Acta neurobiologiae experimentalis最新文献

The study aimed to investigate the significance of serum biomarkers in the severity grading of traumatic brain injury (TBI). For this purpose, mice underwent fluid percussion injury (FPI) at three discrete severity levels, mild, moderate, and severe. The severity of trauma was verified by the qualitative and quantitative histopathology of the brain. The serum samples were analyzed for the potential changes in ubiquitin C‑terminal hydrolase‑1 (UCHL‑1), S100β, interleukin‑6 (IL‑6), corticosterone, and β‑endorphin at 24 and 72 h post injury. A multifold increase in the values of UCHL‑1 was reported at all severity extents of FPI. However, TBI severity‑dependent increase in UCHL‑1 was reported on 72 h following FPI but not at 24 h. S100β values were significantly augmented in the mild and moderate group at both the time point but not in the severe group. Serum level of IL‑6 was significantly increased in the mild injury group at 24 h but not in the moderate and severe. At 72 h, IL‑6 showed a reverse trend. β‑endorphin and corticosterone were sensitive at an early stage only. Such unique dynamics of each biomarker enable us to propose TBI severity scale in the term of biomarkers codes to predict the extent of neurotrauma. Our preclinical study presents a predictive model for further clinical validation.

Acetaminophen is one of the most widely used over‑the‑counter drugs worldwide for the treatment of pain and fever. Although acetaminophen use is known to impair hippocampus‑related learning and memory, its effect on anxiety is not clear. Insulin‑like growth factor‑1 (IGF‑1) and matrix metalloproteinase‑2 (MMP2) are important for cellular survival, maintenance and tissue integrity. The aim of this study was to investigate the dose‑dependent effects of acetaminophen on anxiety levels as well as on hippocampus, prefrontal cortex and liver tissue. Doses of 100, 200 and 400 mg/kg acetaminophen were administered to male Sprague Dawley rats for 11 days and anxiety tests were conducted on the last day. Twenty‑four hours after the last acetaminophen administration, all animals were sacrificed and hippocampus, prefrontal cortex and liver tissues were removed for analyses. Hippocampal IGF‑1 and MMP2 levels were shown to decrease only at the highest dose of acetaminophen, which was accompanied by pathological changes in histology. The prefrontal cortex was not affected. Behavioral analyses also did not indicate changes in anxiety levels in the rats. Liver IGF‑1 and MMP2 levels decreased in all experimental groups. Serum alanine aminotransferase and aspartate aminotransferase levels increased in the 200 mg/kg and 400 mg/kg acetaminophen groups. Our findings showed that varying doses of acetaminophen did not affect the prefrontal cortex or anxiety levels. Further research is needed to elucidate the hippocampal and hepatic protective roles of IGF‑1 and MMP2 in acetaminophen toxicity and their potential use in therapeutic approaches.

This study aimed to further explore the underlying molecular mechanism of intracerebral hemorrhage (ICH), gene expression profile GSE24265, containing perihematomal tissues, contralateral grey and white matters were retrieved and analyzed. The data was hierarchically clustered and the differentially expressed genes (DEGs) were screened. Functional analysis and protein interaction analysis of DEG hubs were performed, and the miRNA‑transcription factor (TF)‑target network was built. In addition, the candidate small-molecule compounds that might reverse the expression of an ICH‑linked gene were identified by CMap. This method revealed a total of 408 DEGs. Five modules including chemokinerelated, antigen immune-related, pathogen infection, cell reaction, and positive regulation of tyrosine phosphorylation and MAPK cascade were identified. The expression levels of CCL5, CXCL8, ICAM1, IL-1B, IL-6, VCAM1, and VEGFA were correlated with ICH among the top 10 hub genes obtained in the protein-protein interaction (PPI) network. A total of 237 miRNA‑TF‑target regulatory relationships were obtained, including 6 TFs, 11 miRNAs and 105 target genes. Finally, the CMap database identified Prestwick-1083, xamoterol, ifosfamide, methyldopate, nifurtimox, propranolol, and methoxamine as potential therapeutic agents for ICH while doxorubicin, menadione and azacitidine may increase its pathogenicity. Furthermore, CCL5, CXCL8 and VEGFA may be novel candidate susceptibility genes for ICH. Some small-molecule drugs, including xamoterol may be used for the treatment of ICH.

