Hypoxic-ischemic encephalopathy (HIE) is a type of birth injury that occurs when an baby’s brain is deprived of oxygenated blood at or around the time of birth. HIE is a major cause of neurological damage in term and near-term infants, and accounts for about 25% of deaths during the neonatal period.
Even short durations of oxygen deprivation can result in HIE. However, the long-term brain damage is not the result of a single event – rather, the initial insult sets off a chain reaction: rippling outward from the primary site of asphyxia, cells become injured, die, and release certain substances that are toxic to other cells.
A treatment called therapeutic hypothermia can slow down this injury process, allowing the baby’s brain to heal and minimizing the spread of damage. Therapeutic hypothermia can reduce negative outcomes, such as death, cerebral palsy (CP), hearing loss, and other neuromotor disorders from 60 to 45%. In high-income countries, providing therapeutic hypothermia is standard of care for moderate to severe HIE. However, it must begin within six hours of birth (or the oxygen-depriving event), which often does not occur if clinicians fail to quickly recognize the signs of HIE or are unable to transport the baby to a facility that can administer the therapy.
Therapeutic Hypothermia Isn’t Enough: Could NOS Inhibition Make a Difference?
Additional treatments are needed to a) complement therapeutic hypothermia and b) serve as a first-line treatment option when therapeutic hypothermia is not feasible. Some researchers have proposed that inhibiting nitric oxide synthase (NOS) could provide neuroprotective benefits in babies that have sustained hypoxic-ischemic injury. NOS is an enzyme that is upregulated after a hypoxic event; certain isoforms then contribute to neuronal loss.
Laurent Favié and colleagues in the Netherlands recently published a review of research on NOS inhibition in animal models, in order to evaluate the effectiveness of this treatment and identify an inhibiting compound (or compounds) that could be used in future clinical studies. Favié et al. (2018) searched the literature using databases from EMBASE, Medline, Cochrane, and PubMed, and found 26 studies on NOS inhibition in rats, piglets, sheep, and rabbits.
Results: Combined Inhibition of Neuronal NOS and Inducible NOS Holds Promise
Using histological, biochemical, and neurobehavioral outcome parameters, the authors showed that NOS inhibition does have neuroprotective qualities in various animal models. They believe that the most promising strategy for clinical trials in human infants is selective inhibition of both neuronal NOS (nNOS) and inducible NOS (iNOS), and that inhibition of endothelial NOS (eNOS) should be avoided. After hypoxic injury, eNOS is actually very important in maintaining pulmonary blood flow and preventing pulmonary hypertension. Inhibitors that are non-selective could also target eNOS, which may counteract the benefits of inhibiting nNOS and iNOS.
Conclusions and Limitations
Favié et al. recommend that trials on nNOS and iNOS inhibition examine the safety and effectiveness of this combined approach, as well as whether its effects are sex-specific. They note that females are generally less susceptible to brain injury, and that there is some evidence that 2-iminobiotin (2-IB), an inhibitor of nNOS and iNOS, offered neuroprotective benefits in female rats, but not male rats (Nijboer et al. 2007, as cited within Favié et al.).
The authors report a few limitations to their research. First, the studies they used were of low and moderate quality – they could not be especially selective due to a scarcity of data. Additionally, there was a lot of variability in methods, species used, etc. Although all of these animal models have certain similarities to humans in terms of brain development, it is difficult to make direct comparisons across species. Moreover, many of the studies they reviewed found that NOS inhibition was effective only when administered before the animal was deprived of oxygen (for ethical reasons, this type of experimental treatment is not possible in clinical trials on humans) or very shortly after (which may be difficult in clinical trials if physicians are not prompt in their diagnosis of HIE). There is no data on delayed administration, so this treatment may not necessarily extend the window of time to prevent permanent brain damage past what is possible with therapeutic hypothermia. However, the effectiveness may be dosage-dependent and could interact with other treatments; Favié et al. recommend that clinical studies use a repeated dosing regimen and test NOS inhibition both with and without therapeutic hypothermia. They note that a few studies currently in phase II may shed light on these factors (NTR5221, NCT01626924, EudraCT2015-003063-12).
Related Readings on HIE Treatment
- Hypoxic-Ischemic Encephalopathy (HIE)
- Therapeutic Hypothermia for Babies with Hypoxic-Ischemic Encephalopathy (HIE)
- Hypothermia Therapy May Be Effective 6-24 Hours After Birth
- Hypothermia Therapy Shortly After Birth Reduces Risk of Epilepsy
- Erythropoietin/Hypothermia Therapy in Combination: Potential New Treatment for HIE?
- Long-Term Outcomes and Care for People with HIE
Favié, Laurent, et al. “Nitric Oxide Synthase Inhibition as a Neuroprotective Strategy Following Hypoxic–Ischemic Encephalopathy: Evidence From Animal Studies.” Frontiers in Neurology 9 (2018): 258.
Nijboer, Cora HA, et al. “Gender-Specific Neuroprotection by 2-Iminobiotin after Hypoxia—Ischemia in the Neonatal Rat via a Nitric Oxide Independent Pathway.” Journal of Cerebral Blood Flow & Metabolism 27.2 (2007): 282-292.