Neuroreport最新文献

Poststroke depression (PSD) affects approximately one-third of stroke survivors, contributing to poor outcomes and elevated mortality. This study aimed to investigate the therapeutic effects of hydrogen sulfide (H2S), administered as sodium hydrosulfide (NaHS), on PSD-induced inflammation, with a focus on the modulation of the cyclic GMP-AMP synthase (cGAS)-stimulator of interferon gene (STING) pathway and the enhancement of endoplasmic reticulum (ER) autophagy in microglial cells. An in-vivo rat model was established to evaluate the effects of NaHS on depression-like behaviors and inflammation. Mechanistic studies were conducted in vitro using BV2 microglia subjected to oxygen-glucose deprivation (OGD) and corticosterone. Key inflammatory markers, cGAS-STING pathway activity, and ER-autophagy-related proteins were analyzed using quantitative reverse transcription PCR, Western blotting, ELISA, transmission electron microscopy, and immunofluorescence staining. Depression-like behaviors in rats were assessed using the forced swimming and tail suspension tests. H2S treatment ameliorated depression-like symptoms, mitigated hippocampal damage, and reduced pro-inflammatory markers, including NOD-like receptor protein 3, interleukin-1β (IL-1β), and IL-18 by inhibiting the cGAS-STING pathway. Furthermore, H2S significantly upregulated autophagy-related proteins (LC3, Beclin-1, and FAM134B) and autophagic vesicles, indicating enhanced ER autophagy. Notably, silencing FAM134B reversed the inhibitory effects of H2S on the cGAS-STING pathway, underscoring the pivotal role of ER autophagy in H2S-mediated neuroprotection. These findings demonstrate that H2S mitigates PSD-induced microglial inflammation and depression-like behaviors by inhibiting the cGAS-STING pathway and promoting ER autophagy, suggesting its potential as a therapeutic strategy for PSD. Further investigation into H2S and autophagy-related pathways could reveal novel therapeutic avenues for neuroinflammatory conditions.

To investigate the effects of resveratrol (RES) on cognitive function and its modulation of the NRF2/HO-1 signaling pathway in a rodent model of postoperative cognitive dysfunction (POCD). A POCD model was established in aged Sprague-Dawley rats using sevoflurane anesthesia and laparotomy. Rats were divided into four groups: control, POCD, RES, and POCD + RES. Cognitive performance was assessed using the Morris water maze. Hippocampal tissues were analyzed for neuronal condition using hematoxylin and eosin and Nissl staining. The expression levels of inflammatory cytokines and oxidative stress markers were quantified by enzyme-linked immunosorbent assay. The messenger RNA and protein levels of NRF2, KEAP1, HO-1, and SOD2 were measured using real-time quantitative polymerase chain reaction and western blotting. RES treatment improved cognitive function, as evidenced by reduced escape latency and increased platform crossings in the Morris water maze. Histopathological analysis showed restoration of hippocampal structure and increased neuronal viability. RES significantly reduced proinflammatory cytokines interleukin (IL)-1 and IL-6 while increasing IL-10 levels. In addition, RES activated the NRF2/HO-1 pathway by upregulating NRF2, HO-1, and SOD2 expression while downregulating KEAP1. RES mitigates cognitive deficits in POCD by reducing neuroinflammation and oxidative stress through activation of the NRF2/HO-1 signaling pathway. These findings suggest RES is a potential therapeutic candidate for the treatment of POCD in elderly patients.

Traumatic brain injury (TBI) is often accompanied by secondary brain injury (SBI), with neuroinflammation being a core mechanism of SBI. Pyroptosis is a key driver of neuroinflammatory responses, and inhibiting pyroptosis can reduce neuroinflammation after TBI and promote tissue and functional recovery. The activation of the NLRP3 inflammasome mediates the classical pyroptosis pathway, and ticagrelor can inhibit NLRP3 inflammasome activation. This study aimed to investigate the differences in pyroptosis inhibition induced by TBI with different doses of ticagrelor by targeting the activation of the NLRP3 inflammasome. Mice were randomly divided into four groups: sham, TBI, 50 mg/kg ticagrelor treatment, and 150 mg/kg ticagrelor treatment. After 24 h of treatment, brain tissue surrounding the injury was collected for immunoblot detection of pyroptosis-related protein expression and ELISA detection of inflammatory cytokine release. On day 3 after treatment, BBB permeability and brain edema were assessed by injection of Evans blue and measurement of brain tissue water content. On day 7 after treatment, mice were sacrificed, and the extent of injury was assessed through hematoxylin and eosin and Nissl staining, while the levels of pyroptosis markers and neuroinflammation in brain tissue were detected by immunohistochemistry. On day 21 after treatment, the Morris water maze was used to evaluate neural function recovery. Compared with the TBI group, high-dose ticagrelor treatment inhibited pyroptosis in mouse brain tissue, reduced the release of inflammatory cytokines, alleviated brain edema, lowered neuroinflammation levels, and promoted neural function recovery (P < 0.05). Therefore, ticagrelor holds promise as a clinical drug for treating TBI.

