NeuroMolecular Medicine最新文献

Exposure to cadmium, a heavy metal distributed in the environment is a cause of concern due to associated health effects in population around the world. Continuing with the leads demonstrating alterations in brain cholinergic signalling in cadmium induced cognitive deficits by us; the study is focussed to understand involvement of N-Methyl-D-aspartate receptor (NMDA-R) and its postsynaptic signalling and Nrf2-ARE pathways in hippocampus. Also, the protective potential of quercetin, a polyphenolic bioflavonoid, was assessed in cadmium induced alterations. Cadmium treatment (5 mg/kg, body weight, p.o., 28 days) decreased mRNA expression and protein levels of NMDA receptor subunits (NR1, NR2A) in rat hippocampus, compared to controls. Cadmium treated rats also exhibited decrease in levels of NMDA-R associated downstream signalling proteins (CaMKIIα, PSD-95, TrkB, BDNF, PI3K, AKT, Erk_1/2, GSK3β, and CREB) and increase in levels of SynGap in hippocampus. Further, decrease in protein levels of Nrf2 and HO1 associated with increase in levels of Keap1 exhibits alterations in Nrf2/ARE signalling in hippocampus of cadmium treated rats. Degeneration of pyramidal neurons in hippocampus was also evident on cadmium treatment. Simultaneous treatment with quercetin (25 mg/kg body weight p.o., 28 days) was found to attenuate cadmium induced changes in hippocampus. The results provide novel evidence that cadmium exposure may disrupt integrity of NMDA receptors and its downstream signaling targets by affecting the Nrf2/ARE signaling pathway in hippocampus and these could contribute in cognitive deficits. It is further interesting that quercetin has the potential to protect cadmium induced changes by modulating Nrf2/ARE signaling which was effective to control NMDA-R and PI3K/AKT cell signaling pathways.

Interleukin-17A plays a crucial role in multiple sclerosis and other autoimmune diseases. Although the link between IL-17 and disease activity has been clearly demonstrated, the precise function of this cytokine remains elusive. Here, we investigated the function of astrocyte-targeted IL-17A production in GF/IL-17 transgenic mice during EAE. In particular, IL-17A is important during disease induction. In mice with transgenic IL-17A production, disease occurs earlier and peak disease is more severe, whereas remission is unimpaired. IL-17A synthesis is associated with increased infiltration of granulocytes into the CNS and microglial activation. Moreover, IL-17A synthesis allows induction of MOG-EAE without the additional administration of the co-adjuvant pertussis toxin. Examination of double transgenic GF/IL-17 2D2 mice revealed that, in addition, local IL-17A production facilitates spontaneous infiltration of immune cells into the CNS in mice expressing a MOG-specific T-cell receptor. Overall, we provide evidence for a crucial effect of IL-17A in the induction phase of EAE, facilitating the infiltration of granulocytes and autoreactive T-cells into the CNS.

Glioblastoma (GBM) is the most frequent tumor of the central nervous system, and its heterogeneity is a challenge in treatment. This study examined tumoral heterogeneity involving PDGFRA, KIT, and KDR gene amplification (GA) in 4q12 and its association with clinical parameters. Specimens from 22 GBM cases with GA for the 4q12 amplicon detected by FISH were investigated for homogeneous or heterogeneous coamplification patterns, diffuse or focal distribution of cells harboring GA throughout tumor sections, and pattern of clustering of fluorescence signals. Sixteen cases had homogenously amplification for all three genes (45.5%), for PDGFRA and KDR (22.7%), or only for PDGFRA (4.6%); six cases had heterogeneous GA patterns, with subpopulations including GA for all three genes and for two genes - PDGFRA and KDR (13.6%), or GA for all three and for only one gene - PDGFRA (9.1%) or KIT (4.6%). In 6 tumors (27.3%), GA was observed in focal tumor areas, while in the remaining 16 tumors (72.7%) it was diffusely distributed throughout the pathological specimen. Amplification was universally expressed as double minutes and homogenously stained regions. Coamplification of all three genes PDGFRA, KIT, and KDR, age ≥ 60 years, and total tumor resection were statistically associated with poor prognosis. FISH proved effective for detailed interpretation of molecular heterogeneity. The study uncovered an even more diverse range of amplification patterns involving the 4q12 oncogenes in GBM than previously described, thus highlighting a complex tumoral heterogeneity to be considered when devising more effective therapies.

