NLRP3-GABA signaling pathway contributes to the pathogenesis of impulsive-like behaviors and cognitive deficits in aged mice.

BACKGROUND: Perioperative neurocognitive disorders (PND), such as delirium and cognitive impairment, are commonly encountered complications in aged patients. The inhibitory neurotransmitter γ-aminobutyric acid (GABA) is aberrantly synthesized from reactive astrocytes following inflammatory stimulation and is implicated in the pathophysiology of neurodegenerative diseases. Additionally, the activation of NOD-like receptor protein 3 (NLRP3) inflammasome is involved in PND. Herein, we aimed to investigate whether the NLRP3-GABA signaling pathway contributes to the pathogenesis of aging mice's PND. METHODS: 24-month-old C57BL/6 and astrocyte-specific NLRP3 knockout male mice were used to establish a PND model via tibial fracture surgery. The monoamine oxidase-B (MAOB) inhibitor selegiline (1 mg/kg) was intraperitoneally administered once a day for 7 days after the surgery. PND, including impulsive-like behaviors and cognitive impairment, was evaluated by open field test, elevated plus maze, and fear conditioning. Thereafter, pathological changes of neurodegeneration were explored by western blot and immunofluorescence assays. RESULTS: Selegiline administration significantly ameliorated TF-induced impulsive-like behaviors and reduced excessive GABA production in reactive hippocampal astrocytes. Moreover, astrocyte-specific NLRP3 knockout mice reversed TF-induced impulsive-like and cognitive impairment behaviors, decreased GABA levels in reactive astrocytes, ameliorated NLRP3-associated inflammatory responses during the early stage, and restored neuronal degeneration in the hippocampus. CONCLUSIONS: Our findings suggest that anesthesia and surgical procedures trigger neuroinflammation and cognitive deficits, which may be due to NLRP3-GABA activation in the hippocampus of aged mice.

[Systemic Influencing Factors of Dentition Defect in Type 2 Diabetes Mellitus Patients with Periodontitis].

Objective: To analyze the influencing factors of dentition defect in people with type 2 diabetes mellitus (T2DM) and periodontitis and to provide evidence-based support for improving the oral health and quality of life of T2DM patients. Methods: A total of 169 patients with T2DM and periodontitis were selected by convenience sampling. According to the number of remaining teeth, the subjects were divided into two groups, group A (number of remaining teeth in the mouth≥20, n=115) and group B (the number of remaining teeth in the mouth<20, n=54). Questionnaire surveys, systemic and oral examinations, and laboratory blood tests were performed. Systematic influencing factors of dentition defect in people with T2DM and periodontitis were analyzed with logistic regression. Results: Compared with patients in group A, patients in group B had higher findings in age, systolic blood pressure (SBP), prevalence of coronary heart disease and hyperlipidemia, glycosylated hemoglobin (HbA1c), periodontal probing depth (PD), and clinical attachment loss (CAL). Furthermore, their behaviors and awareness of oral health were not as good as those of patients in group A. Logistic regression showed that age, HbA1c, and SBP were independent risk factors for the number of remaining teeth in the mouth <20 among T2DM patients with periodontitis ( P<0.05). Conclusion: Increasing age, lower HbA1c, and increased SBP are the most important influencing factors for the number of remaining teeth in the mouth <20 in T2DM patients with periodontitis. Clinical practitioners should give more attention to the general health status of the patients and strengthen health education, thereby improving patients' quality.

STING mediates neuroinflammatory response by activating NLRP3-related pyroptosis in severe traumatic brain injury.

