hypothermia, and b) after oxygen glucose deprivation of human cells in vitro; (2) Test the hypothesis that administering Xe and Ar MBs alone or in combination with therapeutic hypothermia after HI will provide long- term preservation of neurological function. Successful completion of these objectives will lead to a pioneering new local delivery agent (MBs) with no adverse side-effects, that penetrates the BBB for image-guided treatment of neonatal HIE using a relatively inexpensive and non-invasive clinical ultrasound technique. Project Number: 1R21NS142731-01A1 | Fiscal Year: 2026 | NIH Institute/Center: National Institute of Neurological Disorders and Stroke (NINDS) | Principal Investigator: Rajarshi Chattaraj | Institution: NEW JERSEY INSTITUTE OF TECHNOLOGY, NEWARK, NJ | Award Amount: $426,456 | Activity Code: R21 | Study Section: Bioengineering and Tissue Engineering for Neuroscience Study Section[BTEN] View on NIH RePORTER: https://reporter.nih.gov/project-details/11374366