Abstract:Heat stress causes many pathophysiological responses in the brain, including neuroinflammation and cognitive deficits. β‐Hydroxybutyric acid (BHBA) has been shown to have neuroprotective effects against inflammation induced by lipopolysaccharide. The aim of the present study was to evaluate the effects of BHBA on neuroinflammation induced by heat stress, as well as the underlying mechanisms. Mice were pretreated with vehicle, BHBA or minocycline (positive control group) and followed by heat exposure (43°C) for… Show more
“…In the current study, overproduced TLR4 was found in the hippocampus of HS broilers regardless of dietary treatments ( P < 0.05, Figure 2A and B ). Similarly, overregulation of TRL4 in the hippocampus has been found in heat stress-induced neuroinflammation in mice ( Huang et al, 2022 ). Figure 2 The effects of temperature and Bacillus subtilis -based probiotic on hippocampal (A) TLR4 protein concentrations, (B) TLR4 mRNA expressions, (C) HSP70 protein concentrations, and (D) HSP70 mRNA expressions in broilers at 43 d of age.…”
“…In the current study, overproduced TLR4 was found in the hippocampus of HS broilers regardless of dietary treatments ( P < 0.05, Figure 2A and B ). Similarly, overregulation of TRL4 in the hippocampus has been found in heat stress-induced neuroinflammation in mice ( Huang et al, 2022 ). Figure 2 The effects of temperature and Bacillus subtilis -based probiotic on hippocampal (A) TLR4 protein concentrations, (B) TLR4 mRNA expressions, (C) HSP70 protein concentrations, and (D) HSP70 mRNA expressions in broilers at 43 d of age.…”
“…Upon binding, GPR109a activates anti‐inflammatory signaling pathways, including Nrf2/HO‐1, and reduces p38 MAPK and NF‐κB signaling (Viatchenko‐Karpinski et al, 2022; Zhang et al, 2022). This is supported by in vivo data, demonstrating a reduction in microglial p38 MAPK/NF‐κB signaling following BHB supplementation in a heat‐stress model of neuroinflammation (Huang et al, 2022). The ketogenic diet is used clinically as non‐pharmacological adjuvant therapy for neurological disorders, such as multiple drug‐resistant epileptic syndromes where it significantly reduces the number and frequency of epileptic seizures (Caraballo, Flesler, et al, 2014; Caraballo, Fortini, et al, 2014; Sondhi et al, 2020; Wang et al, 2020).…”
Traumatic brain injury (TBI) is a devastating neurological disorder caused by a physical impact to the brain that promotes diffuse damage and chronic neurodegeneration. Key mechanisms believed to support secondary brain injury include mitochondrial dysfunction and chronic neuroinflammation. Microglia and brain‐infiltrating macrophages are responsible for neuroinflammatory cytokine and reactive oxygen species (ROS) production after TBI. Their production is associated with loss of homeostatic microglial functions such as immunosurveillance, phagocytosis, and immune resolution. Beyond providing energy support, mitochondrial metabolic pathways reprogram the pro‐ and anti‐inflammatory machinery in immune cells, providing a critical immunometabolic axis capable of regulating immunologic response to noxious stimuli. In the brain, the capacity to adapt to different environmental stimuli derives, in part, from microglia's ability to recognize and respond to changes in extracellular and intracellular metabolite levels. This capacity is met by an equally plastic metabolism, capable of altering immune function. Microglial pro‐inflammatory activation is associated with decreased mitochondrial respiration, whereas anti‐inflammatory microglial polarization is supported by increased oxidative metabolism. These metabolic adaptations contribute to neuroimmune responses, placing mitochondria as a central regulator of post‐traumatic neuroinflammation. Although it is established that profound neurometabolic changes occur following TBI, key questions related to metabolic shifts in microglia remain unresolved. These include (a) the nature of microglial mitochondrial dysfunction after TBI, (b) the hierarchical positions of different metabolic pathways such as glycolysis, pentose phosphate pathway, glutaminolysis, and lipid oxidation during secondary injury and recovery, and (c) how immunometabolism alters microglial phenotypes, culminating in chronic non‐resolving neuroinflammation. In this basic neurochemistry review article, we describe the contributions of immunometabolism to TBI, detail primary evidence of mitochondrial dysfunction and metabolic impairments in microglia and macrophages, discuss how major metabolic pathways contribute to post‐traumatic neuroinflammation, and set out future directions toward advancing immunometabolic phenotyping in TBI.image
“…Although several reports have described biochemical and neurophysiological changes occurring in the hippocampus following heat stress (Lee et al 2015 ; Moon et al 2017 ; Elvira et al 2020 ; Huang et al 2022 ), the impact of heat stress on adult hippocampal neurogenesis has been largely unaddressed. BHBA, a ketone body, has been shown to have neuroprotective roles in previous studies.…”
Section: Discussionmentioning
confidence: 99%
“…Recently, we found that BHBA processed properties of excellent anti-inflammatory effects in heat stress-treated mice (Huang et al 2022 ). Besides, the effects of heat stress on adult hippocampal neurogenesis and the underlying connections to cognitive dysfunction are unclear.…”
Heat stress has multiple potential effects on the brain, such as neuroinflammation, neurogenesis defects, and cognitive impairment. β-hydroxybutyric acid (BHBA) has been demonstrated to play neuroprotective roles in various models of neurological diseases. In the present study, we investigated the efficacy of BHBA in alleviating heat stress-induced impairments of adult hippocampal neurogenesis and cognitive function, as well as the underlying mechanisms. Mice were exposed to 43 ℃ for 15 min for 14 days after administration with saline, BHBA, or minocycline. Here, we showed for the first time that BHBA normalized memory ability in the heat stress-treated mice and attenuated heat stress-impaired hippocampal neurogenesis. Consistently, BHBA noticeably improved the synaptic plasticity in the heat stress-treated hippocampal neurons by inhibiting the decrease of synapse-associated proteins and the density of dendritic spines. Moreover, BHBA inhibited the expression of cleaved caspase-3 by suppressing endoplasmic reticulum (ER) stress, and increased the expression of brain-derived neurotrophic factor (BDNF) in the heat stress-treated hippocampus by activating the protein kinase B (Akt)/cAMP response element binding protein (CREB) and methyl-CpG binding protein 2 (MeCP2) pathways. These findings indicate that BHBA is a potential agent for improving cognitive functions in heat stress-treated mice. The action may be mediated by ER stress, and Akt-CREB-BDNF and MeCP2 pathways to improve adult hippocampal neurogenesis and synaptic plasticity.
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