Long-term neurological deficits after severe traumatic brain injury (TBI), including cognitive dysfunction and emotional impairments, can significantly impair rehabilitation. Glial activation induced by inflammatory response is involved in the neurological deficits post-TBI. This study aimed to investigate the role of the stimulator of interferon genes (STING)-nucleotide-binding oligomerization domain-like receptor pyrin domain-containing-3 (NLRP3) signaling in a rodent model of severe TBI. Severe TBI models were established using weight-drop plus blood loss reinfusion model. Selective STING agonist ADU-S100 or antagonist C-176 was given as a single dose after modeling. Further, NLRP3 inhibitor MCC950 or activator nigericin, or caspase-1 inhibitor VX765, was given as an intracerebroventricular injection 30 min before modeling. After that, a novel object recognition test, open field test, force swimming test, western blot, and immunofluorescence assays were used to assess behavioral and pathological changes in severe TBI. Administration of C-176 alleviated TBI-induced cognitive dysfunction and emotional impairments, neuronal loss, and inflammatory activation of glia cells. However, the administration of STING agonist ADU-S100 exacerbated TBI-induced behavioral and pathological changes. In addition, STING activation exacerbated pyroptosis-associated neuroinflammation via promoting glial activation, as evidenced by increased cleaved caspase-1 and GSDMD N-terminal expression. In contrast, the administration of C-176 showed anti-pyroptotic effects. The neuroprotective effects of C-176 were partially reversed by the NLRP3 activator, nigericin. Collectively, glial STING is responsible for neuroinflammation post-TBI. However, pharmacologic inhibition of STING led to a remarkable improvement of neuroinflammation partly through suppressing NLRP3 signaling. The STING-NLRP3 signaling is a potential therapeutic target in TBI-induced neurological dysfunction.

Decreased LF/HF ratio is associated with worse outcomes in patients who received mechanical thrombectomy under general anesthesia for emergent large vessel occlusion: a retrospective study.

BACKGROUND AND PURPOSE: We aimed to determine whether heart rate variability (HRV) was correlated to long-term outcome in patients who received mechanical thrombectomy (MT) under general anesthesia for emergent large vessel occlusion (ELVO). METHODS: Data from 106 patients receiving MT under general anesthesia to treat ELVO between January 1, 2017 and December 31, 2019 were collected in a multicenter chart review. Univariate analysis, Chi-square test, and bivariate logistic regression were performed to assess the correlations between preoperative risk factors such as HRV and long-term outcome (as indicated by the modified Rankin score [mRS] at 90 days after MT). RESULTS: Bivariate logistic regression revealed that decreased LF/HF (low frequency/high frequency in HRV) ratio was correlated with unfavorable functional outcome as indicated by mRS ≥ 2 (odds ratio [OR], 0.650; 95% confidence interval [CI], 0.157-0.839; p = 0.018), and functionally dependent outcome as indicated by mRS ≥ 3 (OR, 0.704; 95% CI, 0.360-0.914; p = 0.021). It was also found that ELVO in the right anterior circulation was correlated with lower LF/HF ratio, as compared with ELVO in the contralateral side (p < 0.05). CONCLUSION: Our retrospective study demonstrated that worse outcome in patients with ELVO who received MT under general anesthesia induced autonomic changes and that decreased LF/HF ratio.

Decrease of Coronal Optic Nerve Sheath Diameter is Associated With Postoperative Cognitive Decline in Patients Undergoing Carotid Endarterectomy.

OBJECTIVE: Patients undergoing carotid endarterectomy (CEA) have a significant possibility of developing postoperative cognitive decline (POCD). POCD after surgery could be result from cerebral hypotension induced by cross-clamping or postoperative hyperperfusion. Optic nerve sheath diameter (ONSD) exhibits an excellent correlation with invasive intracranial pressure monitoring, Here, the authors explored the risk factors of POCD in patients undergoing CEA, paying close attention to ONSD to test the hypothesis that decrease of coronal ONSD was related to the incidence of POCD. DESIGN: Observational retrospective review. SETTING: Single tertiary academic center. PARTICIPANTS: One hundred sixteen patients undergoing CEA from January 1, 2019 to December 31, 2019. INTERVENTION: None. MEASUREMENTS AND MAIN RESULTS: A multivariate logistic regression, scatter diagrams, and a receiver operating curve were used to evaluate the ability to predict POCD though the change in coronal ONSD. This study ultimately enrolled 84 patients and the incidence of POCD within postoperative two days was 28.6%. Decrease of coronal ONSD (odds ratio [OR], 0.438; 95% confidence interval [CI] 0.217-0.881; p = 0.021) and total intravenous anesthesia (TIVA) (OR, 25.541, 95% CI 2.100-310.614, p = 0.011) were independent risk factors for POCD. Changes in coronal ONSD had an area under the curve to distinguish POCD of 0.716 (95% CI 0.531-0.902). Using a cutoff of 0.05 cm, changes of coronal ONSD had a sensitivity of 66.7% and specificity of 66.7%. CONCLUSIONS: Decrease of coronal ONSD, measured by ultrasonography and TIVA, were associated with POCD. Change in coronal ONSD was a moderate predictor of incidence of POCD.

