Endogenous synthesis and transport of creatine in the rat brain: an in situ hybridization study

Braissant, Olivier; Henry, Hugues; Loup, Marc; Eilers, Barbara; Bachmann, C.

doi:10.1016/s0169-328x(00)00269-2

Cited by 206 publications

(243 citation statements)

References 38 publications

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“…Although it was assumed that systemic carnitine was essential to supply energy to the brain but nowadays there is evidence that all cells in the CNS can also synthesize creatine from arginine. The absence of expression of CRT1 in astrocytes reinforces the idea that under normal conditions the creatine used by the brain is synthesized mainly in the CNS (40). All patients with inherited creatine deficiency syndromes (AGAT deficiency, GAMT deficiency, and CT1 deficiency) reveal developmental delay/regression, mental retardation, and severe disturbance of their expressive and cognitive speech.…”

Section: Discussionsupporting

confidence: 63%

The Arginine-Creatine Pathway is Disturbed in Children and Adolescents With Renal Transplants

Andrade¹,

Rodríguez‐Soriano²,

Prieto³

et al. 2008

Pediatr Res

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Cardiovascular disease is an important cause of morbidity in recipients of renal transplants. The aim of the present study was to analyze the status of the arginine-creatine pathway in such patients, given the relationship between the arginine metabolism and both renal function and the methionine-homocysteine cycle. Twentynine children and adolescents (median age 13, range 6 -18 years), who had received a renal allograft 14.5-82.0 months before, were recruited for the study. On immunosuppressive therapy, all patients evidenced an adequate level of renal function. Plasma concentrations of homocysteine and glycine were significantly higher, whereas urinary excretions of guanidinoacetate and creatine were significantly lower than controls. Urinary excretions of guanidinoacetate and creatine correlated positively with creatinine clearance. Urinary excretion of creatine was negatively correlated with plasma concentration of homocysteine. The demonstration of disturbances in the arginine-creatine pathway in patients with well-functioning renal transplants and in absence of chronic renal failure represents a novel finding. We speculate that the low urinary excretion of guanidinoacetate and creatine is probably related to the nephrotoxic effect of immunosuppressive therapy and to defective methylation associated with the presence of hyperhomocysteinemia. (Pediatr Res 64: [218][219][220][221][222] 2008)

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Section: Discussionsupporting

confidence: 63%

The Arginine-Creatine Pathway is Disturbed in Children and Adolescents With Renal Transplants

Andrade¹,

Rodríguez‐Soriano²,

Prieto³

et al. 2008

Pediatr Res

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“…44 A representative example of images of a crystalline creatine microdeposit observed at the boundary of the granular and molecular tissue layers of a cerebellar tissue section from a control mouse is presented in Figure 1. Although the creatine deposit is clearly evident in both the optical image ( Figure 1A) of the unstained section and the false color functional image generated from the second-derivative intensity at 1402 cm −1 (Figure 1E), no visible evidence of the creatine deposit was observed after the tissue section was stained (H&E) for routine histology.…”

Section: ■ Results and Discussionmentioning

confidence: 99%

FTIR Imaging of Brain Tissue Reveals Crystalline Creatine Deposits Are an ex Vivo Marker of Localized Ischemia during Murine Cerebral Malaria: General Implications for Disease Neurochemistry

Hackett

Lee

El‐Assaad³

et al. 2012

ACS Chem. Neurosci.

