Dataset Information

Proton magnetic resonance spectroscopy detects cerebral metabolic derangement in a mouse model of brain coenzyme a deficiency.

ABSTRACT:

Background

Pantothenate kinase (PANK) is the first and rate-controlling enzymatic step in the only pathway for cellular coenzyme A (CoA) biosynthesis. PANK-associated neurodegeneration (PKAN), formerly known as Hallervorden-Spatz disease, is a rare, life-threatening neurologic disorder that affects the CNS and arises from mutations in the human PANK2 gene. Pantazines, a class of small molecules containing the pantazine moiety, yield promising therapeutic effects in an animal model of brain CoA deficiency. A reliable technique to identify the neurometabolic effects of PANK dysfunction and to monitor therapeutic responses is needed.

Methods

We applied ¹H magnetic resonance spectroscopy as a noninvasive technique to evaluate the therapeutic effects of the newly developed Pantazine BBP-671.

Results

¹H MRS reliably quantified changes in cerebral metabolites, including glutamate/glutamine, lactate, and N-acetyl aspartate in a neuronal Pank1 and Pank2 double-knockout (SynCre⁺ Pank1,2 dKO) mouse model of brain CoA deficiency. The neuronal SynCre⁺ Pank1,2 dKO mice had distinct decreases in Glx/tCr, NAA/tCr, and lactate/tCr ratios compared to the wildtype matched control mice that increased in response to BBP-671 treatment.

Conclusions

BBP-671 treatment completely restored glutamate/glutamine levels in the brains of the mouse model, suggesting that these metabolites are promising clinically translatable biomarkers for future therapeutic trials.

SUBMITTER: Li Y

PROVIDER: S-EPMC8867880 | biostudies-literature | 2022 Feb

REPOSITORIES: biostudies-literature

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Publications

Proton magnetic resonance spectroscopy detects cerebral metabolic derangement in a mouse model of brain coenzyme a deficiency.

Li Yanan Y Steinberg Jeffrey J Coleman Zane Z Wang Shubo S Subramanian Chitra C Li Yimei Y Patay Zoltan Z Akers Walter W Rock Charles O CO Jackowski Suzanne S Bagga Puneet P

Journal of translational medicine 20220223 1

<h4>Background</h4>Pantothenate kinase (PANK) is the first and rate-controlling enzymatic step in the only pathway for cellular coenzyme A (CoA) biosynthesis. PANK-associated neurodegeneration (PKAN), formerly known as Hallervorden-Spatz disease, is a rare, life-threatening neurologic disorder that affects the CNS and arises from mutations in the human PANK2 gene. Pantazines, a class of small molecules containing the pantazine moiety, yield promising therapeutic effects in an animal model of bra ...[more]

PMID: 35197056

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Project description:Vitamin E, a potent antioxidant, is a necessary and complex micronutrient for cows. During the transition period, vitamin E deficiency (VED) is among the highest prevalent micronutrient deficits in dairy cows. It may eventually result in oxidative stress and immunological malfunction, and it increases the risk of peripartum disorders. At present, detailed data on blood metabolites in VED cows are limited. Consequently, the purpose of this research was to examine the alterations in the serum metabolic profile of VED cows throughout the early postpartum period. Using comprehensive 1H nuclear magnetic resonance (1H NMR), the alterations in serum metabolic activities of VED cows were analyzed. In total, 28 multiparous Holstein cows were assigned according to serum α-tocopherol (α-Toc) concentrations into normal (α-Toc ≥ 4 μg/mL, n = 14) and VED (α-Toc < 3 μg/mL, n = 14) groups at 21 days postpartum, and their blood samples were collected for biochemical and 1H NMR analyses. A t-test on independent samples as well as multivariate statistics were used to assess the findings. In comparison with normal cows, VED cows showed significantly worse body condition scores, milk yield, and dry matter intake (p < 0.05). Significantly higher levels of serum non-esterified fatty acids, aspartate aminotransferase, low-density lipoprotein, and malonaldehyde were found in VED-affected cows, as well as lesser concentrations of serum albumin, high-density lipoprotein, and total antioxidant capacity in comparison with normal cows (p < 0.01), while other vitamins and minerals concentrations showed no distinction between the groups (p > 0.05). Furthermore, 24 upregulated serum metabolites were identified under VED conditions. The metabolomics pathway analysis of these metabolites demonstrated that a global metabolic response to VED in cows was represented by changes in 11 metabolic pathways, comprising energy, carbohydrate, and amino acid metabolism. From these results, we conclude that VED cows were more likely to experience a negative energy balance characterized by alterations of common systemic metabolic processes and develop oxidative stress, inflammation, and ultimately liver injury. This study provides the first evidence of metabolic changes in cows with VED.

Dataset Information

Proton magnetic resonance spectroscopy detects cerebral metabolic derangement in a mouse model of brain coenzyme a deficiency.

Background

Methods

Results

Conclusions

Publications

Proton magnetic resonance spectroscopy detects cerebral metabolic derangement in a mouse model of brain coenzyme a deficiency.

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