The Dual Neuroprotective-Neurotoxic Effects of Sevoflurane After Hemorrhagic Shock Injury.

BACKGROUND: The neuroprotection and neurotoxicity induced by sevoflurane have been gradually established. Choosing anesthetic agents after hemorrhage shock and resuscitation (HSR) induced by bleeding can be challenging. We determined the dual neuroprotective-neurotoxic effects of sevoflurane postconditioning after HSR injury using a model of blood loss and reinfusion in rats via the heme oxygenase-1 (HO-1)/reactive oxygen species (ROS) signal pathway. METHODS: The rats were exposed to 2%-4% sevoflurane postconditioning in vivo after HSR. Learning ability was assessed 30 d after HSR by Morris water maze tests. Hippocampal apoptosis was assessed 7 d after HSR by TdT-mediated dUTP nick-end labeling combined with cleaved caspase-3 (17 kDa). The ROS, mitochondrial membrane potential (MMP), HO-1 expression, and HO activity 1 d after HSR were assessed by fluorometric, JC-1, Western blot, and bilirubin assays, respectively. RESULTS: Compared with HSR alone, 2% sevoflurane postconditioning improved latency and increased MMP levels, HO-1 expression, and HO activity but decreased TdT-mediated dUTP nick-end labeling-positive cells, cleaved caspase-3 (17 kDa) expression, and ROS production. Pretreatment with hemin, an HO-1 agonist, reversed these effects. Compared with 2% sevoflurane postconditioning plus HSR, slower latency; decreased MMP levels; and increased TdT-mediated dUTP nick-end labeling-positive cells, cleaved caspase-3 (17 kDa), HO-1 expression, HO activity, and ROS production were shown in HSR plus 4% sevoflurane postconditioning, whereas Tin-mesoporphyrin, an HO-1 inhibitor, partially reversed the neurodegeneration of 4% sevoflurane postconditioning. CONCLUSION: The dual neuroprotective-neurotoxic effects of 2%-4% sevoflurane postconditioning after HSR injury might be associated with increased ROS via the "threshold effect" of HO-1.

VX-765 Alleviates Circadian Rhythm Disorder in a Rodent Model of Traumatic Brain Injury Plus Hemorrhagic Shock and Resuscitation.

Severe traumatic brain injury (TBI) can result in persistent complications, including circadian rhythm disorder, that substantially affect not only the injured people, but also the mood and social interactions with the family and the community. Pyroptosis in GFAP-positive astrocytes plays a vital role in inflammatory changes post-TBI. We determined whether VX-765, a low molecular weight caspase-1 inhibitor, has potential therapeutic value against astrocytic inflammation and pyroptosis in a rodent model of TBI plus hemorrhagic shock and resuscitation (HSR). A weight-drop plus bleeding and refusion model was used to establish traumatic exposure in rats. VX-765 (50 mg/kg) was injected via the femoral vein after resuscitation. Wheel-running activity was assessed, brain magnetic resonance images were evaluated, the expression of pyroptosis-associated molecules including cleaved caspase-1, gasdermin D (GSDMD), and interleukin-18 (IL-18) in astrocytes in the region of anterior hypothalamus, were explored 30 days post-trauma. VX-765-treated rats had significant improvement in circadian rhythm disorder, decreased mean diffusivity (MD) and mean kurtosis (MK), increased fractional anisotropy (FA), an elevated number and branches of astrocytes, and lower cleaved caspase-1, GSDMD, and IL-18 expression in astrocytes than TBI + HSR-treated rats. These results demonstrated that inhibition of pyroptosis-associated astrocytic activations in the anterior hypothalamus using VX-765 may ameliorate circadian rhythm disorder after trauma. In conclusion, we suggest that interventions targeting caspase-1-induced astrocytic pyroptosis by VX-765 are promising strategies to alleviate circadian rhythm disorder post-TBI.

Application of three-dimensional material CZIF-8/CS-MS as adsorbents for the determination of plant growth regulators in Schisandra chinensis.