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Phosphocreatine is a major cellular source of high energy phosphates, which is crucial to maintain cell viability under conditions of impaired metabolic states, such as decreased oxygen and energy availability (i.e., ischemia). Many methods exist for the bulk analysis of phosphocreatine and its dephosphorylated product creatine; however, no method exists to image the distribution of creatine or phosphocreatine at the cellular level. In this study, Fourier transform infrared (FTIR) spectroscopic imaging has revealed the ex vivo development of creatine microdeposits in situ in the brain region most affected by the disease, the cerebellum of cerebral malaria (CM) diseased mice; however, such deposits were also observed at significantly lower levels in the brains of control mice and mice with severe malaria. In addition, the number of deposits was observed to increase in a time-dependent manner during dehydration post tissue cutting. This challenges the hypotheses in recent reports of FTIR spectroscopic imaging where creatine microdeposits found in situ within thin sections from epileptic, Alzheimer's (AD), and amlyoid lateral sclerosis (ALS) diseased brains were proposed to be disease specific markers and/or postulated to contribute to the brain pathogenesis. As such, a detailed investigation was undertaken, which has established that the creatine microdeposits exist as the highly soluble HCl salt or zwitterion and are an ex-vivo tissue processing artifact and, hence, have no effect on disease pathogenesis. They occur as a result of creatine crystallization during dehydration (i.e., air-drying) of thin sections of brain tissue. As ischemia and decreased aerobic (oxidative metabolism) are common to many brain disorders, regions of elevated creatine-tophosphocreatine ratio are likely to promote crystal formation during tissue dehydration (due to the lower water solubility of creatine relative to phosphocreatine). The results of this study have demonstrated that although the deposits do not occur in vivo, and do not directly play any role in disease pathogenesis, increased levels of creatine deposits within air-dried tissue sections serve as a highly valuable marker for the identification of tissue regions with an altered metabolic status. In this study, the location of crystalline creatine deposits were used to identify whether an altered metabolic state exists within the molecular and granular layers of the cerebellum during CM, which complements the recent discovery of decreased oxygen availability in the brain during this disease. KEYWORDS: FTIR imaging, cerebral malaria, metabolism, creatine, ischemia, neurodegeneration T he total brain creatine pool (Cr T ) is the sum of the phosphorylated (Cr P ) and dephosphorylated (Cr) forms, and serves as an immediate supply of high energy phosphates under ATP depleting conditions. 1,2 A decrease in the Cr P level, and a corresponding increase in the dephosphorylated product (Cr), is observed in many neurodegenerative disorders in which ischemic conditions (reduce...

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“…Creatine is synthesized from arginine and glycine by a two-step mechanism involving L-arginine: glycine amidinotransferase (AGAT) and S-adenosyl-L-methionine: N-guanidinoacetate methyltransferase (GAMT). Using a combination of in situ hybridization and immunohistochemistry, Braissant et al 43 demonstrated that all cells of the central nervous system can synthesize creatine because they contain both AGAT and GAMT. Furthermore, neurons and oligodendrocytes, by expressing the creatine transporter CRT1, can take up some of the creatine released by astrocytes.…”

Section: C-label Incorporation Into Cerebral Metabolitesmentioning

confidence: 99%

Feeding versus infusion: a novel approach to study the NAA metabolism in rat brain

et al. 2003

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Using in vivo 13 C-NMR spectroscopy, the energy metabolism in rat brain has commonly been studied via infusion of 13 C-labeled substrates on a minute to hour time scale. In the present study, as a novel approach, 13 C-enriched animal chow was administered over several days and compared with a 2 h infusion of [U-13 C 6 ]-glucose. Rats received chow containing either [U-13 C 6 ]-glucose or [U-13 C]-biomass (a mixture of proteins, lipids, DNA, and carbohydrates) during 3 to 5 days. During feeding with 13 C-labeled glucose and biomass, in vivo 13 C-NMR spectroscopy was carried out daily and revealed slow but successive label incorporation into a large number of metabolites. Lipids and proteins were not significantly 13 C-enriched during a 2 h infusion of 13 C-labeled glucose, but became the most prominent resonances in the 13 C feeding experiment. Likewise, feeding with 13 C-enriched biomass led to additional 13 C-label incorporation into creatine, urea carbons and glycogen. Finally, only the acetyl moiety of N-acetyl-aspartate (NAA) became significantly enriched during the 2 h infusion experiment, whereas the aspartyl moiety remained at natural abundance levels. In the feeding experiments, however, label incorporation into all carbons of NAA could be observed. Moreover, isotopomer analysis of brain extracts revealed that the acetyl moiety of NAA in feeding experiments was always more strongly 13 C-enriched than its aspartyl moiety, suggesting that the turnover of the acetyl moiety is faster than that of the aspartyl moiety. The different enrichment kinetics of acetyl and aspartyl moiety could be explained by the existence of two different metabolic pathways reflecting the compartmentalised synthesis of NAA.

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Endogenous synthesis and transport of creatine in the rat brain: an in situ hybridization study

Cited by 206 publications

References 38 publications

The Arginine-Creatine Pathway is Disturbed in Children and Adolescents With Renal Transplants

The Arginine-Creatine Pathway is Disturbed in Children and Adolescents With Renal Transplants

FTIR Imaging of Brain Tissue Reveals Crystalline Creatine Deposits Are an ex Vivo Marker of Localized Ischemia during Murine Cerebral Malaria: General Implications for Disease Neurochemistry

Feeding versus infusion: a novel approach to study the NAA metabolism in rat brain

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