Acute cerebral infarction (CI) is characterized by acute onset, high disability rate, and high morbidity rate, which seriously threatens the health and safety of people and places a heavy burden on individuals and the country. This study aimed to explore the effects of butylphthalide on nerve cell ferroptosis in CI rats and its underlying mechanisms. Middle cerebral artery occlusion (MCAO) rat model was used to study the effect of butylphthalide on acute CI in vivo and oxygen glucose deprivation (OGD) model was used to study the effect of butylphthalide on acute CI in vitro. Our findings demonstrated that butylphthalide markedly reduced oxidative damage and ferroptosis in the brains of MCAO rats. Furthermore, we found that butylphthalide upregulated the netrin-1/deleted in colorectal cancer (DCC)/vascular endothelial growth factor (VEGF) signaling axis, which regulates NF-E2-related factor-2 (NRF2) expression and contributes to ferroptosis in the MCAO rat model and OGD-treated HT22 cells. Collectively, our findings indicate that butylphthalide inhibits oxidative stress-mediated ferroptosis in the MCAO rat model and OGD-treated HT22 cells by modulating the netrin-1/DCC/VEGF/NRF2 axis. In conclusion, our results reveal a novel mechanism for the protection of acute CIs by butylphthalide.

This study explored the role of cathepsin B (CTSB) in optic nerve regeneration. Sprague-Dawley rats were utilized for optic nerve crush and long-range crush injury model. Gene and protein expression changes were analyzed via reverse transcription quantitative polymerase chain reaction and western blot. Primary cortical neurons and BV2 cells were cultured to assess CTSB's effects on neuronal outgrowth and microglial activity. Local CTSB administration degraded chondroitin sulfate proteoglycans (CSPGs), promoting axonal growth in-vivo. In-vitro, CTSB neutralized CSPG-mediated inhibition of neuronal growth. Quantitative proteomics revealed elevated microglial marker proteins in the regenerative environment. Activation of signal transducer and activator of transcription 3 (STAT3) and signal transducer and activator of transcription 6 (STAT6) pathways in BV2 cells increased CTSB secretion. These findings suggest that postinjury regenerative microenvironment reconstruction is associated with upregulated CTSB, which degrades CSPGs to facilitate axonal growth. Microglia-derived CTSB, regulated by STAT3/STAT6 signaling, may play a key role in this process. Modulating CTSB expression could thus be a therapeutic strategy to enhance optic nerve regeneration by modifying the injury microenvironment.

DNA-dependent protein kinase catalytic subunit (DNA-PKcs) is one of the key enzymes involved in DNA double-strand break (DSB) repair. However, recent studies using DNA-PKcs knockout mice revealed that DNA-PKcs plays an important role in neuronal plasticity. The aim of this study was to examine the role of DNA-PKcs on synaptic plasticity in severe combined immunodeficiency disease (SCID) mice that carry a mutation resulting in a DNA-PKcs protein devoid of kinase activity but still expressed in cells, although with a small COOH-terminal truncation. To this aim, we carried out electrophysiological and molecular analysis on hippocampal slices from wild-type (WT) and SCID mice. Electrophysiological analysis showed an impairment in the basal synaptic transmission in SCID mice compared with WT, whereas paired-pulse facilitation, caused by presynaptic mechanisms, was not different in the two groups of animals. By contrast, tetanic stimulation induced long-term potentiation (LTP) with values that were approximately 43% lower in slices from SCID mice compared with WT. The same slices used for electrophysiology were analyzed to study the phosphorylation state of cAMP response element-binding protein (CREB) and extracellular signal-regulated kinases and to evaluate mRNA expression levels of CREB-target genes at different times after LTP induction. In conclusion, molecular analysis did not show significant differences between SCID and WT brain slices, thus confirming the evidence that DNA-PKcs kinase activity directly regulates neuronal functions and plays a novel role beyond DSB repair. Moreover, these results indicate that studies using SCID mice involving analysis of synaptic function need to be interpreted with caution.

This study was conducted to examine the effects and mechanisms of hypoxia-preconditioned human dental pulp stem cells (H-hDPSCs) transplantation on microglial pyroptosis in neonatal rats with hypoxic-ischemic brain damage (HIBD). The hDPSCs were extracted using the tissue block method and identified by immunofluorescence staining. The HIBD model was constructed using the classical Rice-Vannucci method. 24 h after HIBD, normoxic preconditioning hDPSCs (N-hDPSCs) and H-hDPSCs were transplanted into the lateral ventricle. The brain damage was examined by hematoxylin & eosin and Nissl stainings 72 h after transplantation. The expression of signal transducer and activator of transcription 3 (STAT3)/NOD-like receptor family pyrin domain-containing 3 (NLRP3)/Caspase-1 axis-related proteins was analyzed by immunofluorescence staining and western blots. Tissue levels of interleukin-1 beta (IL-1β) were derived from ELISA. After modeling, the neural cells in the HIBD group were disordered and sparsely scattered, with a deficiency of nitrosamines. The data revealed that the phosphorylated STAT3, NLRP3, Cleaved-Caspase 1, N-terminal fragment of gasdermin D (GSDMD-N), and IL-1β protein expression were significantly lower in the H-hDPSCs and N-hDPSCs groups compared to the HIBD group. The protein expression in the H-hDPSCs group was considerably lower than in the N-hDPSCs group. H-hDPSCs may protect microglia from pyroptosis by regulating the STAT3/NLRP3/Caspase-1/GSDMD axis to alleviate inflammatory damage, and attenuate HIBD in newborn rats at the same time. Moreover, the therapeutic effect of H-hDPSCs transplantation was superior to that of N-hDPSCs transplantation.