In this study, we employed a melamine sponge (MS) as the skeleton material and utilized carbonized ZIF-8 (CZIF-8) and chitosan (CS) as the raw materials to prepare CZIF-8/CS-MS, a novel material featuring a three-dimensional interconnected porous network. The resulting CZIF-8/CS-MS material possesses a unique porous structure, significant specific surface area and abundant active sites. These characteristics make CZIF-8/CS-MS a promising absorbent for selective purification of plant growth regulators (PGRs) including 1-naphthlcetic acid (NAA), naphthoxyacetic acid (NOA), 4-chlorophenoxyacetic acid (4-CPA), 2,4-dichlorophenoxyacetic acid (2,4-D). After optimizing the extraction conditions, excellent linearity (r > 0.9994) was observed within a wide linear range of 1-100 ng/mL using ultra high performance liquid chromatography-tandem quadrupole mass spectrometry. The detection limits (LODs) and limits of quantification (LOQs) were found to be in the range of 0.013-0.154 ng/mL and 0.044-0.515 ng/mL, respectively. Additionally, the relative recovery of Schisandra chinensis fruit samples was determined to be 89.7-99.4 %, with a relative standard deviation (RSDs) of ≤ 8.4 % (n = 3). Compared to other methods, this approach offers a multitude of benefits, which include but are not limited to exceptional sensitivity, reduced sample volume requirements, low LODs, a comparable linear range, and high reproducibility. The findings of this study pave the way for exploring novel functionalized sponge columns, which leverage the integration of nano-sorbent materials and coating agents, for the purpose of analyzing PGRs within intricate matrix samples.

Icariin mitigates anxiety-like behaviors induced by hemorrhagic shock and resuscitation via inhibiting of astrocytic activation.

BACKGROUND: Abnormal activation of astrocytes in the amygdala contributes to anxiety after hemorrhagic shock and resuscitation (HSR). Nuclear factor κ-light-chain-enhancer of activated B cells (NF-κB)-associated epigenetic reprogramming of astrocytic activation is crucial to anxiety. A bioactive monomer derived from Epimedium icariin (ICA) has been reported to modulate NF-κB signaling and astrocytic activation. PURPOSE: The present study aimed to investigate the effects of ICA on post-HSR anxiety disorders and its potential mechanism of action. METHODS: We first induced HSR in mice through a bleeding and re-transfusion model and selectively inhibited and activated astrocytes in the amygdala using chemogenetics. Then, ICA (40 mg/kg) was administered by oral gavage once daily for 21 days. Behavioral, electrophysiological, and pathological changes were assessed after HSR using the light-dark transition test, elevated plus maze, recording of local field potential (LFP), and immunofluorescence assays. RESULTS: Exposure to HSR reduced the duration of the light chamber and attenuated open-arm entries. Moreover, HSR exposure increased the theta oscillation power in the amygdala and upregulated NF-κB p65, H3K27ac, and H3K4me3 expression. Contrarily, chemogenetic inhibition of astrocytes significantly reversed these changes. Chemogenetic inhibition in astrocytes was simulated by ICA, but chemogenetic activation of astrocytes blocked the neuroprotective effects of ICA. CONCLUSION: ICA mitigated anxiety-like behaviors induced by HSR in mice via inhibiting astrocytic activation, which is possibly associated with NF-κB-induced epigenetic reprogramming.

Synthesis of α-iodoketals from methyl ketones via sustainable and orthogonal tandem catalysis.

A highly efficient method for the direct synthesis of α-iodoketals from methyl ketones has been developed via sustainable integration of orthogonal tandem catalytic reactions: copper(II) oxide catalyzed iodination reaction and the subsequent excess or regenerated iodine catalyzed regioselective ketalization reaction.

Synthesis of benzimidazoles by potassium tert-butoxide-promoted intermolecular cyclization reaction of 2-iodoanilines with nitriles.

The synthesis of benzimidazoles by intermolecular cyclization reaction of 2-iodoanilines with nitriles has been developed. These reactions proceeded without the aid of any transition metals or ligands and just using KOBu(t) as the base. A variety of substituted benzimidazole derivatives can be synthesized by the approach.

The predictive value of anti-Mullerian hormone on embryo quality, blastocyst development, and pregnancy rate following in vitro fertilization-embryo transfer (IVF-ET).

