Abstract:β-Hydroxybutyrate (BHB) is a representative ketone body that may play a role in the mitigation of neonatal hypoxic-ischemic encephalopathy by altering energy metabolism. This study aimed to investigate the neuroprotective efficacy of exogenous BHB administration in a suckling rat model after hypoxia-ischemia (HI). Thirteen-day-old (P13) rat pups were subjected to 120 min of hypoxia according to the Rice-Vannucci model. BHB (5.0 mmol/kg, HI-BHB) or vehicle (0.9% saline, HI-Veh) was administered 0, 2, 4, and 6 h… Show more
“…4). Initially thought of as a passive carrier of energy, BHB has proven to be an important signaling molecule in a variety of processes including neuroprotection and anti-inflammatory responses 34,37–39 .Figure 4Systemic levels of β-hydroxybutyric acid are significantly decreased post-cranial irradiation. ( A ) Systemic levels of β-hydroxybutyric acid 2 days (top) or 2 weeks (bottom) post 9 Gy cranial irradiation.…”
Ionizing radiation exposure to the brain is common for patients with a variety of CNS related malignancies. This exposure is known to induce structural and functional alterations to the brain, impacting dendritic complexity, spine density and inflammation. Over time, these changes are associated with cognitive decline. However, many of these impacts are only observable long after irradiation. Extracellular vesicles (EVs) are shed from cells in nearly all known tissues, with roles in many disease pathologies. EVs are becoming an important target for identifying circulating biomarkers. The aim of this study is to identify minimally invasive biomarkers of ionizing radiation damage to the CNS that are predictors of late responses that manifest as persistent cognitive impairments. Using a clinically relevant 9 Gy irradiation paradigm, we exposed mice to cranial (head only) irradiation. Using metabolomic and lipidomic profiling, we analyzed their plasma and plasma-derived EVs two days and two weeks post-exposure to detect systemic signs of damage. We identified significant changes associated with inflammation in EVs. Whole-plasma profiling provided further evidence of systemic injury. These studies are the first to demonstrate that profiling of plasma-derived EVs may be used to study clinically relevant markers of ionizing radiation toxicities to the brain.
“…4). Initially thought of as a passive carrier of energy, BHB has proven to be an important signaling molecule in a variety of processes including neuroprotection and anti-inflammatory responses 34,37–39 .Figure 4Systemic levels of β-hydroxybutyric acid are significantly decreased post-cranial irradiation. ( A ) Systemic levels of β-hydroxybutyric acid 2 days (top) or 2 weeks (bottom) post 9 Gy cranial irradiation.…”
Ionizing radiation exposure to the brain is common for patients with a variety of CNS related malignancies. This exposure is known to induce structural and functional alterations to the brain, impacting dendritic complexity, spine density and inflammation. Over time, these changes are associated with cognitive decline. However, many of these impacts are only observable long after irradiation. Extracellular vesicles (EVs) are shed from cells in nearly all known tissues, with roles in many disease pathologies. EVs are becoming an important target for identifying circulating biomarkers. The aim of this study is to identify minimally invasive biomarkers of ionizing radiation damage to the CNS that are predictors of late responses that manifest as persistent cognitive impairments. Using a clinically relevant 9 Gy irradiation paradigm, we exposed mice to cranial (head only) irradiation. Using metabolomic and lipidomic profiling, we analyzed their plasma and plasma-derived EVs two days and two weeks post-exposure to detect systemic signs of damage. We identified significant changes associated with inflammation in EVs. Whole-plasma profiling provided further evidence of systemic injury. These studies are the first to demonstrate that profiling of plasma-derived EVs may be used to study clinically relevant markers of ionizing radiation toxicities to the brain.
