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Published on: August 12, 2020
Positive and negative conditioning in the neonatal brain
Zinaida S Vexler1, Carina Mallard2, Henrik Hagberg3
1Department of Neurology, University California San Francisco, San Francisco, California, USA.
Insights
Perinatal brain injuries cause lifelong disabilities. Understanding how immature brains respond to stress is key to developing new neuroprotective strategies beyond therapeutic hypothermia.
Area of Science:
- Neuroscience
- Developmental Biology
- Pediatrics
Background:
- Perinatal brain injuries, including hypoxic-ischemic encephalopathy (HIE), neonatal stroke, and infections, lead to severe long-term disabilities such as cerebral palsy and cognitive deficits.
- Therapeutic hypothermia (TH) is effective for mild to moderate HIE in term infants, but research is ongoing for adjuvant strategies to improve outcomes.
- Brain immaturity significantly influences the response to injury, necessitating a deeper understanding of endogenous vulnerability mechanisms.
Purpose of the Study:
- To review the mechanisms of neuroprotection achieved through preconditioning and postconditioning strategies in the immature brain.
- To explore how systemic and brain-level changes, as well as intracellular and mitochondrial signaling, contribute to protection.
- To identify barriers in understanding how brain maturity and insult type affect conditioning efficacy.
Main Methods:
- Review of pre-clinical and clinical literature on neuroprotection in perinatal brain injury.
- Analysis of studies investigating sublethal stress (preconditioning/postconditioning) in the developing central nervous system (CNS).
- Examination of molecular mechanisms, including systemic, brain-level, intracellular, and mitochondrial signaling pathways.
Main Results:
- CNS immaturity is a critical factor in the response to perinatal brain insults.
- Sublethal stressors can induce endogenous protective mechanisms, offering potential therapeutic avenues.
- Understanding the interplay of systemic and cellular responses is crucial for developing effective neuroprotective strategies.
Conclusions:
- Further research into the molecular regulation of immature brain vulnerability is essential for advancing neuroprotection.
- Investigating diverse sublethal stressors can elucidate conserved and distinct protective mechanisms.
- Addressing how brain immaturity and insult type influence conditioning efficacy is critical for clinical translation.
Abstract:
Brain injury in the perinatal period occurs in many clinical settings, e.g. hypoxic-ischemic encephalopathy (HIE) in term infants, neonatal stroke, encephalopathy of prematurity, and infections. These insults often result in life-long disabilities including cerebral palsy, cognitive deficits, visual dysfunction, hearing impairments, and epilepsy. However, the success of clinical implementation of a broad array of potential neuroprotective strategies tested experimentally has been limited with the exception of therapeutic hypothermia (TH) used within hours of birth in term human babies with mild to moderate HIE. There is an extensive search for adjuvant therapeutic approaches to enhance the outcomes. One strategy is to modify susceptibility in the developing CNS by means of preconditioning or postconditioning using sublethal stress. The pre-clinical and clinical literature has shown that CNS immaturity at the time of ischemic insult plays a central role in the response to injury. Thus, better understanding of the molecular regulation of the endogenous vulnerability of the immature brain is needed. Further, the use of sublethal stressors of different origin may help shed light on mechanistic similarities and distinctions beween conditioning strategies. In this review we discuss the mechanisms of protection that are achieved by an interplay of changes on the systemic level and brain level, and via changes of intracellular and mitochondrial signaling. We also discuss the barriers to improving our understanding of how brain immaturity and the type of insult-hypoxic, ischemic or inflammatory-affect the efficacy of conditioning efforts in the immature brain.
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