Neurochemical Research最新文献

The shift of microglia towards an anti-inflammatory phenotype has been shown to decrease neuroinflammation, improve neurological function, and is considered a potential therapeutic approach for stroke. Abnormal expression of multiple long noncoding RNA (LncRNA) has been discovered to be crucially related to the pathogenesis progress of ischemic brain injury. Here we concentrated on a novel LncRNA NR_037961.1, which we named ischemic stroke associated LncRNA1 (LncRNA ISA1). The expression of LncRNA ISA1 was notably decreased in brain tissue of middle cerebral artery occlusion (MCAO) mice. Overexpression of LncRNA ISA1 decreases cerebral infarction and brain edema, and improves cerebral blood flow and neurological outcome, promoting recovery of MCAO mice. Additionally, the neuroprotective effects that LncRNA ISA1 plays on MCAO mice are mediated by encouraging the transformation of microglia toward anti-inflammatory phenotype and alleviating neuroinflammation. LncRNA ISA1 facilitates the phenotypic transformation of microglia, closely linked to its promotion of SOCS3 expression and subsequent inhibition of the JAK2/STAT3 signaling pathway. Furthermore, downregulation of SOCS3 eliminated the effects of LncRNA ISA1 on transformation of microglia to anti-inflammatory phenotype. Our results indicate that LncRNA ISA1 promotes the anti-inflammatory polarization of microglia via regulation of the SOCS3/JAK2/STAT3 signaling pathway, and contributes to its neuroprotective effects in ischemic stroke.

Subarachnoid hemorrhage (SAH) is a type of hemorrhagic stroke with high morbidity, mortality and disability, and early brain injury (EBI) after SAH is crucial for prognosis. Recently, stem cell therapy has garnered significant attention in the treatment of neurological diseases. Compared to other stem cells, dental pulp stem cells (DPSCs) possess several advantages, including abundant sources, absence of ethical concerns, non-invasive procurement, non-tumorigenic history and neuroprotective potential. Therefore, we aim to investigate whether DPSCs can improve EBI after SAH, and explore the mechanisms. In our study, we utilized the endovascular perforation method to establish a SAH mouse model and investigated whether DPSCs administered via tail vein injection could improve EBI after SAH. Furthermore, we used hemin-stimulated HT22 cells to simulate neuronal cell injury induced by SAH and employed a co-culture approach to examine the effects of DPSCs on these cells. To gain insights into the potential mechanisms underlying the improvement of SAH-induced EBI by DPSCs, we conducted bioinformatics analysis. Finally, we further validated our findings through experiments. In vivo experiments, we found that DPSCs administration improved neurological dysfunction, reduced brain edema, and prevented neuronal apoptosis in SAH mice. Additionally, we observed a decrease in the expression level of miR-26a-5p in the cortical tissues of SAH mice, which was significantly increased following intravenous injection of DPSCs. Through bioinformatic analysis and luciferase reporter assay, we confirmed the target relationship between miR-26a-5p and PTEN. Moreover, we demonstrated that DPSCs exerted neuroprotective effects by modulating the miR-26a-5p/PTEN/AKT pathway. Our study demonstrates that DPSCs can improve EBI after SAH through the miR-26a-5p/PTEN/AKT pathway, laying a foundation for the application of DPSCs in SAH treatment. These findings provide a theoretical basis for further investigating the therapeutic mechanisms of DPSCs and developing novel treatment strategies in SAH.

Neuropathic pain (NP) imposes a significant burden on individuals, manifesting as nociceptive anaphylaxis, hypersensitivity, and spontaneous pain. Previous studies have shown that traumatic stress in the nervous system can lead to excessive production of hydrogen sulfide (H₂S) in the gut. As a toxic gas, it can damage the nervous system through the gut-brain axis. However, whether traumatic stress in the nervous system leading to excessive production of H₂S in the gut can ultimately cause neuropathic pain through the gut-brain axis remains to be investigated. This study established a model of chronic constriction injury (CCI) in mice to determine its effects on gut H₂S production, the associated damage via the gut-brain axis, the potential neuropathic pain, as well as the probable mechanism. A CCI mouse model was developed using a spinal nerve ligation approach. Subsequently, the mechanical withdrawal threshold (MWT) and thermal withdrawal latency (TWL) were used to determine the mice’s pain thresholds. A variety of assays were performed, including immunofluorescence, western blotting, real-time quantitative Polymerase Chain Reaction (PCR), and membrane clamp whole-cell recordings. Mice subjected to CCI showed decreased MWT and TWL, decreased ZO-1 staining, decreased HuD staining, increased Glial fibrillary acidic protein (GFAP) staining, increased expression of tumor necrosis factor-alpha (TNF-α) protein and interleukin-6 (IL-6) protein, increased expression of NMDAR2B (NR2B) protein and NR2B mRNA, increased colocalization of vGlut2- and c-fos-positive cells, and a higher amplitude of evoked excitatory postsynaptic potential (EPSP) compared to Sham group. These changes were significantly reversed by H₂S inhibitor treatment, and the specific NMDA receptor inhibitor MK-801 effectively restored the neurotoxicity of H₂S. H₂S is involved in CCI-induced neuropathic pain in mice, which might be mediated by the activation of the NMDA signaling pathway.

