Therapeutic Hypothermia Attenuates Cortical Interneuron Loss after Cerebral Ischemia in Near-Term Fetal Sheep

Abstract

Therapeutic hypothermia significantly improves outcomes after neonatal hypoxic-ischemic (HI) encephalopathy but is only partially protective. There is evidence that cortical inhibitory interneuron circuits are particularly vulnerable to HI and that loss of interneurons may be an important contributor to long-term neurological dysfunction in these infants. In the present study, we examined the hypothesis that the duration of hypothermia has differential effects on interneuron survival after HI. Near-term fetal sheep received sham ischemia or cerebral ischemia for 30 min, followed by cerebral hypothermia from 3 h after ischemia end and continued up to 48 h, 72 h, or 120 h recovery. Sheep were euthanized after 7 days for histology. Hypothermia up to 48 h recovery resulted in moderate neuroprotection of glutamate decarboxylase (GAD)+ and parvalbumin+ interneurons but did not improve survival of calbindin+ cells. Hypothermia up to 72 h recovery was associated with significantly increased survival of all three interneuron phenotypes compared with sham controls. By contrast, while hypothermia up to 120 h recovery did not further improve (or impair) GAD+ or parvalbumin+ neuronal survival compared with hypothermia up to 72 h, it was associated with decreased survival of calbindin+ interneurons. Finally, protection of parvalbumin+ and GAD+ interneurons, but not calbindin+ interneurons, with hypothermia was associated with improved recovery of electroencephalographic (EEG) power and frequency by day 7 after HI. The present study demonstrates differential effects of increasing the duration of hypothermia on interneuron survival after HI in near-term fetal sheep. These findings may contribute to the apparent preclinical and clinical lack of benefit of very prolonged hypothermia.

Current status and controversies in the treatment of neonatal hypoxic-ischemic encephalopathy: A review

“…This suggests that subcooling treatment lasting 72 hours is more effective than 48 hours or 120 hours. [ 19 ] The target temperature for subcooling therapy is generally 2 to 4 °C below brain body temperature, with body surface temperature maintained at 33.5 to 34.0 °C. [ 20 ] Shankaran et al [ 21 ] did extensive research on moderate-to-severe neonatal HIE, exploring whether 120 hours of subcooling or a body surface temperature of 32.0 °C could reduce mortality or disability in 18-month-old infants, and ultimately concluded that subcooling for more than 72 hours or a body surface temperature as low as 33.5 °C did not further improve the mortality or disability rates of the infants.…”

Abnormal local cortical functional connectivity due to interneuron dysmaturation after neonatal intermittent hypoxia

“…These findings suggest that perinatal hypoxia disrupts the delicate balance between excitatory and inhibitory circuits within the developing brain. Studies report a decrease in major interneuron types (Komitova, Xenos et al 2013, Chavez-Valdez, Emerson et al 2018, Stolp, Fleiss et al 2019, Yang, Davidson et al 2023). However, the functional impact of this interneuron injury on neuronal network activity and glutamatergic transmission remains unclear.…”