Involvement of brain metabolism in neurodevelopmental disorders.

Neurodevelopmental disorders (NDDs) affect a significant portion of the global population and have a substantial social and economic impact worldwide. Most NDDs manifest in early childhood and are characterized by deficits in cognition, communication, social interaction and motor control. Due to a limited understanding of the etiology of NDDs, current treatment options primarily focus on symptom management rather than on curative solutions. Moreover, research on NDDs is problematic due to its reliance on a neurocentric approach. However, recent studies are broadening the scope of research on NDDs, to include dysregulations within a diverse network of brain cell types, including vascular and glial cells. This review aims to summarize studies from the past few decades on potential new contributions to the etiology of NDDs, with a special focus on metabolic signatures of various brain cells. In particular, we aim to convey how the metabolic functions are intimately linked to the onset and/or progression of common NDDs such as autism spectrum disorders, fragile X syndrome, Rett syndrome and Down syndrome.

Choline metabolism underpins macrophage IL-4 polarization and RELMα up-regulation in helminth infection.

Type 2 cytokines like IL-4 are hallmarks of helminth infection and activate macrophages to limit immunopathology and mediate helminth clearance. In addition to cytokines, nutrients and metabolites critically influence macrophage polarization. Choline is an essential nutrient known to support normal macrophage responses to lipopolysaccharide; however, its function in macrophages polarized by type 2 cytokines is unknown. Using murine IL-4-polarized macrophages, targeted lipidomics revealed significantly elevated levels of phosphatidylcholine, with select changes to other choline-containing lipid species. These changes were supported by the coordinated up-regulation of choline transport compared to naïve macrophages. Pharmacological inhibition of choline metabolism significantly suppressed several mitochondrial transcripts and dramatically inhibited select IL-4-responsive transcripts, most notably, Retnla. We further confirmed that blocking choline metabolism diminished IL-4-induced RELMα (encoded by Retnla) protein content and secretion and caused a dramatic reprogramming toward glycolytic metabolism. To better understand the physiological implications of these observations, naïve or mice infected with the intestinal helminth Heligmosomoides polygyrus were treated with the choline kinase α inhibitor, RSM-932A, to limit choline metabolism in vivo. Pharmacological inhibition of choline metabolism lowered RELMα expression across cell-types and tissues and led to the disappearance of peritoneal macrophages and B-1 lymphocytes and an influx of infiltrating monocytes. The impaired macrophage activation was associated with some loss in optimal immunity to H. polygyrus, with increased egg burden. Together, these data demonstrate that choline metabolism is required for macrophage RELMα induction, metabolic programming, and peritoneal immune homeostasis, which could have important implications in the context of other models of infection or cancer immunity.

16p11.2 haploinsufficiency reduces mitochondrial biogenesis in brain endothelial cells and alters brain metabolism in adult mice.

Neurovascular abnormalities in mouse models of 16p11.2 deletion autism syndrome are reminiscent of alterations reported in murine models of glucose transporter deficiency, including reduced brain angiogenesis and behavioral alterations. Yet, whether cerebrovascular alterations in 16p11.2df/+ mice affect brain metabolism is unknown. Here, we report that anesthetized 16p11.2df/+ mice display elevated brain glucose uptake, a phenomenon recapitulated in mice with endothelial-specific 16p11.2 haplodeficiency. Awake 16p11.2df/+ mice display attenuated relative fluctuations of extracellular brain glucose following systemic glucose administration. Targeted metabolomics on cerebral cortex extracts reveals enhanced metabolic responses to systemic glucose in 16p11.2df/+ mice that also display reduced mitochondria number in brain endothelial cells. This is not associated with changes in mitochondria fusion or fission proteins, but 16p11.2df/+ brain endothelial cells lack the splice variant NT-PGC-1α, suggesting defective mitochondrial biogenesis. We propose that altered brain metabolism in 16p11.2df/+ mice is compensatory to endothelial dysfunction, shedding light on previously unknown adaptative responses.

Pharmacokinetic profile, tissue residue depletion and anthelmintic efficacy of supramolecular fenbendazole.

A supramolecular complex of fenbendazole (SFBZ) with polyvinylpyrrolidone (PVP) was created by mechanochemical processing to increase its anthelmintic efficacy and to reduce the dose of applied drugs. The aim of our research was to study the pharmacokinetic profile and tissue residue depletion of fenbendazole (FBZ) and its metabolites: sulfoxide and sulfone in sheep after SFBZ treatment by high-performance liquid chromatography with tandem mass spectrometric detection and to evaluate its efficacy against gastrointestinal strongylatosis of sheep in field trials. The results revealed that FBZ and its metabolites were detected in blood serum in 2 h after SFBZ administration and in 4-6 h after the administration of the basic - FBZ. Pharmacokinetic parameters of SFBZ and its metabolites were characterized by higher rate of absorption, concentration of the drug and longer retention times in the blood serum. The maximum concentration of FBZ and its metabolites was detected on the 3rd day in the organs and tissues of sheep that received SFBZ. Thus, in the liver, the content of FBZ was 4878.0 ng/g, sulfoxide and sulfone - 18682.4 and 2483.6 ng/g respectively while the indicators of the basic FBZ and its metabolites were tenfold lower. FBZ and its metabolites were not detected in the organs and tissues of sheep on the 16th day in animals treated with the basic drug and on the 21st day after SFBZ administration. In field trials SFBZ demonstrated a high anthelmintic activity against nematodosis of sheep. It showed 98.2% efficacy against nematodirosis and 99.0 % against other types of gastrointestinal strongylatosis at a dose of 2 mg/kg of active substance (a.s.). Efficacy of mechanical mixture and efficacy of FBZ substance was in 3.1-3.4 times lower in the same dose.

Ingested Ketone Ester Leads to a Rapid Rise of Acetyl-CoA and Competes with Glucose Metabolism in the Brain of Non-Fasted Mice.

The role of ketone bodies in the cerebral energy homeostasis of neurological diseases has begun to attract recent attention particularly in acute neurological diseases. In ketogenic therapies, ketosis is achieved by either a ketogenic diet or by the administration of exogenous ketone bodies. The oral ingestion of the ketone ester (KE), (R)-3-hydroxybutyl (R)-3-hydroxybutyrate, is a new method to generate rapid and significant ketosis (i.e., above 6 mmol/L) in humans. KE is hydrolyzed into ß-hydroxybutyrate (ßHB) and its precursor 1,3-butanediol. Here, we investigate the effect of oral KE administration (3 mg KE/g of body weight) on brain metabolism of non-fasted mice using liquid chromatography in tandem with mass spectrometry. Ketosis (Cmax = 6.83 ± 0.19 mmol/L) was obtained at Tmax = 30 min after oral KE-gavage. We found that ßHB uptake into the brain strongly correlated with the plasma ßHB concentration and was preferentially distributed in the neocortex. We showed for the first time that oral KE led to an increase of acetyl-CoA and citric cycle intermediates in the brain of non-fasted mice. Furthermore, we found that the increased level of acetyl-CoA inhibited glycolysis by a feedback mechanism and thus competed with glucose under physiological conditions. The brain pharmacodynamics of this oral KE strongly suggest that this agent should be considered for acute neurological diseases.