Acute Injection of Omega-3 Triglyceride Emulsion Provides Very Similar Protection as Hypothermia in a Neonatal Mouse Model of Hypoxic-Ischemic Brain Injury.

Denny Joseph Manual Kollareth,Vadim S Ten,Hylde Zirpoli,Richard J Deckelbaum

doi:10.3389/fneur.2020.618419

Denny Joseph Manual Kollareth, Vadim S Ten + Show 2 more

Open Access

https://doi.org/10.3389/fneur.2020.618419

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Abstract

Therapeutic hypothermia (HT) is a currently accepted treatment for neonatal asphyxia and is a promising strategy in adult stroke therapy. We previously reported that acute administration of docosahexaenoic acid (DHA) triglyceride emulsion (tri-DHA) protects against hypoxic-ischemic (HI) injury in neonatal mice. We questioned if co-treatment with HT and tri-DHA would achieve synergic effects in protecting the brain from HI injury. Neonatal mice (10-day old) subjected to HI injury were placed in temperature-controlled chambers for 4 h of either HT (rectal temperature 31–32°C) or normothermia (NT, rectal temperature 37°C). Mice were treated with tri-DHA (0.375 g tri-DHA/kg bw, two injections) before and 1 h after initiation of HT. We observed that HT, beginning immediately after HI injury, reduced brain infarct volume similarly to tri-DHA treatment (~50%). Further, HT delayed 2 h post-HI injury provided neuroprotection (% infarct volume: 31.4 ± 4.1 vs. 18.8 ± 4.6 HT), while 4 h delayed HT did not protect against HI insult (% infarct volume: 30.7 ± 5.0 vs. 31.3 ± 5.6 HT). HT plus tri-DHA combination treatment beginning at 0 or 2 h after HI injury did not further reduce infarct volumes compared to HT alone. Our results indicate that HT offers similar degrees of neuroprotection against HI injury compared to tri-DHA treatment. HT can only be provided in tertiary care centers, requires intense monitoring and can have adverse effects. In contrast, tri-DHA treatment may be advantageous in providing a feasible and effective strategy in patients after HI injury.

Highlights

Hypoxic-ischemic (HI) brain injury is a serious occurrence that frequently results in death or significant long-term neurologic disability in both neonates and adults [1,2,3]
Our results showed that tri-docosahexaenoic acid (DHA) provides similar degrees of neuroprotection as that of HT and combining HT with tri-DHA emulsion does not offer additional therapeutic benefit in HI injury
Our results show that HT administration exerts similar degrees of neuroprotection as that of tri-DHA

Summary

Introduction

Hypoxic-ischemic (HI) brain injury is a serious occurrence that frequently results in death or significant long-term neurologic disability in both neonates and adults [1,2,3]. Therapeutic hypothermia (HT) is the only established treatment for neonates with HI encephalopathy [4]. Hypothermia in Ischemic Brain Injury blankets are used for treatment in neonatal HI encephalopathy [5, 6]. With regard to acute ischemic stroke in adults, tissuetype plasminogen activator (tPA) is the only drug approved by the U.S Food and Drug Administration (FDA) [7]. The narrow therapeutic window and the risk of hemorrhage are major limitations of tPA treatment, resulting in only 8–10% of adult stroke patients eligible for this drug [8]. Preclinical studies and small scale clinical trials in adults after stroke have shown that HT substantially diminishes the degree of neural damage, reduces the rate of mortality and improves neurofunctional recovery [9,10,11]

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