In recent decades, researchers and clinicians have increasingly focused on glial cell function. One of the primary mechanisms influencing these functions is through extracellular vesicles (EVs), membrane-bound particles released by cells that are essential for intercellular communication. EVs can be broadly categorized into four main types based on their size, origin, and biogenesis: large EVs, small EVs (sEVs), autophagic EVs, and apoptotic bodies. Small EVs (sEVs) are involved in various physiological and pathological processes such as immune responses, angiogenesis, and cellular communication, primarily by transferring proteins, lipids, and nucleic acids to recipient cells. Interactions among glial cells mediated by small EVs can significantly modulate cell polarization and influence glial behavior through miRNA transfer. This communication, facilitated by small EVs in glial cells, is crucial for neuroinflammation, immune responses, and disease progression. This comprehensive review focuses on driven by glial small EVs, highlighting their roles in transporting biomolecules and modulating the functions of recipient cells. Furthermore, we provide an in-depth overview of the specific contributions of small EVs derived from three principal types of glial cells: oligodendrocytes, astrocytes, and microglia.

The specific pathogeneses of schizophrenia (SCZ) remain an enigma despite extensive research that has implicated both genetic and environmental factors. Recent revelations that dysregulated immune system caused by glial cell overactivation result in neuroinflammation, a key player in neurodegenerative as well as neuropsychiatric disorders including SCZ are providing novel clues on potential therapeutic interventions. Here, we review the roles of glial cells (Dr. Arne Schousboe’s passion) and two of their most implicated receptors, toll-like receptors (TLRs), and nicotinic cholinergic receptors, in SCZ pathology with suggestions as potential targets in this devastating neuropsychiatric condition.

Alzheimer’s disease (AD) is the most prevalent neurodegenerative disorder characterized by cognitive decline. Despite extensive research, therapeutic options remain limited. Varenicline, an α₄β₂ nicotinic acetylcholine receptor agonist, shows promise in enhancing cognitive function. This study aimed to evaluate varenicline’s effect on memory and hippocampal activity in rat model of AD. Forty-eight adult male Wistar rats were randomly assigned to control, sham, AD, and varenicline (0.1, 1, and 3 mg/kg/po for 14 days) groups. AD was induced by intracerebroventricular (i.c.v.) injection of 4 µl amyloid-beta (Aβ)₁₋₄₂ (1 µg/µl). Spatial learning and memory, hippocampal synaptic function, and CA1 electrophysiological activity were evaluated using appropriate methods. Barnes maze and T-maze behavioral tests revealed that varenicline, particularly at 1 mg/kg, significantly improved spatial memory compared to the AD group. Western blot analysis showed varenicline’s ability to upregulate synaptic proteins PSD-95, synaptophysin, and GAP-43 in the hippocampus, with the most significant effects observed at 1 mg/kg. Electrophysiological recordings demonstrated that varenicline at 1 mg/kg enhanced hippocampal long-term potentiation (LTP), indicating improved synaptic plasticity. Single-unit recordings showed an increase in spike count with varenicline administration. These findings suggest that varenicline, particularly at 1 mg/kg, ameliorates memory deficits in AD rats possibly through modulation of synaptic proteins and enhancement of hippocampal LTP and electrical activity. Further investigations are warranted to elucidate varenicline’s precise mechanisms of action in alleviating AD-induced cognitive deficits and its potential as a therapeutic intervention for AD-related cognitive impairment.

