Neurochemical Research最新文献

Astrocytes play a crucial role in regulating the structure, function, and interactions between the synaptic and vascular compartments in the brain. Toll-like receptor 3 (TLR3) is expressed in astrocytes and recognizes double-stranded RNA (dsRNA), a pathogen-associated molecular pattern (PAMP). This review examines the current understanding of TLR3 signaling, with a focus on its specific role in astrocytes, and the use of the viral mimetic polyinosinic: polycytidylic acid (poly(I: C)) to model the effects of viral infections in both in vitro and in vivo studies. Poly(I: C) is a useful tool for studying neuro-immune communication and has significantly added to our knowledge of how the brain responds to immune challenges. Upon poly(I: C) exposure, TLR3 activation in astrocytes triggers inflammatory signaling pathways, leading to both antiviral responses and neuroinflammation. However, further research is required to investigate the cell-specific impacts of TLR3 activation, along with the influence of developmental stages, brain regions, and sex-specific responses, to gain a comprehensive understanding of how immune activation shapes the development and function of the central nervous system (CNS).

Cerebral ketone bodies are crucial for understanding both physiological brain metabolism and pathological states, such as diabetic ketoacidosis (DKA). However, the metabolic consequences of elevated ketone body levels on brain metabolism during DKA remain poorly described to date. In this study, we utilized non-invasive magnetic resonance spectroscopy to detect and quantify ketone bodies and their correlation with neurotransmitter and neurotransmitter precursor levels in situ in the living brain of the streptozotocin (STZ)-induced type 1 diabetes (T1D) rat model. This well-characterized T1D model develops insulin deficiency with chronic hyperglycemia, which can trigger DKA. We report the detection and quantification of the acetone signal at 2.22 ppm in the STZ-induced T1D rat brain, along with two other ketone bodies, β-hydroxybutyrate and acetoacetate at 9.4 T. Cerebral levels of all three ketone bodies significantly increased as diabetes progressed compared to baseline levels prior to STZ injection. Moreover, ketone body levels correlated strongly with the inhibitory neurotransmitter γ-aminobutyric acid (GABA) and glutamine, as well as several other neurochemicals. Overall, DKA is characterized by a marked increase in brain ketone bodies as T1D progresses, accompanied by elevated GABA and glutamine levels. This study demonstrates the direct measurement of ketone bodies in the brain in vivo, enabling further investigation of their impact on brain metabolism in both health and disease.

In the clinical settings, patients often develop opioid-induced hyperalgesia (OIH) after utilization of high dose intra-operative remifentanil. It is widely considered that systemic α₂ agonists, including dexmedetomidine (DEX), have the potential to mitigate postoperative pain and minimize the needs for opioid, thus leading to a decrease in the incidence of hyperalgesia. However, the regulating method remains ambiguous. Recent studies have shown that DEX can alleviate spinal nerve injury via regulating P2 X 4. Although the effects of DEX on remifentanil-induced hyperalgesia (RIH) have been previously reported, the specific mechanisms remain to be fully elucidated. The objective of our study was to investigate the potential of intraperitoneal injections of DEX in attenuate RIH in rats through the modulation of P2 X 4Rs and brain-derived neurotrophic factor (BDNF) in spinal cord. The findings of this study indicate that intraperitoneal administration of DEX at a dosage of 50 µg/kg could alleviate mechanical allodynia and thermal hyperalgesia, as demonstrated through a behavioral test. Moreover, DEX suppressed the enhancement of P2 X 4 and BDNF expression induced by RIH. Furthermore, the structure of synaptic clefts caused by RIH showed improvement to a certain extent after DEX treatment, as shown using TEM transmission electron microscopy. In summary, we examined the protective effect of DEX on remifentanil-induced hyperalgesia. The findings indicates that the reduced expression of P2 X 4 and decreased synthesis and release of BDNF may be responsible for the analgesic processes. This study would provide a new perspective and strategy for the pharmacological treatment on RIH.

Microglia are the drivers of neuroinflammation. Microglia activation plays a critical role in the pathogenesis of aging. However, the mechanisms underlying microglial activation during aging are still not fully understood. Here, we investigated the role of S-adenosylmethionine (SAM) and its interplay with microglial activation in aging. In this study, we investigated the effect of SAM on BV2 cells treated with D-galactose (D-gal) and its molecular mechanism by Cell Counting Kit-8 (CCK8) assay, Senescence-associated β-Galactosidase (SA-β-gal) staining, western blot and immunofluorescence. We found that D-gal could induce microglia senescence. SAM intervention induced a significant decrease in the levels of inducible nitric oxide synthase (iNOS), tumor necrosis factor-α (TNF-α) and interleukin-1β (IL-1β) and increased arginase-1 (Arg1), α7 nicotinic acetylcholine receptor (α7nAChR), nuclear factor erythrocyte 2-related factor 2 (Nrf2) and heme oxygenase 1 (HO-1) expression. Moreover, after administration of α7nAChR selective antagonist methyllycaconitine citrate (MLA), our results showed that SAM enhanced expression of α7nAChR, Nrf2 and HO-1, promoted the transformation of microglia from M1 to M2 subtype, and decreased the proinflammatory cytokines compared with MLA + D-gal group. These results suggest that SAM attenuates neuroinflammation by inhibiting microglia polarization through the α7nAChR/Nrf2/HO-1 pathway.

