Omega-3 fatty acid diglyceride emulsions as a novel injectable acute therapeutic in neonatal hypoxic-ischemic brain injury

• Published in: Biomedicine & pharmacotherapy Vol. 175; p. 116749
• Main Authors: Zirpoli, Hylde, Bernis, Maria Eugenia, Sabir, Hemmen, Manual Kollareth, Denny Joseph, Hamilton, James A., Huang, Nasi, Ng, Jesse, Sosunov, Sergey A., Gaebler, Ben, Ten, Vadim S., Deckelbaum, Richard J.
• Format: Journal Article
• Language: English
• Published: France Elsevier Masson SAS 01-06-2024; Editions Scientifiques Elsevier; Elsevier
• Subjects: diglycerides; gliosis; hypoxic-ischemic encephalopathy; lipid emulsion; neuroprotection; omega-3 fatty acids; DG; HIE; omega-3 fatty acids; diglycerides; TG; TH; N-3; hypoxic-ischemic encephalopathy; neuroprotection; EPA; FAs; lipid emulsion; gliosis; DHA; PL
• ISSN: 0753-3322; 1950-6007; 1950-6007
• DOI: 10.1016/j.biopha.2024.116749

Hypoxic-ischemic encephalopathy (HIE), resulting from a lack of blood flow and oxygen before or during newborn delivery, is a leading cause of cerebral palsy and neurological disability in children. Therapeutic hypothermia (TH), the current standard of care in HIE, is only beneficial in 1 of 7–8 cases. Therefore, there is a critical need for more efficient treatments. We have previously reported that omega-3 (n-3) fatty acids (FA) carried by triglyceride (TG) lipid emulsions provide neuroprotection after experimental hypoxic-ischemic (HI) injury in neonatal mice. Herein, we propose a novel acute therapeutic approach using an n-3 diglyceride (DG) lipid emulsions. Importantly, n-3 DG preparations had much smaller particle size compared to commercially available or lab-made n-3 TG emulsions. We showed that n-3 DG molecules have the advantage of incorporating at substantially higher levels than n-3 TG into an in vitro model of phospholipid membranes. We also observed that n-3 DG after parenteral administration in neonatal mice reaches the bloodstream more rapidly than n-3 TG. Using neonatal HI brain injury models in mice and rats, we found that n-3 DG emulsions provide superior neuroprotection than n-3 TG emulsions or TH in decreasing brain infarct size. Additionally, we found that n-3 DGs attenuate microgliosis and astrogliosis. Thus, n-3 DG emulsions are a superior, promising, and novel therapy for treating HIE.
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•Therapeutic hypothermia (TH), the standard of care in HIE, has substantial limitations in the clinical practice.•To improve n-3 FA bioavailability, we formulated a diglyceride (DG) lipid emulsion for acute parenteral administration.•n-3 DG emulsion showed superior neuroprotection compared to TH and other n-3 based lipid emulsions.