Brain benefits from physical exercise associated with antioxidant supplements such as flaxseed oil. This low cost and simple association may improve hippocampal plasticity, which may work as a preventive and effective therapy in neuroprotection and neuroplasticity processes. This work evaluated the effects of physical exercise with flaxseed oil supplementation (Linum usitatissimum L.) in the hippocampus of Wistar rats. We separated male Wistar rats into four experimental groups: control group (sedentary), a sedentary group with a supplemental diet of flaxseed oil, a group under exercise program with flaxseed oil supplementation, and a group exclusively under exercise program. The swimming exercise consisted of a progressive 28‑day protocol followed by behavioral assessment, brain perfusion, microtomy, immunohistochemistry for glial fibrillary acidic protein (GFAP), cellular morphology, and optical density analysis. We used the ANOVA test with Tukey's post‑test for behavioral analysis. The exercise program with flaxseed oil supplementation was able to alter the GFAP expression in astrocytes in the CA1, CA3 and dentate gyrus regions of the hippocampus and modulate the behavioral aspects of memory and anxiety.

The functional connectivity (FC) of striatal subregions is correlated with cognitive functions in child attention deficit hyperactivity disorder (ADHD). However, increasing age changes the pattern of cognitive functions and clinical presentation. The changes in the pattern of cognitive functions may be associated with underlying age‑dependent striatal subregional FC alterations. We attempted to explore aberrancies in FC in striatal subregions and their associations with a predominant cognitive symptom (inattention) in adult ADHD. The FCs of ten bilateral subregions (seeds) of the striatum along with the whole brain were investigated, and FC maps of adults with ADHD (N=15) and healthy controls (N=15) were compared. Finally, we evaluated the associations of striatal subregional FCs with cognitive functions. Case‑control differences in striatal subregional FC were not significant; however, attention scores were marginally significantly positively correlated with FC between the right dorsal‑caudal putamen and right‑superior temporal gyrus in the ADHD group. Our results suggested that cognitive deficits (inattention) may be associated with FC aberrancy in a substriatal connection (between the right dorsal‑caudal putamen and right‑superior temporal gyrus) in adult ADHD.

GPR55 is an orphan receptor whose endogenous agonists include lysophosphatidylinositol (LPI) and N‑acetylethanolamides (NAEs), such as palmitoylethanolamide (PEA) and anandamide. Furthermore, its physiology in the central nervous system involves motor coordination, procedural and spatial memory, pain, and anxiety, among others. Recent reports indicate that systemic injections of O‑1602 (a GPR55 and GPR18 agonist) blocked the reinforcing effects of morphine and nicotine in the conditioned place preference (CPP) paradigm, suggesting a possible participation of peripheral and/or central GPR55/GPR18 in brain reward/anti‑reward systems. In this pilot study, the endogenous GPR55 agonists LPI and PEA, the highly selective GPR55 synthetic agonist ML184 or the selective GPR55 antagonist ML193 were injected to examine their pharmacological effects on the reinforcing actions of nicotine in the CPP paradigm. Our preliminary study shows that injections of LPI, PEA, ML184 and ML193 interfered with the change in place preference induced by nicotine via mechanisms that remain to be identified (which probably include central GPR55).

Hypoxia inducible factor 1α (HIF‑1α) has been reported to play a key role in protecting neurons from ischaemic injury. However, the exact molecular mechanisms remain largely unclear. PC12 cells were exposed to oxygen glucose deprivation/reoxygenation (OGD/R) conditions to mimic ischaemic injury in vitro. The expression of the HIF‑1α mRNA, miR‑20a‑5p, and kinesin family member 5A (KIF5A) mRNA was tested using qRT-PCR. Levels of the HIF‑1α, LC3I/II, P62, LAMP2, cathepsin B (CTSB) and KIF5A proteins were determined using western blotting. The CCK‑8 assay was conducted to assess PC12 cell viability. DQ‑Red‑BSA and LysoSensor Green DND‑189 dyes were employed to measure the proteolytic activity and pH of lysosomes, respectively. The interaction between miR‑20a‑5p and HIF‑1α or KIF5A was verified by performing chromatin immunoprecipitation (ChIP) and/or dual‑luciferase reporter assays. TUNEL staining was adopted to assess PC12 cell death. GFP‑LC3 and RFP‑GFP‑LC3 probes were used to examine the autophagy status and autophagy flux of PC12 cells. A rat middle cerebral artery occlusion‑reperfusion (MCAO/R) model was established to investigate the role of the HIF‑1α/miR‑20a‑5p/KIF5A axis in ischaemic stroke in vivo. OGD/R exposure initiated PC12 cell autophagy and injury. HIF‑1α expression was substantially increased in PC12 cells after OGD/R exposure. Overexpression of HIF‑1α reversed the effects of OGD/R on reducing cell viability, blocking autophagy flux and inducing lysosome dysfunction. These rescue effects of HIF‑1α depended on KIF5A. HIF‑1α negatively regulated miR‑20a‑5p expression by targeting its promoter region, and miR‑20a‑5p directly targeted and negatively regulated the KIF5A mRNA. Overexpression of miR‑20a‑5p abolished the effects of HIF‑1α on rescuing OGD/R‑induced injury in PC12 cells. The effects of the HIF‑1α/miR‑20a‑5p/KIF5A axis were verified in MCAO/R rats. HIF‑1α protects PC12 cells from OGD/R‑induced cell injury by regulating autophagy flux through the miR‑20a‑5p/KIF5A axis.

