New possibilities for neuroprotection in neonatal hypoxic-ischemic encephalopathy

Abstract

Around 0.75 million babies worldwide suffer from moderate or severe hypoxic-ischemic encephalopathy (HIE) each year resulting in around 400,000 babies with neurodevelopmental impairment. In 2010, neonatal HIE was associated with 2.4% of the total Global Burden of Disease. Therapeutic hypothermia (TH), a treatment that is now standard of care in high-income countries, provides proof of concept that strategies that aim to improve neurodevelopment are not only possible but can also be implemented to clinical practice. While TH is beneficial, neonates with moderate or severe HIE treated with TH still experience devastating complications: 48% (range: 44–53) combined death or moderate/severe disability. There is a concern that TH may not be effective in low- and middle-income countries. Therapies that further improve outcomes are desperately needed, and in high-income countries, they must be tested in conjunction with TH. We have in this review focussed on pharmacological treatment options (e.g. erythropoietin, allopurinol, melatonin, cannabidiol, exendin-4/exenatide). Erythropoietin and allopurinol show promise and are progressing towards the clinic with ongoing definitive phase 3 randomised placebo-controlled trials. However, there remain global challenges for the next decade. Conclusion: There is a need for more optimal animal models, greater industry support/sponsorship, increased use of juvenile toxicology, dose-ranging studies with pharmacokinetic-pharmacodynamic modelling, and well-designed clinical trials to avoid exposure to harmful medications or abandoning putative treatments. What is Known:• Therapeutic hypothermia is beneficial in neonatal hypoxic-ischemic encephalopathy.• Neonates with moderate or severe hypoxic-ischemic encephalopathy treated with therapeutic hypothermia still experience severe sequelae. What is New:• Erythropoietin, allopurinol, melatonin, cannabidiol, and exendin-4/exenatide show promise in conjunction with therapeutic hypothermia.• There is a need for more optimal animal models, greater industry support/sponsorship, increased use of juvenile toxicology, dose-ranging studies with pharmacokinetic-pharmacodynamic modelling, and well-designed clinical trials.

Pathophysiology of Perinatal Asphyxia in Humans and Animal Models

“…With the possible exception of melatonin, none of the therapeutical approaches examined herein necessarily requires intensive care measures. However, additional pre-clinical research on the processes of infection and inflammation are needed before trials can be contemplated [ 142 ].…”

Biomarker und Neuromonitoring zur Entwicklungsprognose nach perinataler Hirnschädigung

“…Trotz TH leiden Patienten mit moderater und schwerer HIE an neurologischen Langzeitfolgen (16–30 %), was die Suche nach additiven Therapiestrategien notwendig macht. Auch die Frage nach TH für leichtere Verläufe (HIE I) bleibt zu klären, da auch diese Kinder an Spätfolgen leiden [ 104 ].…”

Analysis of Givinostat/ITF2357 Treatment in a Rat Model of Neonatal Hypoxic-Ischemic Brain Damage

“…In recent years, several strategies for the treatment of neonatal HIE were tested in clinical trials (e.g., erythropoietin, allopurinol, melatonin, cannabidiol, doxycycline, minocycline, exendin-4/exenatide); however, most of them cause side effects (e.g., arthralgia, embolism and thrombosis, hypertension, influenza-like illness, skin reactions, abnormal behavior, insomnia, fever, diarrhea, vomiting, tremor, stroke) (Victor et al, 2022). Therefore, there is still an urgent need to identify new compounds that may be hopefully adapted as a therapeutic option in infants with hypoxic-ischemic insult [ 3 , 4 ]. Consistently, a number of studies have pointed to broad-acting inhibitors of histone deacetylases as anti-inflammatory agents.…”