Asexuality has a prevalence of approximately 1% in the population and should not be confused with hypoactive sexual desire disorder as defined in the DSM-5. Asexuality is characterized by minimal to no sexual attraction to others. The neural correlates of asexuality remain largely unknown, and the test-retest reliability of sexually induced brain activity is still elusive. In this functional MRI study, we used the Asexual Identification Scale to identify 14 asexual women (mean score ~ 46) and 21 sexual women (mean score ~ 14). We modeled brain activity in response to sexual stimuli using the canonical hemodynamic response function and performed voxel-wise test-retest reliability analysis on contrast weight maps. Additionally, we applied pattern recognition methods to distinguish asexual from sexual women. The voxel-wise test-retest reliability of brain activity in response to sexual stimuli was remarkably robust for sexuality relevant brain areas [mean ICC(2,1) = 0.66]. The conjunction analysis comparing sexual stimuli to baseline showed that group brain activity was reproducible at a Bonferroni-corrected P value of 1.78e -6 . The direct contrast between asexual and sexual women yielded no significant differences at the single-voxel level. A support vector machine, however, identified 71% ( P  < 0.03) of asexual and sexual women correctly when test and retest runs were combined. In conclusion, although our sample size is small, our findings suggest that differences between asexual and sexual women may have their neural roots in subtle variations in brain activity across extensive brain regions, which might be identified using classification methods.

Electroacupuncture (EA) demonstrates neuroprotective in cerebral ischemia-reperfusion (I/R) injury. N6-methyladenosine (m6A) is found to contribute to the pathogenesis of neurological conditions recently. The objective of this study is to investigate the effects of EA on m6A and related mechanism in cerebral I/R injury. After the middle cerebral artery occlusion/reperfusion (MCAO/R) operation was used to establish rat models with cerebral I/R injury, EA was applied to Baihui (GV20) and Dazhui (GV14) once daily for 7 consecutive days. Subsequently, the modified Neurological Severity Score, 2,3,5-triphenyltetrazolium chloride staining, and hematoxylin and eosin staining were performed to assess the neurological damage. To investigate the potential target, the total RNA m6A level and relevant regulators (METTL3, METTL14, WTAP, FTO, and ALKBH5) were examined. In the next step, FTO, Nrf2, NLRP3, IL-18, IL-1β, and TUNEL-positive rates were detected, while the shRNA-FTO was administered to suppress FTO expression. EA improved neurobehavioral disorders, infarct volume, and pathological damage induced by cerebral I/R injury. Mechanically, EA reduced the total RNA m6A level by selectively regulating FTO, but not METTL3, METTL14, WTAP, and ALKBH5. Furthermore, EA could enhance Nrf2 and suppress NLRP3, IL-18, IL-1β, and TUNEL-positive rates, which was reversed by the shRNA-FTO injection. Our findings indicate that EA may alleviate FTO/Nrf2/NLRP3 axis-mediated pyroptosis in cerebral I/R injury, providing a more unified understanding of the neuroprotective effects of EA. Specifically, EA intervention appears to promote the expression of FTO, leading to a reduction of m6A level, which activates Nrf2 and subsequently suppresses NLRP3-mediated pyroptosis.

Autistic traits exist on a continuum within the general population, yet how these traits influence regional neural activity during real-world social interactions remains unclear. Using functional near-infrared spectroscopy (fNIRS), we investigated how autistic traits relate to the fractional amplitude of low-frequency fluctuations (fALFF) during both resting-state and real-time conversations in 62 high autistic trait and 58 low autistic trait neurotypical adults. While resting-state differences were minimal, significant group differences emerged during conversation. Specifically, individuals with high autistic traits showed lower ΔfALFF in the right superior temporal gyrus, with the largest differences observed during emotionally positive topics. Interestingly, although fALFF strongly correlated with functional connectivity across both states, only ΔfALFF demonstrated sensitivity to autistic traits. These findings reveal state-dependent neural differences linked to autistic traits, emphasizing the importance of studying brain activity during naturalistic social interactions. Our results provide new insights into how autistic traits modulate neural processing during dynamic social contexts and suggest fALFF change as a sensitive marker for studying social processing differences.