PURPOSE: The objective of this study was to investigate the predictive value of anti-Mullerian hormone (AMH) on fertilization rate (FR), blastocyst development, embryo quality, the outcome of the pregnancy and the live birth rate (LBR) following in vitro fertilization-embryo transfer (IVF-ET)/intracytoplasmic sperm injection (ICSI). METHOD: In this prospective study outcomes were followed in 83 women undergoing cycles of IVF/ICSI within a university hospital. Basal serum AMH, follicle stimulating hormone (FSH), luteinizing hormone (LH) and antral follicle count (AFC) were measured on Day 3. Serum AMH (Gn6 AMH ) level was measured on Day 6 after the administration of gonadotrophin (Gn). AMH was measured in follicle fluid (FF AMH) on the day of ovum pick-up (dOPU). The numbers of retrieved and fertilized oocytes, good quality embryos and blastocysts were counted. Secondary outcome variables included clinical pregnancy rate (CPR) and LBR. RESULTS: Spearman correlation analysis indicated that the numbers of oocytes, good quality embryos and blastocysts were associated with AMH (P < 0.05) and that LBR was correlated with FF AMH (r = 0.495, P < 0.05). No associations were found between FR and AMH (P > 0.05). Receiver operating characteristic analysis showed that the sensitivity of FF AMH at predicting CPR was 91.2%; the specificity was 86.5% and ROC(AUC) was 0.893 (P < 0.0001). CONCLUSION: AMH parameters were correlated with good quality embryos and blastocysts, but only FF AMH showed a significant correlation with LBR and CPR.

CORM-3 alleviates the intestinal injury in a rodent model of hemorrhage shock and resuscitation: roles of GFAP-positive glia.

Hemorrhagic shock and resuscitation (HSR) can induce severe intestinal damages, thereby leading to sepsis and long-term complications including dysbacteriosis and pulmonary injury. The NOD-like receptor protein 3 (NLRP3) inflammasome facilitates inflammation-associated cell recruitment in the gastrointestinal tract, and participates in many inflammatory bowel diseases. Previous studies have shown that exogenous carbon monoxide (CO) exerts neuroprotective effects against pyroptosis after HSR. We aimed to investigate whether carbon monoxide-releasing molecules-3 (CORM-3), an exogenous CO compound, could attenuate HSR-induced intestinal injury and the potential underlying mechanism.Rats were subjected to a HSR model by bleeding and re-infusion. Following resuscitation, 4 mg/kg of CORM-3 was administered intravenously into femoral vein. At 24 h and 7 d after HSR modeling, the pathological changes in intestinal tissues were evaluated by H&E staining. The intestinal pyroptosis, glial fibrillary acidic protein (GFAP)-positive glial pyroptosis, DAO (diamine oxidase) content, intestine tight junction proteins including zonula occludens-1 (ZO-1) and claudin-1 were further detected by immunofluorescence, western blot and chemical assays at 7 d after HSR. CORM-3 administration led to significantly mitigated HSR-induced intestinal injury, aggravation of intestinal pyroptosis indicated by cleaved caspase-1, IL-1ß and IL-18, upregulation of GFAP-positive glial pyroptosis, decreased intensity of ZO-1 and claudin-1 in the jejunum, and increased of DAO in the serum. Nigericin, an agonist of NLRP3, significantly reversed the protective effects of CORM-3. CORM-3 alleviates the intestinal barrier dysfunction in a rodent model of HSR, and the potential mechanism may be associated with inhibition of NLRP3-associated pyroptosis. CORM-3 administration could be a promising therapeutic strategy for intestinal injury after hemorrhagic shock.

Advanced MRI to assess hippocampal injury after incomplete cerebral ischemia-reperfusion in rats.

BACKGROUND AND PURPOSE: The purpose of this study was to evaluate advanced MRI findings in the bilateral hippocampus CA1 region of rats with hemorrhagic shock reperfusion (HSR) and their correlation with histopathological results. Additionally, this study aimed to identify effective MRI examination methods and detection indexes for assessing HSR. METHODS: Rats were randomized into the HSR and the Sham groups with 24 rats in each group. MRI examination included diffusion kurtosis imaging (DKI) and 3-dimensional arterial spin labeling (3D-ASL). Apoptosis and pyroptosis were evaluated directly from tissue. RESULTS: In the HSR group, cerebral blood flow (CBF) was significantly lower than that of the Sham group, while radial kurtosis (Kr), axial kurtosis (Ka), and mean kurtosis (MK) were all higher. In the HSR group, fractional anisotropy (FA) at 12 and 24 hours and radial diffusivity, axial diffusivity (Da), and mean diffusivity (MD) at 3 and 6 hours were lower than in the Sham group. MD and Da at 24 hours in the HSR group were significantly higher. The apoptosis rate and pyroptosis rate were also enhanced in the HSR group. CBF, FA, MK, Ka, and Kr values in the early stage were strongly correlated with apoptosis rate and pyroptosis rate. The metrics were obtained from DKI and 3D-ASL. CONCLUSIONS: Advanced MRI metrics from DKI and 3D-ASL, including CBF, FA, Ka, Kr, and MK values, are useful to evaluate abnormal blood perfusion and microstructural changes in the hippocampus CA1 area in the setting of incomplete cerebral ischemia-reperfusion in rats induced by HSR.