“…injection of b-OHB during an ischemic attack of the brain can provide favorable effects on brain function 30 days after the b-OHB administration. 51 Another study also reported that 6-hour continuous infusion of b-OHB ameliorated spinal cord injury 2 weeks after the treatment, which is concomitant with the increased H3K9 acetylation of the spinal tissues. 52 It can be of interest to examine the longer-term remote effects than in the present study, especially the progression to chronic renal damages after IR injury in this model several days after the termination of b-OHB treatment.…”
Section: The Effects Of Foxo3 Knockdown On B-ohb Mediated Anti-pyroptmentioning
Ketone bodies including b-hydroxybutyrate (b-OHB) have been shown to protect against ischemic tissue injury when present at low concentrations. We evaluated the impact of b-OHB on renal ischemia/reperfusion injury (IRI). Mice were treated with a continuous infusion of b-OHB using an osmotic mini-pump before and after IRI. We also tested the effects of increasing endogenous serum b-OHB levels by fasting. Renal IRI was attenuated by b-OHB treatment compared to saline control, with similar results in the fasting condition. b-OHB treatment reduced the number of terminal deoxynucleotidyl transferase-mediated dUTP nick end-labeling (TUNEL)-positive cells and increased expression of forkhead transcription factor O3 (FOXO3), an upstream regulator of pyroptosis. Although b-OHB treatment did not impact markers of apoptosis, it decreased the expression of caspase-1 and proinflammatory cytokines, indicating that b-OHB blocked pyroptosis. In a human proximal tubular cell line exposed to hypoxia and reoxygenation, b-OHB reduced cell death in a FOXO3-dependent fashion. Histone acetylation was decreased in kidneys exposed to IRI and in proximal tubular cells exposed to hypoxia and reoxygenation, and this effect was ameliorated by b-OHB through the inactivation of histone deacetylases. In vitro, b-OHB treatment restored histone acetylation at the FOXO3 promoter. Consistent with epigenetic molecular effects, the renoprotective effects of b-OHB were still observed when the continuous infusion was stopped at the time of IRI. Thus, b-OHB attenuates renal IRI through anti-pyroptotic effects, likely mediated by an epigenetic effect on FOXO3 expression.
“…11 Ketone bodies (acetone, acetoacetate, β-hydroxybutyrate) are efficiently transported into the brain where they serve as an alternative fuel source for oxidative metabolism (Ruderman et al , 1974). Exogenous administration of β-hydroxybutyrate in a rodent model of neonatal HIE decreased neurological injury (Lee et al , 2018a). In the same “Rice-Vannucci” model, Takenouchi et al (2015) showed that hypothermia decreased β-hydroxybutyrate and acetyl-CoA levels in the brain.…”
Section: The Csh Response During Cold Stress: Potential Applications mentioning
confidence: 99%
“…Total calorie content was equivalent in mice fed a ketogenic versus standard diet, indicating that the induction of UMH, and increased CIRBP expression, was not due to caloric restriction. Exogenous administration of ketones, in some models, improves histological outcomes after an acute brain injury and decreases neuropathology/cognitive impairment in chronic neurodegenerative disease (Kashiwaya et al , 2013; Pawlosky et al , 2017; Lee et al , 2018a). It is unclear if neuronal CIRBP levels might be increased by administration of ketones in the setting of brain injury, and if it influences recovery (i.e., direct CIRBP-mediated neuroprotective effects versus harmful activation of proinflammatory microglia).…”
Section: Induction Of Csps During Cold Stress: Potential Applicationsmentioning
Three decades of animal studies have reproducibly shown that hypothermia is profoundly cerebroprotective during or after a central nervous system (CNS) insult. The success of hypothermia in preclinical acute brain injury has not only fostered continued interest in research on the classic secondary injury mechanisms that are prevented or blunted by hypothermia but has also sparked a surge of new interest in elucidating beneficial signaling molecules that are increased by cooling. Ironically, while research into cold-induced neuroprotection is enjoying newfound interest in chronic neurodegenerative disease, conversely, the scope of the utility of therapeutic hypothermia (TH) across the field of acute brain injury is somewhat controversial and remains to be fully defined. This has led to the era of Targeted Temperature Management, which emphasizes a wider range of temperatures (33–36°C) showing benefit in acute brain injury. In this comprehensive review, we focus on our current understandings of the novel neuroprotective mechanisms activated by TH, and discuss the critical importance of developmental age germane to its clinical efficacy. We review emerging data on four cold stress hormones and three cold shock proteins that have generated new interest in hypothermia in the field of CNS injury, to create a framework for new frontiers in TH research. We make the case that further elucidation of novel cold responsive pathways might lead to major breakthroughs in the treatment of acute brain injury, chronic neurological diseases, and have broad potential implications for medicines of the distant future, including scenarios such as the prevention of adverse effects of long-duration spaceflight, among others. Finally, we introduce several new phrases that readily summarize the essence of the major concepts outlined by this review—namely, Ultramild Hypothermia, the “Responsivity of Cold Stress Pathways,” and “Hypothermia in a Syringe.”
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