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Mechanisms of asphyxial brain damage, and possible pharmacologic interventions, in the fetus
1Cardiovascular Research Institute, University of California, San Francisco 94143.
Abstract:
An examination of the cellular and molecular mechanisms of neuronal cell damage may lead to the design of pharmacologic interventions during presumed or actual fetal asphyxia. Hypoxia-ischemia in its severest form results in insufficient adenosine 5'-triphosphate production. The most important effect of this is failure of adenosine 5'-triphosphate-dependent membrane functions, which maintain ionic homeostasis, that is, ionic pumping. There is K+ efflux and Na+ influx across the cell membrane, depolarization of the cell membrane, opening of the voltage-dependent calcium channels, and entrance of Ca++ into the cell. Cytosolic Ca++ is also increased by Ca++ efflux from the mitochondria and the sarcoplasmic reticulum. Ca++ is a toxin in high cytosolic concentrations; it activates phospholipases A and C, which cause membrane breakdown and release of free fatty acids, including arachidonic acid. The membrane is damaged, lysis occurs, and the neuron dies. High cytosolic Ca++ also causes release of excitatory amino acids (especially glutamate), which overwhelm the suppressant neurotransmitters, causing seizures, increased metabolism, and aggravation of the insufficient adenosine 5'-triphosphate availability. Thromboxane A2 is generated from arachidonic acid, increasing smooth muscle tone and thereby worsening the ischemia. Cyclooxygenase activity also results in formation of oxygen-free radicals that contribute to cell membrane damage, lysis, and death. Possibilities for pharmacologic interventions include (1) calcium channel blockers and antagonists, (2) excitatory neurotransmitter blockers, (3) oxygen-free radical scavengers (e.g., superoxide dismutase), (4) cyclooxygenase or prostaglandin synthesis inhibitors, and (5) seizure suppressants (e.g., phenobarbital). Some of these treatments have been shown experimentally to limit neuronal death in the adult and fetus, and after more investigative work they may be applicable to clinical practice.
Insights
Understanding fetal asphyxia
Area of Science:
- Neuroscience
- Biochemistry
- Pharmacology
Background:
- Fetal asphyxia can cause severe neuronal cell damage due to hypoxia-ischemia.
- This leads to insufficient adenosine 5'-triphosphate (ATP) production, impairing essential cellular functions.
- Failure of ATP-dependent membrane functions disrupts ionic homeostasis, leading to cell depolarization and calcium influx.
Purpose of the Study:
- To examine the cellular and molecular mechanisms of neuronal damage in fetal asphyxia.
- To identify potential pharmacologic interventions for fetal asphyxia.
Main Methods:
- Review of cellular and molecular pathways involved in neuronal injury.
- Analysis of the role of calcium (Ca++) and excitatory amino acids.
- Investigation of the generation of free radicals and thromboxane A2.
Main Results:
- High cytosolic Ca++ activates enzymes, causing membrane breakdown and neuronal lysis.
- Excitatory amino acids (e.g., glutamate) contribute to seizures and exacerbate energy deficits.
- Ischemia is worsened by thromboxane A2 and free radicals, leading to further cell death.
Conclusions:
- Pharmacologic interventions targeting calcium channels, excitatory neurotransmitters, free radicals, and seizures are potential treatments.
- Experimental studies show promise in limiting neuronal death.
- Further research may lead to clinical applications for fetal asphyxia treatment.