Recent advances in emerging application of functional materials in sample pretreatment methods for liquid chromatography-mass spectrometry analysis of plant growth regulators: A mini-review.

Plant growth regulators (PGRs) are a class of small molecular compounds, which can remarkably affect the physiological process of plants. The complex plant matrix along with a wide polarity range and unstable chemical properties of PGRs hinder their trace analysis. In order to obtain a reliable and accurate result, a sample pretreatment process must be carried out, including eliminating the interference of the matrix effect and pre-concentrating the analytes. In recent years, the research of functional materials in sample pretreatment has experienced rapid growth. This review comprehensively overviews recent development in functional materials covering one-dimensional materials, two-dimensional materials, and three-dimensional materials applied in the pretreatment of PGRs before liquid chromatography-mass spectrometry (LC-MS) analysis. Besides, the advantages and limitations of the above functionalized enrichment materials are discussed, and their future trends have been prospected. The work could be helpful to bring new insights for researchers engaged in functional materials in sample pretreatment of PGRs based on LC-MS.

Subanesthetic dose of S-ketamine improved cognitive dysfunction via the inhibition of hippocampal astrocytosis in a mouse model of post-stroke chronic stress.

Post-stroke chronic stress (PSCS) is generally associated with the poorer recovery and more pronounced cognitive dysfunction. Recent evidence has implied that S-ketamine can reduce suicidal ideation in treatment-resistant depression. In this current study, we aimed to investigate whether the administration of S-ketamine ameliorated cognitive deficits under PSCS conditions, which was established by a model combining middle cerebral artery occlusion (MCAO) and chronic restraint stress. Our data suggested that mice exposed to PSCS exhibited depression-like behavior and cognitive impairment, which coincided with astrocytosis as indicated by increased GFAP-positive cells and impairment of long-time potentiation (LTP) in the hippocampal CA1. Subanesthetic doses (10 mg/kg) of S-ketamine have significantly mitigated depression-like behaviors, cognitive deficits and LTP impairment, reduced astrocytosis, excessive GABA, and inflammatory factors, including NLRP3 and IL-18 in astrocytes in the CA1. Besides, neuroprotective effects induced by S-ketamine administration were found in vitro but could be partially reversed by an agonist of the NLRP3 nigericin. Our current data also suggests that the subanesthetic doses of S-ketamine improved cognitive dysfunction via the inhibition of hippocampal astrocytosis in a mouse model of PSCS.

Spautin-1 Protects Against Mild TBI-Induced Anxiety-Like Behavior in Mice via Immunologically Silent Apoptosis.

Anxiety is reportedly one of the most common mental changes after traumatic brain injury (TBI). Perineuronal nets (PNNs) produced by astrocytes in the lateral hypothalamus (LHA) that surround gamma-aminobutyric acid-ergic (GABAergic) neurons have been associated with anxiety. The potent anti-tumor effects of Spautin-1, a novel autophagy inhibitor, have been documented in malignant melanoma; moreover, the inhibition of autophagy is reported to mitigate anxiety disorders. However, little is known about the ability of spautin-1 to alleviate anxiety. In this study, we sought to investigate whether spautin-1 could alleviate anxiety-like behaviors post-TBI by reducing the loss of PNNs in the LHA. A mild TBI was established in mice through Feeney's weight-drop model. Then, Spautin-1 (20 mmol/2 µl) was immediately administered into the left lateral ventricle. Behavioral and pathological changes were assessed at 24 h, 7 days, 30 days, 31 days and 32 days after TBI by the neurological severity scores (NSS), open field test (OFT), elevated plus-maze (EPM) test, western blot, immunofluorescence assays and electron microscopy. Spautin-1 significantly reversed TBI-induced decreased time in the central zone during OFT and in the open-arm during the EPM test. Spautin-1 also increased PNNs around GABAergic neurons indicated by WFA- plus GAD2- positive A2-type astrocytes and attenuated M1-type microglia in the LHA 32 days after TBI compared to TBI alone. Moreover, compared to mice that only underwent TBI, spautin-1 downregulated autophagic vacuoles, abnormal organelles, the expression of Beclin 1, USP13, phospho-TBK1, and phospho-IRF3 and upregulated the levels of cleaved caspase-3, -7 and -9, but failed to increase TUNEL-positive cells in the LHA at 24 h. Spautin-1 alleviated anxiety-like behavior in mice exposed to mild TBI; this protective mechanism may be associated with decreased PNNs loss around GABAergic neurons via immunologically silent apoptosis induced by the caspase cascade.

