The cAMP Inducers Modify N-Acetylaspartate Metabolism in Wistar Rat Brain.

Robert Kowalski,Tadeusz Pawełczyk,Piotr Pikul,Krzysztof Lewandowski,Monika Sakowicz-Burkiewicz,Marlena Zyśk

doi:10.3390/antiox10091404

Robert Kowalski, Tadeusz Pawełczyk + Show 4 more

Open Access

https://doi.org/10.3390/antiox10091404

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Abstract

Neuronal N-acetylaspartate production appears in the presence of aspartate N-acetyltransferase (NAT8L) and binds acetyl groups from acetyl-CoA with aspartic acid. Further N-acetylaspartate pathways are still being elucidated, although they seem to involve neuron-glia crosstalk. Together with N-acetylaspartate, NAT8L takes part in oligoglia and astroglia cell maturation, myelin production, and dopamine-dependent brain signaling. Therefore, understanding N-acetylaspartate metabolism is an emergent task in neurobiology. This project used in in vitro and in vivo approaches in order to establish the impact of maturation factors and glial cells on N-acetylaspartate metabolism. Embryonic rat neural stem cells and primary neurons were maturated with either nerve growth factor, trans-retinoic acid or activators of cAMP-dependent protein kinase A (dibutyryl-cAMP, forskolin, theophylline). For in vivo, adult male Wistar rats were injected with theophylline (20 mg/kg b.w.) daily for two or eight weeks. Our studies showed that the N-acetylaspartate metabolism differs between primary neurons and neural stem cell cultures. The presence of glia cells protected N-acetylaspartate metabolism from dramatic changes within the maturation processes, which was impossible in the case of pure primary neuron cultures. In the case of differentiation processes, our data points to dibutyryl-cAMP as the most prominent regulator of N-acetylaspartate metabolism.

Highlights

Aspartate N-acetyltransferase (NAT8L) is a neuronal enzyme producing N-acetylaspartate (NAA) from aspartate and acetyl-CoA [1,2]
Dibutyryl-cyclic adenosine monophosphate (cAMP), forskolin, and theophylline activate the protein kinase A followed by the activation of CREB dependent gene expression [20]
The protein kinase A-dependent pathway occurs in any kind of cells, so unlike the Nerve growth factor (NGF) treatment, cAMP differentiates all neural stem cell subpopulations

Summary

Introduction

Aspartate N-acetyltransferase (NAT8L) is a neuronal enzyme producing N-acetylaspartate (NAA) from aspartate and acetyl-CoA [1,2]. Acetyl-CoA is produced either from pyruvate (in the presence of pyruvate dehydrogenase) or is a final product of fatty acid β-oxidation [3]. Acetyl-CoA fuels the tricarboxylic acid cycle, which together with the electron transport chain, constitutes the main energy source [3]. It has been shown that NAA is a messenger conducting neuronal crosstalk with oligodendrocytes and astrocytes [1,4,5]. Once oligodendrocytes have taken up the NAA, they utilize it to produce myelin and energy [1,4,5]. Astrocytes incorporate NAA derivates into glutamine metabolism [1,4,5]

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