Graphical Abstract

Our aim was to evaluate the regulation of messenger RNAs (mRNAs) and biological pathways by long non-coding RNAs (lncRNAs) and circular RNAs (circRNAs) in ischemic stroke. We employed weighted gene co-expression network analysis (WGCNA) to construct two co-expression networks for mRNAs with circRNAs and lncRNAs, respectively, to investigate their association with ischemic stroke. We compared the overlap of mRNAs and biological pathways in the stroke-associated modules of the two networks. Furthermore, we validated the association of key non-coding RNAs with the risk of ischemic stroke and poor prognosis using quantitative real-time polymerase chain reaction. Ischemic stroke patients exhibited lower eigengene expression in the turquoise module associated with lncRNAs and mRNAs, as well as in the turquoise, red, and greenyellow modules associated with circRNAs and mRNAs in ischemic stroke. In the lncRNA-mRNA network and circRNA-mRNA network, we observed a significant overlap of the 5126 mRNAs (P < 0.001) and 51 biological pathways (P < 0.001), respectively. Among the ten key non-coding RNAs, lnc-TPRG1-AS1, lnc-GUK1, and hsa_circ_RELL1 were significantly increased (P < 0.05), while hsa_circ_ZBTB20 and hsa_circ_ERBB2 were significantly decreased (P < 0.05) in ischemic stroke. Additionally, ischemic stroke patients with poor functional outcome had significantly lower levels of hsa_circ_ZBTB20 and hsa_circ_ERBB2 compared to those with favorable prognosis (P < 0.05). Our findings suggest lncRNAs and circRNAs display similar biological functions in ischemic stroke. Key non-coding RNAs may be associated with the risk and clinical prognosis of ischemic stroke. These results warrant further validation in the future studies.

Glioblastoma (GBM) is the most malignant type of glioma with a very poor prognosis. N6-methyladenosine (m6A) is well-documented to be involved in GBM progression, and FTO is a demethylase. GSTO1 is also associated with tumor progression. This study aimed to investigate the impact of FTO and GSTO1 on GBM progression and the regulation of FTO on m6A modification of GSTO1. T98G cell phenotypes including proliferation and apoptosis were analyzed by cell counting kit 8, colony formation assay, and flow cytometry. The regulation of m6A methylation mediated by FTO was evaluated by methylated RNA immunoprecipitation, RNA immunoprecipitation, and dual-luciferase reporter assay. The results showed that FTO expression was downregulated in GBM. Overexpression of FTO inhibited cell proliferation and facilitated apoptosis in vitro. Additionally, GSTO1 expression was elevated in GBM, and knockdown of GSTO1 suppressed cell proliferation and promoted apoptosis and oxidative stress. Moreover, FTO inhibited m6A methylation of GSTO1 and reduced the stability of GSTO1. Overexpression of GSTO1 abrogated T98G cellular processes mediated by FTO. The in vivo experiments showed that FTO inhibited tumor growth by downregulating GSTO1 expression. In conclusion, FTO decelerates GBM progression by inducing apoptosis through suppressing m6A methylation of GSTO1.

Methionine sulfoximine (MSO) is a compound originally discovered as a byproduct of agene-based milled flour maturation. MSO irreversibly inhibits the astrocytic enzyme glutamine synthase (GS) but also interferes with the transport of glutamine (Gln) and of glutamate (Glu), and γ-aminobutyric acid (GABA) synthesized within the Glu/Gln-GABA cycle, in this way dysregulating neurotransmission balance in favor of excitation. No wonder that intraperitoneal administration of MSO has long been known to induce behavioral and/or electrographic seizures. Recently, a temporal lobe epilepsy (TLE) model based on local continuous infusion of MSO into the hippocampus has been developed reproducing the main features of human mesial TLE: induction of focal seizures, their spreading, increase in intensity over time, and development of spontaneous recurrent seizures. Fully developed TLE in this model is associated with hippocampal degeneration, hallmarked by reactive astrogliosis, and causally related to the concomitant loss of GS-containing astrocytes. By contrast, short-term pre-exposure of rats to relatively low MSO doses that only moderately inhibited GS, attenuated and delayed the initial seizures in the lithium-pilocarpine model of TLE and in other seizure-associated contexts: in the pentylenetetrazole kindling model in rat, and in spontaneously firing or electrically stimulated brain slices. The anti-initial seizure activity of MSO may partly bypass inhibition of GS: the postulated mechanisms include: (i) decreased release of excitatory neurotransmitter Glu, (ii) prevention or diminution of seizure-associated brain edema, (iii) stimulation of glycogenesis, an energy-sparing process; (iv) central or peripheral hypothermia. Further work is needed to verify either of the above mechanisms.