Abdominal surgery plus sevoflurane exposure induces abnormal emotional changes and cognitive dysfunction in aged rats.

BACKGROUND: Cognitive impairment, which includes perioperative psychological distress and cognitive dysfunction, can be determined by preoperative and post-operative neuropsychological tests. Several mechanisms have been proposed regarding the two-way communication between the immune system and the brain after surgery. We aimed to understand the mechanisms underlying perioperative neurocognitive disorders (PND) in elderly rats using an experimental abdominal surgery model. METHODS: 24-month-old SD rats were exposed to the abdominal surgery model (AEL) under 3% anesthesia. On day 15 and day 30 post-surgery, fractional anisotropy (FA) using diffusion kurtosis imaging (DKI) was measured. From day 25 to day 30 post-surgery, behavioral tests, including open field test (OFT), Morris water maze (MWM), novel object recognition (NOR), force swimming test (FST), and elevated plus maze (EPM), were performed. Then, the rats were euthanized to perform pathological analysis and western blot measurement. RESULTS: The rats exposed to AEL surgical treatment demonstrated significantly decreased time crossing the platform in the MWM, decreased recognition index in the NOR, reduced time in the open arm in the EPM, increased immobility time in the FST, and increased number of crossings in the OFT. Aged rats, after AEL exposure, further demonstrated decreased FA in the mPFC, nucleus accumbens (NAc), and hippocampus, together with reduced MAP2 intensity, attenuation of GAD65, VGlut2, CHAT, and phosphorylated P38MAPK expression, and increased reactive astrocytes and microglia. CONCLUSIONS: In this study, the aged rats exposed to abdominal surgery demonstrated both emotional changes and cognitive dysfunction, which may be associated with neuronal degeneration and reduced phosphorylated P38MAPK.

Spautin-1 administration mitigates mild TBI-induced cognitive and memory dysfunction in mice via activation of caspase-3.

BACKGROUND: Cognitive and memory dysfunction, a common sequela of traumatic brain injury (TBI), places a heavy social and economic burden on individuals, families, communities, and countries. Although the potent anti-tumor effects of spautin-1, a novel autophagy inhibitor, have been documented in malignant melanoma, little is known regarding its efficacy on alleviation of cognitive and memory dysfunction. Here, we describe the effect of spautin-1 administration on cognitive and memory impairment post-TBI, and reveal its underlying mechanism of action. METHODS: We first induced mild TBI in mice through Feeney's weight-drop model, then immediately administered spautin-1 (10 mmol/µl, 2 µl) into the left lateral ventricle. Behavioral and pathological changes were assessed at 24 h, 7 and 30 days after TBI by analyzing neurological severity scores (NSS), novel objective recognition (NOR), Morris water maze (MWM) test, recording of local field potential (LFP), as well as western blot, and immunofluorescence assays. RESULTS: Mild TBI not only reduced recognition index and times crossing platform, but also aggravated neuronal injury, including reduced MAP2, GAD2, VGlut2, and CHAT intensity. It also elevated activated microglia and CD86-occupied areas in TMEM119-positive cells, but suppressed θ, ß, and γ oscillation power in the hippocampal CA1. However, spautin-1 administration significantly reversed these changes, whereas AC-DEVD-CHO an inhibitor of caspase-3 partially blocked the neuroprotective effects of spautin-1. CONCLUSION: Spautin-1 administration mitigates mild TBI-induced cognitive and memory dysfunction in mice, potentially through activation of caspase-3.