PET CMRglc mapping and 1H-MRS show altered glucose uptake and neurometabolic profiles in BDL rats

Mosso, Jessie; Yin, Ting; Poitry‐Yamate, Carole; Simicic, Dunja; Lepore, Mario; Mclin, Valérie Anne; Braissant, Olivier; Cudalbu, Cristina; Lanz, Bernard

doi:10.1016/j.ab.2022.114606

Cited by 10 publications

(7 citation statements)

References 46 publications

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“…24 A striking example is hepatic encephalopathy, in which brain Gln is increased by more than 100% as a result of excessive ammonia reaching the brain. [25][26][27][28] In that context, DWS probed an increase in metabolite diffusivities, including in Gln, in the cerebellum of a rat model of the disease, consistent with the loss of neuronal and astrocytic internal structure observed by histology. 29,30 Yet, a reliable estimation of Gln diffusion properties in the control group, in which its concentration is not as high as in hepatic encephalopathy, still remains challenging.…”

Section: Introductionsupporting

confidence: 59%

“…Yet, Gln is a desired target for DWS studies because it plays an important role in various pathologies and is an astrocyte‐specific marker due to the exclusive location of glutamine synthetase in the astrocytes 24 . A striking example is hepatic encephalopathy, in which brain Gln is increased by more than 100% as a result of excessive ammonia reaching the brain 25–28 . In that context, DWS probed an increase in metabolite diffusivities, including in Gln, in the cerebellum of a rat model of the disease, consistent with the loss of neuronal and astrocytic internal structure observed by histology 29,30 .…”

Section: Introductionmentioning

confidence: 99%

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Diffusion‐weighted SPECIAL improves the detection of J‐coupled metabolites at ultrahigh magnetic field

Mosso,

Simicic,

Lanz

et al. 2023

Magnetic Resonance in Med

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PurposeTo improve the detection and subsequent estimation of the diffusion properties of strongly J‐coupled metabolites in diffusion‐weighted MRS (DWS).MethodsA new sequence for single‐voxel diffusion‐weighted 1H MR spectroscopy, named DW‐SPECIAL, is proposed. It combines the semi‐adiabatic SPECIAL sequence with a stimulated echo diffusion block. Acquisitions with DW‐SPECIAL and STE‐LASER, the current gold standard for rodent DWS experiments at high fields, were performed at 14.1T on phantoms and in vivo on the rat brain. The apparent diffusion coefficient and intra‐stick diffusivity (Callaghan's model, randomly‐oriented sticks) were fitted and compared between the sequences for glutamate, glutamine, myo‐inositol, taurine, total NAA, total Cho, total Cr, and the macromolecules.ResultsThe shorter TE achieved with DW‐SPECIAL (18 ms against 33 ms with STE‐LASER) substantially limited the metabolites' signal loss caused by J‐evolution. In addition, DW‐SPECIAL preserved the main advantages of STE‐LASER: absence of cross‐terms, diffusion time during a stimulated echo, and limited sensitivity to B1 inhomogeneities. In vivo, compared to STE‐LASER, DW‐SPECIAL yielded the same spectral quality and reduced the Cramer Rao Lower Bounds for J‐coupled metabolites, irrespective of the b‐value. DW‐SPECIAL also reduced the SD of the metabolites' diffusion estimates based on individual animal fitting without loss of accuracy compared to the fit on the averaged decay.ConclusionWe conclude that due to its reduced TE, DW‐SPECIAL can serve as an alternative to STE‐LASER when strongly J‐coupled metabolites like glutamine are investigated, thereby extending the range of accessible metabolites in the context of DWS acquisitions.

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Section: Introductionsupporting

confidence: 59%

Section: Introductionmentioning

confidence: 99%

Diffusion‐weighted SPECIAL improves the detection of J‐coupled metabolites at ultrahigh magnetic field

Mosso,

Simicic,

Lanz

et al. 2023

Magnetic Resonance in Med

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“… 42 On the other hand, brain glutamine showed the largest increase in the cerebellum and the smallest in the striatum of BDL rats using identical magnetic resonance spectroscopy measurements, 42 confirming the already suspected brain metabolic regional difference in cirrhosis-induced HE. 10 In parallel, decreased glucose uptake has previously been measured ex vivo (brain tissue) 15 and in vivo ([18F]-fluorodeoxyglucose positron emission tomography [ 18 F-FDG PET] 43 ; plasma and cortex) using animal models similar to those used in the present study. These brain alterations indicate a dysmetabolic state and dysfunctional neurotransmission that could be arising owing to impaired delivery production and/or release of these energy substrates/neurotransmitters.…”

Section: Discussionmentioning

confidence: 97%

Abnormal brain oxygen homeostasis in an animal model of liver disease

et al. 2022

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“…The glutamatergic and GABAergic neurotransmission systems are known to be affected in HE 60 . Previous works in BDL rats reported decreased cerebellar Glu 52 , 53 , while GABA levels in the cerebellum were either stable 52 or decreased 53 . Herein, the reasons behind the observed decrease in Glu and GABA compared to the negative control and the role of 2-octynoHA in this process remain unclear warranting further investigation.…”

Section: Resultsmentioning

confidence: 67%

“…The metabolites were assessed in the cerebellum as this region was previously shown to exhibit more distinct changes (i.e. in Gln) compared to the hippocampus in HE in BDL rats 52 , 53 . A significant 28% decrease in brain Gln was observed in the group treated with 2-octynoHA-based solution compared to the negative control group (5.1 ± 1.1 vs. 7.1 ± 1.2 mmol/kg ww , multiplicity adjusted p = 0.0019) (Fig.…”

Section: Resultsmentioning

confidence: 99%

Inhibition of urease-mediated ammonia production by 2-octynohydroxamic acid in hepatic encephalopathy

Evstafeva,

Ilievski,

Bao

et al. 2024

Nat Commun

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Hepatic encephalopathy is a neuropsychiatric complication of liver disease which is partly associated with elevated ammonemia. Urea hydrolysis by urease-producing bacteria in the colon is often mentioned as one of the main routes of ammonia production in the body, yet research on treatments targeting bacterial ureases in hepatic encephalopathy is limited. Herein we report a hydroxamate-based urease inhibitor, 2-octynohydroxamic acid, exhibiting improved in vitro potency compared to hydroxamic acids that were previously investigated for hepatic encephalopathy. 2-octynohydroxamic acid shows low cytotoxic and mutagenic potential within a micromolar concentration range as well as reduces ammonemia in rodent models of liver disease. Furthermore, 2-octynohydroxamic acid treatment decreases cerebellar glutamine, a product of ammonia metabolism, in male bile duct ligated rats. A prototype colonic formulation enables reduced systemic exposure to 2-octynohydroxamic acid in male dogs. Overall, this work suggests that urease inhibitors delivered to the colon by means of colonic formulations represent a prospective approach for the treatment of hepatic encephalopathy.

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PET CMRglc mapping and 1H-MRS show altered glucose uptake and neurometabolic profiles in BDL rats

Cited by 10 publications

References 46 publications

Diffusion‐weighted SPECIAL improves the detection of J‐coupled metabolites at ultrahigh magnetic field

Diffusion‐weighted SPECIAL improves the detection of J‐coupled metabolites at ultrahigh magnetic field

Abnormal brain oxygen homeostasis in an animal model of liver disease

Inhibition of urease-mediated ammonia production by 2-octynohydroxamic acid in hepatic encephalopathy

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