The medial prefrontal cortex (mPFC) is critical for both the sensory and emotional/cognitive components of pain. However, the underlying mechanism remains largely unknown. Here, we examined changes in the transcriptomic profiles in the mPFC of mice with chronic pain using RNA sequencing (RNA-seq) technology. A mouse model of peripheral neuropathic pain was established via chronic constriction injury (CCI) of the sciatic nerve. CCI mice developed sustained mechanical allodynia and thermal hyperalgesia, as well as cognitive impairment four weeks after surgery. RNA-seq was conducted 4 weeks after CCI surgery. Compared with contral group, RNA-seq identified a total 309 and 222 differentially expressed genes (DEGs) in the ipsilateral and contralateral mPFC of CCI model mice, respectively. GO analysis indicated that the functions of these genes were mainly enriched in immune- and inflammation-related processes such as interferon-gamma production and cytokine secretion. KEGG analysis further showed the enrichment of genes involved in the neuroactive ligand-receptor interaction signaling pathway and Parkinson disease pathway that have been reported to be importantly involved in chronic neuralgia and cognitive dysfunction. Our study may provide insights into the possible mechanisms underlying neuropathic pain and pain-related comorbidities.

Parkinson's disease (PD) is the most common neurodegenerative movement disorder. There are no available therapeutics that slow or halt the progressive loss of dopamine-producing neurons, which underlies the primary clinical symptoms. Currently approved PD drugs can provide symptomatic relief by increasing brain dopamine content or activity; however, the alleviation is temporary, and the effectiveness diminishes with the inevitable progression of neurodegeneration. Discovery and development of disease-modifying neuroprotective therapies has been hampered by insufficient understanding of the root cause of PD-related neurodegeneration. The etiology of PD involves a combination of genetic and environmental factors. Although a single cause has yet to emerge, genetic, cell biological and neuropathological evidence implicates mitochondrial dysfunction and protein aggregation. Postmortem PD brains show pathognomonic Lewy body intraneuronal inclusions composed of aggregated α-synuclein, indicative of failure to degrade misfolded protein. Mutations in the genes that code for α-synuclein, as well as the E3 ubiquitin ligase Parkin, cause rare inherited forms of PD. While many ubiquitin ligases label proteins with ubiquitin chains to mark proteins for degradation by the proteasome, Parkin has been shown to mark dysfunctional mitochondria for degradation by mitophagy. The ubiquitin proteasome system participates in several aspects of the cell's response to mitochondrial damage, affording numerous therapeutic opportunities to augment mitophagy and potentially stop PD progression. This review examines the role and therapeutic potential of such UPS modulators, exemplified by both ubiquitinating and deubiquitinating enzymes.

Neurodegenerative diseases and postoperative cognitive dysfunction involve the accumulation of β-amyloid peptide (Aβ). High glucose can inhibit autophagy, which facilitates intracellular Aβ clearance. The α2-adrenoreceptor agonist dexmedetomidine (DEX) can provide neuroprotection against several neurological diseases; however, the mechanism remains unclear. This study investigated whether DEX regulated autophagy via the AMPK/mTOR pathway to improve high glucose-induced neurotoxicity in SH-SY5Y/APP695 cells. SH-SY5Y/APP695 cells were cultured with high glucose with/without DEX. To examine the role of autophagy, the autophagy activator rapamycin (RAPA) and autophagy inhibitor 3-methyladenine (3-MA) were used. The selective AMPK inhibitor compound C was used to investigate the involvement of the AMPK pathway. Cell viability and apoptosis were examined by CCK-8 and annexin V-FITC/PI flow cytometric assays, respectively. Autophagy was analyzed by monodansylcadaverine staining of autophagic vacuoles. Autophagy- and apoptosis-related protein expression and the phosphorylation levels of AMPK/mTOR pathway molecules were quantified by western blotting. DEX pretreatment significantly suppressed high glucose-induced neurotoxicity in SH-SY5Y/APP695 cells, as evidenced by the enhanced viability, restoration of cellular morphology, and reduction in apoptotic cells. Furthermore, RAPA had a protective effect similar to that of DEX, but 3-MA eliminated the protective effect of DEX by promoting mTOR activation. Moreover, the AMPK/mTOR pathway was involved in DEX-mediated autophagy. Compound C significantly suppressed autophagy and reversed the protective effect of DEX against high glucose in SH-SY5Y/APP695 cells. Our findings demonstrated that DEX protected SH-SY5Y/APP695 cells against high glucose-induced neurotoxicity by upregulating autophagy through the AMPK/mTOR pathway, suggesting a role of DEX in treating POCD in diabetic patients.

