Hypoxic-Ischemic Encephalopathy: New Insights into Treatment and the Role of Interneurons

Hypoxic-ischemic encephalopathy (HIE) is a leading cause of neurodevelopmental disability in infants, resulting from reduced oxygen and blood supply to the brain. While therapeutic hypothermia (HT) is the standard of care in many countries, its effectiveness is variable, and new therapeutic targets are urgently needed. Recent research is focusing on the role of interneurons and a protein called TDP43 in the development of HIE-related brain damage and seizures.

Understanding Hypoxic-Ischemic Encephalopathy

HIE can occur during birth due to factors such as placental insufficiency, asphyxia, or cardiac arrest. The incidence of neonatal encephalopathy varies geographically, with higher rates observed in low- and middle-income countries. In 2019, the incidence was 6.5 cases per 100,000 population in high-income countries, approximately 20 cases per 100,000 in South Asia, and around 54 cases per 100,000 in Sub-Saharan Africa.

Challenges with Current Treatment: Therapeutic Hypothermia

Moderate to severe HIE often affects bilateral brain structures, including the basal ganglia, thalamus, and cerebral cortex, and can lead to refractory seizures, increased mortality, and long-term disabilities like cerebral palsy and epilepsy. Therapeutic hypothermia (HT) involves cooling infants to reduce their body temperature by 4°C for approximately 72 hours, followed by rewarming.

While HT is used in many neonatal intensive care units, its efficacy is not universal, and some infants still experience significant impairments. HT has been contraindicated in some low- and middle-income countries, and rewarming can sometimes trigger seizures. The impact of HT on seizure development remains an area of ongoing investigation.

The Role of Interneurons in HIE-Related Seizures

Seizures in HIE are thought to arise from an imbalance between excitation and inhibition in the brain, regulated by interneurons (INs). There are approximately 25 different subtypes of INs, characterized by their unique shapes and the presence of calcium-binding proteins (CBPs) like parvalbumin (PV) and calretinin (CR). These CBPs help regulate neuronal activity by dampening excitatory signals.

New Research: Aggreosis and TDP43 Pathology

Recent research suggests that IN degeneration in HIE is linked to the abnormal accumulation of CBPs, which then trap and sequester a vital protein called TAR-DNA binding protein-43 (TDP43). TDP43 normally functions in the cell nucleus, playing a crucial role in RNA processing, DNA repair, and maintaining genomic stability. Inactivation of TDP43 is lethal.

Studies using a piglet model of HIE, which closely resembles the human neocortex, have shown that both CR and PV INs die following HIE. HT treatment can rescue some of these INs. Researchers discovered that CR protein becomes damaged, and both CR and PV form abnormal inclusions that trap TDP43, hindering its function. This process, termed “aggreosis,” leads to DNA damage and IN cell death, correlating with seizure burden.

Implications for Future Therapies

The research suggests that vulnerabilities in INs are driven by their intrinsic calcium-binding proteins, which abnormally trap proteins like TDP43. Loss of TDP43 function can lead to faulty RNA processing, impaired DNA repair, and cell death. Targeting these mechanisms could lead to the development of new adjunctive therapies for HIE.

Key Takeaways

• HIE is a significant cause of neurodevelopmental disability in infants.
• Therapeutic hypothermia is the current standard of care, but its effectiveness is limited.
• Interneuron degeneration and TDP43 pathology play a critical role in HIE-related brain damage and seizures.
• Understanding the mechanisms of aggreosis could lead to novel therapeutic targets.