What is the role of intracellular Ca++ in the pathophysiology of hypoxic-ischemic encephalopathy (HIE)?

Updated: Jul 18, 2018
  • Author: Santina A Zanelli, MD; Chief Editor: Dharmendra J Nimavat, MD, FAAP  more...
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Answer

Intracellular Ca++ concentration increases following hypoxia-ischemia as a result of (1) NMDA receptor activation, (2) release of Ca++ from intracellular stores (mitochondria and endoplasmic reticulum [ER]), and (3) failure of Ca++ efflux mechanisms. Consequences of increases intracellular Ca++ concentration include activation of phospholipases, endonucleases, proteases, and, in select neurons, nitric oxide synthase (NOS). Activation of phospholipase A2 leads to release of Ca++ from the ER via activation of phospholipase C. Activation of proteases and endonucleases results in cytoskeletal and DNA damage.

During the reperfusion period, free radical production increases due to activation of enzymes such as cyclooxygenase, xanthine oxidase, and lipoxygenase. Free radical damage is further exacerbated in the neonate because of immature antioxidant defenses. Free radicals can lead to lipid peroxidation as well as DNA and protein damage and can trigger apoptosis. Finally, free radicals can combine with nitric oxide (NO) to form peroxynitrite a highly toxic oxidant.


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