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Ammonium-induced impairment of axonal growth is prevented through glial creatine
Olivier Braissant1, Hugues Henry, Anne-Marie Villard
1Clinical Chemistry Laboratory, University Hospital, CH-1011 Lausanne, Switzerland. Olivier.Braissant@chuv.hospvd.ch
Insights
High ammonia levels in infants impair brain development. Creatine supplementation shows promise in protecting developing axons from ammonia toxicity, suggesting a potential therapeutic strategy.
Area of Science:
- Neuroscience
- Biochemistry
- Developmental Biology
Background:
- Hyperammonemia in neonates and infants is a critical condition impacting brain development and cognitive function.
- Elevated ammonia levels are known to interfere with essential cellular processes in the developing brain.
Purpose of the Study:
- To investigate the effects of ammonium on axonal growth and neurofilament protein during early brain development.
- To explore the role of creatine in mitigating ammonium-induced neurotoxicity in vitro.
Main Methods:
- Utilized rat reaggregated brain cell primary cultures to model early brain development.
- Exposed cultures to ammonium chloride (NH4Cl) during the phase of early maturation.
- Assessed the impact on cholinergic axonal growth, intermediate neurofilament protein localization and phosphorylation, and intracellular energy metabolites.
- Investigated the protective effects of creatine cotreatment and the role of glial cells.
Main Results:
- Ammonium exposure impaired cholinergic axonal growth and altered neurofilament protein dynamics during early maturation, but not after synaptogenesis.
- NH4Cl treatment reduced intracellular creatine, phosphocreatine, and ADP levels.
- Creatine cotreatment protected axons from ammonium toxicity, independent of restoring high-energy phosphates.
- The protective effect of creatine was dependent on the presence of glial cells.
Conclusions:
- Hyperammonemia poses a significant risk to axonogenesis and can lead to irreversible brain damage in developing infants.
- Creatine demonstrates a neuroprotective role against ammonia toxicity in a glial cell-dependent manner.
- Sustaining central nervous system creatine levels in hyperammonemic neonates and infants warrants further investigation as a potential preventative measure.
Abstract:
Hyperammonemia in neonates and infants affects brain development and causes mental retardation. We report that ammonium impaired cholinergic axonal growth and altered localization and phosphorylation of intermediate neurofilament protein in rat reaggregated brain cell primary cultures. This effect was restricted to the phase of early maturation but did not occur after synaptogenesis. Exposure to NH4Cl decreased intracellular creatine, phosphocreatine, and ADP. We demonstrate that creatine cotreatment protected axons from ammonium toxic effects, although this did not restore high-energy phosphates. The protection by creatine was glial cell-dependent. Our findings suggest that the means to efficiently sustain CNS creatine concentration in hyperammonemic neonates and infants should be assessed to prevent impairment of axonogenesis and irreversible brain damage.