Graphical Abstract

Glioblastoma (GBM) is a highly malignant and aggressive brain tumor with a remarkably poor prognosis and is one of the greatest challenges in the field of neurosurgery. Keratin 80 (KRT80) is primarily expressed in epithelial cells and is involved in the stability and integrity of cellular structures. Although it plays a role in skin and hair follicle development, its function in bridging cancer cells with metabolic pathways is gradually being revealed, such as its activation of glycolysis pathways to promote tumor proliferation. Ring finger protein 8 (RNF8) is an E3 ubiquitin ligase, whose expression has been documented to be significantly reduced in gliomas. Predictions from multiple databases suggest that KRT80 may bind specifically with RNF8. This study aimed to explore the function of KRT80 in GBM procession and the regulatory mechanism between RNF8 and KRT80. We confirmed that KRT80 promoted cell proliferation by constructing overexpression and knockout cell lines. This was also demonstrated by in vivo tumor formation experiments. Besides, higher caspase3/9 activity induced by KRT80 knockout prompted active apoptosis, which was confirmed by flow cytometry showing increased rate of apoptosis. Results also found KRT80 overexpression caused the activation of glycolytic pathways (glucose transporter 1, hexokinase2, and lactate dehydrogenase A) by real-time PCR and the increase of metabolites levels by non-targeted metabolomics. Immunofluorescence co-localization and co-immunoprecipitation assays showed RNF8 attenuated KRT80-induced adverse effects via influencing its ubiquitination degradation. In conclusion, KRT80 is regulated by RNF8-mediated ubiquitination, promoting glycolysis and the progression of GBM.

Graphical Abstract

KRT80, regulated by RNF8-mediated ubiquitination, plays a key role in glucose metabolic reprogramming, enhancing energy production and promoting the aggressive progression of GBM.

Alzheimer’s disease (AD) is a prevalent neurodegenerative disorder that is typified by the formation of senile plaques containing Aβ and neurofibrillary tangles containing tau in a hyperphosphorylated state. Celastrol, a natural compound, has proven effective in alleviating AD pathology by enhancing autophagy and reducing tau aggregates. The present study investigates the neuroprotective mechanisms of celastrol, with a particular focus on the participation of the transcription factor T-box transcription factor 21 (TBX21) and triggering receptor expressed on myeloid cells 2 (TREM2) in microglial cells. In AD mouse models, celastrol upregulated TBX21 and TREM2, suppressed phosphorylated tau and inflammatory cytokines, and restored neuronal viability. In vitro, celastrol-treated microglia enhanced neuronal survival under amyloid-beta (Aβ) stress, effects abolished by TBX21/TREM2 knockdown. Mechanistically, TBX21 directly bound the TREM2 promoter to regulate its expression. These findings identified the TBX21-TREM2 axis as a therapeutic target for AD.

Status epilepticus (SE) is a life-threatening disorder associated with neuronal pyroptosis. This study aims to explore the mechanism of HDAC1 in hippocampal neuronal pyroptosis induced by kainic acid in mice, providing a theoretical basis for SE treatment. A mouse model of SE was established by kainic acid. After sh-HDAC1 injection, the severity of SE and hippocampal neuronal damage were assessed. Cell model was established using kainic acid-induced HT22, followed by detection of HDAC1, miR-15a-5p, Caspase-1, cleaved Caspase-1, H3K9ac, and GSDMD-N using qRT-PCR and Western blot assays. Levels of IL-1β, IL-18, and LDH were measured. The enrichment of HDAC1 on the miR-15a-5p promoter was detected. The binding of miR-15a-5p to Caspase-1 was validated. We found that HDAC1 was highly expressed in kainic acid-induced SE. HDAC1 knockdown alleviated the symptoms of SE, inhibited cleaved Caspase-1, GSDMD-N, IL-1β, and IL-18, and suppressed hippocampal neuronal pyroptosis. HDAC1 bound to the miR-15a-5p promoter and reduced H3K9ac, thereby inhibiting miR-15a-5p expression. miR-15a-5p bound to Caspase-1 and inhibited Caspase-1 expression. Inhibiting miR-15a-5p or overexpressing Caspase-1 partially reversed the inhibitory effect of si-HDAC1 on kainic acid-induced cell pyroptosis. In conclusion, HDAC1 aggravates hippocampal neuronal pyroptosis in SE via the miR-15a-5p/Caspase-1 axis through deacetylation of H3K9.

Several psychopathologies may be triggered, among other factors, by stress or trauma in childhood. The maternal deprivation model (MD) replicates some of the core factors that may induce the onset of different psychopathologies like structural and plasticity defects. Among other brain regions, the amygdala is susceptible to stress and trauma and plays a key role in integrating social behavior. Several molecules, such as Cerebrolysin^® (CBL), have been used to treat different symptoms by reversing the underlying neurobiological plasticity-related changes. In this study, maternal deprivation (MD) was conducted on 9-day-old male Sprague-Dawley rats (n = 28; 7 rats per group: Intact, Intact + CBL, MD, and MD + CBL). At 25 postnatal days (PND), CBL treatment was administered for 10 consecutive days, and social behavior was evaluated in a three-chamber social test at 35 PND. Moreover, Sholl analysis and immunohistochemistry were carried out for dendritic intersection and brain-derived neurotrophic factor (BDNF) presence in the amygdala, respectively. CBL treatment had an augmentative effect on intact animals in terms of social behavior and incidences, but no differences between MD and CBL-treated animals. Moreover, dendritic intersections and BDNF decreased after the MD protocol but increased by CBL treatment in MD animals. Our results show that CBL could be part of the treatment in case of a traumatic or stressful event in neurodevelopment, especially in the youth age. According to this preclinical study, CBL could help reverse symptoms of different psychopathologies caused by stress or trauma, with neurobiological changes underlying its effect.