In vivo Investigation of Glutamate–Glutamine Metabolism in Hyperammonemic Monkey Brain Using ¹³C-Magnetic Resonance Spectroscopy

Abstract

To investigate the metabolism of glutamate and glutamine in living monkey brain, a system of in vivo ¹³C magnetic resonance spectroscopy (MRS) using ¹H-decoupled ¹³C spectroscopy combined with monitoring temperature changes in the brain by MR phase mapping was developed. Serial ¹³C-NMR spectra of the amino acids glutamate and glutamine were acquired non-invasively over 4 h from anesthetized monkey brain after the intravenous administration of [1-¹³C]glucose (0.5–1.0 g/kg). In the acute hyperammonemic state induced by the administration of ammonium acetate (77 mg/kg bolus), it was observed that ¹³C incorporation into glutamine-4 was clearly accelerated, without changes of ¹³C incorporation into glutamate-4. During hyperammonemia, it was shown directly by [2-¹³C]glucose administration that the anaplerotic pathway for the TCA cycle was also augmented, contributing to the formation of glutamine in the astroglia.

[1‐13C] glucose MRS in chronic hepatic encephalopathy in man

“…In many studies of acute hyperammonemia elevated glutamine synthesis rates have been reported (27,35,37). In this study we attempted to quantify the putative abnormality in glutamine synthesis by directly measuring the glutamine synthesis rate Vgln and by determining the time delay ⌬t(Glx 2 ) between label appearance in glutamate C 2 and glutamine C 2 .…”

The First in Vivo Observation of 13C–15N Coupling in Mammalian Brain

“…(8)). In vivo observation of 13 C incorporation into C5 and C1 of GLU-GLN has been reported after a bolus injection of [2-13 C]glucose in monkey brain (9). However, to the best of our knowledge, selective 13 C enrichment of neurotransmitter GLU C5 and in vivo observation of the heteronuclear 13 C-15 N coupling in a mammalian brain metabolite have not been attempted previously.…”

A tribute to Leif Hertz: The historical context of his pioneering studies of the roles of astrocytes in brain energy metabolism, neurotransmission, cognitive functions, and pharmacology identifies important, unresolved topics for future studies

“…In fact, the Yale group had spent extensive effort measuring and modeling anaplerosis including studies presented at the meeting (Shen et al, 1998; Sibson, Shen, et al, 1998), as had Rolf Gruetter's group (Gruetter et al, 1998, 2001; Öz et al, 2004) and others, with the reported measurements being similar to presently accepted values (Lanz et al, 2013, 2014; Rothman, Dienel, et al, 2022). However, most of the workers in the in vivo field were not familiar with neurotransmitter Glu oxidation, and therefore assumed, based on in vivo single‐pass brain ammonia uptake and whole brain arteriovenous (AV) difference studies of brain ammonia balance and hyperammonemia (e.g., Cooper et al, 1981, 1985; Cooper & Lai, 1987; Cooper & Plum, 1987; Tsukada et al, 1998) as well as in vivo MRS studies (Shen et al, 1998), that even during normoammonemia anaplerosis was used primarily for removal of ammonia in the brain as Gln. Conversely, the role of anaplerosis in whole‐brain nitrogen balance was largely neglected by neurochemists who worked on in vitro systems.…”