Alzheimer's disease (AD) is a neurodegenerative disease leading to dementia for which no effective medicine exists. Currently, the goal of therapy is only to slow down the inevitable progression of the disease and reduce some symptoms. AD causes the accumulation of proteins with the pathological structure of Aβ and tau and the induction of inflammation of nerves in the brain, which lead to the death of neurons. The activated microglial cells produce pro-inflammatory cytokines that induce a chronic inflammatory response and mediate synapse damage and the neuronal death. Neuroinflammation has been an often ignored aspect of ongoing AD research. There are more and more scientific papers taking into account the aspect of neuroinflammation in the pathogenesis of AD, although there are no unambiguous results regarding the impact of comorbidities or gender differences. This publication concerns a critical look at the role of inflammation in the progression of AD, based on the results of our own in vitro studies using model cell cultures and other researchers.

1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) mice model is one of the most common animal models for Parkinson's disease (PD). It is classified into three types: acute, subacute, and chronic intoxication models. The subacute model has attracted much attention for its short period and similarity to PD. However, whether subacute MPTP intoxication in mouse mimics the movement and cognitive disorders of PD still remains highly controversial. Therefore, the present study reassessed the behavioral performances of subacute MPTP intoxication in mice using open field, rotarod, Y maze,  and gait analysis at different time points (1, 7, 14, and 21 days) after modeling. Results of the current study showed that although MPTP-treated mice using subacute regimen showed severe dopaminergic neuronal loss and evident astrogliosis, they failed to display significant motor and cognitive deficits. Besides, expression of mixed lineage kinase domain-like (MLKL), a marker of necroptosis, was also significantly increased in the ventral midbrain and striatum of MPTP-intoxicated mice. This evidently implies that necroptosis may play an important role in MPTP-induced neurodegeneration. In conclusion, the findings of the present study suggest that subacute MPTP-intoxicated mice may not be a suitable model for studying parkinsonism. However, it can help in revealing the early pathophysiology of PD and studying the compensatory mechanisms which occur in early PD that prevent the emergence of behavioral deficits.

Exosomal microRNAs (miRNAs) are emerging diagnostic biomarkers for neurodegenerative diseases. In this study, we aimed to detect relapsing-remitting multiple sclerosis (RRMS)-specific miRNAs in cerebrospinal fluid (CSF) and serum exosomes with diagnostic potential. One ml of CSF and serum sample were collected from each of the 30 untreated RRMS patients and healthy controls (HCs). A panel of 18 miRNAs affecting inflammatory responses was applied, and qRT-PCR was conducted to detect differentially expressed exosomal miRNAs in CSF and serum of RRMS patients. We identified that 17 out of 18 miRNAs displayed different patterns in RRMS patients compared to HCs. Let-7 g-5p, miR-18a-5p, miR-145-5p, and miR-374a-5p with dual pro-inflammatory and anti-inflammatory actions and miR-150-5p and miR-342-3p with anti-inflammatory action were significantly upregulated in both CSF and serum-derived exosomes of RRMS patients compared to corresponding HCs. Additionally, anti-inflammatory miR-132-5p and pro-inflammatory miR-320a-5p were significantly downregulated in both CSF and serum-derived exosomes of RRMS patients compared to HCs. Ten of 18 miRNAs were differentially expressed in CSF and serum exosomes of the patients. Furthermore, miR-15a-5p, miR-19b-3p, and miR-432-5p were upregulated, and miR-17-5p was downregulated only in CSF exosomes. Interestingly, U6 housekeeping gene was differentially expressed in CSF and serum exosomes, in both RRMS and HCs. As the first report describing CSF exosomal miRNAs expression profile compared to that of serum exosomes in untreated RRMS patients, we showed that CSF and serum exosomes are not identical in terms of biological compounds and display different patterns in miRNAs and U6 expression.

Alzheimer's disease (AD) is the most common type of dementia characterized by abnormal accumulation of amyloid-β (Aβ) plaques, neuroinflammation, and neuronal loss. Dimethyl itaconate (DI), a membrane-permeable derivative of itaconate, has been recently reported to limit inflammation. However, the effect of DI in the APPswe/PS1ΔE9 (APP/PS1) transgenic mouse model of AD remains unclear. We treated APP/PS1 mice with DI or saline. Our results showed that DI ameliorated the cognitive deficits of APP/PS1 mice. Further, DI significantly decreased brain Aβ deposition and Aβ levels, inhibited cell apoptosis, decreased hippocampal and cortical neuronal damage. We also found that DI promoted the expression of the Nrf2/HO-1 signaling pathway, while inhibited cognitive impairment, cell apoptosis, and the proinflammatory cytokine levels in the brains of APP/PS1 mice. Our results indicated that DI attenuated memory impairment and neuroinflammation via the Nrf2 signaling pathway in APP/PS1 mice, suggesting that DI might be recognized as a promising candidate for the treatment of AD.