Our study constructed an in vitro model of cerebral ischemia/reperfusion (I/R) injury to evaluate the protective effect of platelet rich plasma (PRP) on I/R injury and uncover the mechanism behind it. Firstly, N2a cells were exposed in the condition of oxygen and glucose deprivation/reperfusion (OGD/R) to construct a model of cerebral I/R in vitro. MTT assay was employed to access the effects of PRP in N2a cell OGD/R injury. Then, we evaluated the role of the expression of miR‑223, progestin and adipoQ receptors 3 (PAQR3) and autophagy markers in the neuroprotective effect of PRP by qPCR and western blot. And the effect of miR‑223/PAQR3 axis regulated autophagy in the neuroprotection of PRP was verified by overexpressing miR‑223 and PAQR3. Finally, the interaction between miR‑223 and PAQR3 was analyzed by the luciferase reporter gene. The results showed that after OGD/R treatment of N2a cells, the expression of miR‑223 increased and the expression of PAQR3 and autophagy decreased. PRP improved cells damage caused by OGD/R in N2a cell, and reduced the expression of miR‑223 in cells, increased PAQR3 and autophagy. The luciferase reporter assay was used to prove that miR‑223 could target PAQR3 directly. Overexpression of miR‑223 could eliminate the improvement effect of PRP on OGD/R cells, but at the same time, overexpression of PAQR3 restored the protection of PRP from cell damage. Our research found that in the OGD/R injury in vitro model, PRP inhibited the expression of miR‑223 and enhanced autophagy to attenuate the injury by increasing the expression of PAQR3.

As widely reported, dysregulated ferroptosis is closely associated with Parkinson's disease (PD) progression. The goal of the present study was to probe the roles of long non‑coding RNA (lncRNA) nuclear enriched assembly transcript 1 (NEAT1) in regulating ferroptosis in PD. PD cell model was constructed by subjecting SK‑N‑SH cells to 1‑methyl‑4‑phenylpyridinium (MPP+) for 24 h. The RNA levels of NEAT1, miRNA (miR)‑150‑5p, and BRCA1‑associated protein 1 (BAP1) were evaluated using qRT‑PCR. The protein levels of glutathione peroxidase 4 (GPX4), BAP1, and solute carrier family 7 member 11 (SLC7A11) were determined using western blot. Cell viability was assessed using 3‑(4,5‑dimethylthiazolyl2)‑2, 5‑diphenyltetrazolium bromide (MTT) assay. In addition, fluorescent probe 2,7‑dichlorodihydrofluorescein diacetate (DCFH‑DA) was employed to determine the ROS level. Moreover, the levels of GSH, MDA, and Fe2+ were also measured. Finally, the interactions among NEAT1, miR‑150‑5p, and BAP1 were identified by dual luciferase reporter gene assay, and/or RIP assay. Upregulated NEAT1 was observed in PD cell model. Knockdown of NEAT1 elevated viability and GSH level in PD cell model and reduced ROS, MDA, and Fe2+ levels. Moreover, NEAT1 functioned as a sponge to suppress miR‑150‑5p expression. Moreover, miR‑150‑5p overexpression suppressed ferroptosis in PD cell model. We subsequently found that miR‑150‑5p regulated SLC7A11 expression by directly binding to BAP1. miR‑150‑5p inhibition or BAP1 overexpression mitigated the anti‑ferroptosis effect meditated by sh‑NEAT1. Taken together, knockdown of NEAT1 mitigated MPP+‑induced ferroptosis through regulating BAP1/SLC7A11 axis by sponging miR‑150‑5p, indicating the potential of NEAT1 as a promising therapeutic target for PD.

The lateral hypothalamus (LH) sends neural pathways to structures involved on predator‑related defensive behaviours, escape and antinociception. The aim of this study was to investigate the role played by μ-opioid receptors located on LH neurons in defensive behaviour and unconditioned fear‑induced antinociception elicited by electric stimulation of LH. To achieve the goals, the μ1-opioid receptor selective antagonist naloxonazine was administered at different concentrations in the LH, and the defensive behaviour and fear‑induced antinociception elicited by electrical stimulation of LH were evaluated. The electrical stimulation of LH caused escape behaviour followed by defensive antinociception. Microinjections of naloxonazine in a concentration of 5.0 μg/0.2 μL in the LH decreased the aversive stimulus‑induced escape behaviour thresholds, but diminished defensive antinociception. These findings suggest that μ-opioid receptors of LH can be critical to panic attack‑related symptoms and facilitate the unconditioned fear‑induced antinociception produced by LH neurons activation.