Chronic pain accelerates cognitive impairment by reducing hippocampal neurogenesis may via CCL2/CCR2 signaling in APP/PS1 mice.

Patients with chronic pain often have cognitive impairment; this is especially true in elderly patients with neurodegenerative diseases such as Alzheimer's disease (AD), but the mechanism underlying this association remains unclear. This was addressed in the present study by investigating the effect of chronic neuropathic pain on hippocampal neurogenesis and cognitive impairment using amyloid precursor protein/presenilin 1 (APP/PS1) double transgenic mice subjected to spared-nerve injury (SNI). The Von Frey test was performed to determine the mechanical threshold of mouse hind limbs after SNI. The Morris water maze test was used to evaluate spatial learning and memory. Doublecortin-positive (DCX+), 5-bromo-2'-deoxyuridine (BrdU)+, BrdU+/neuronal nuclei (NeuN)+, and C-C motif chemokine ligand 2 (CCL2)+ neurons in the dentate gyrus of the hippocampus were detected by immunohistochemistry and immunofluorescence analysis. CCL2 and C-C chemokine receptor type 2 (CCR2) protein levels in the mouse hippocampus were analyzed by western blotting. The results showed that APP/PS1 mice with chronic neuropathic pain induced by SNI had significant learning and memory impairment. This was accompanied by increased CCL2 and CCR2 expression and decreases in the number of DCX+, BrdU+, and BrdU+/NeuN+ neurons. These results suggest that chronic neuropathic pain is associated with cognitive impairment, which may be caused by CCL2/CCR2 signaling-mediated inhibition of hippocampal neurogenesis. Thus, therapeutic strategies that alleviate neuropathic pain can potentially slow cognitive decline in patients with AD and other neurodegenerative diseases.

Ramsay Hunt syndrome and mandibular alveolar bone necrosis following herpes zoster: A case report and literature review.

Background: Reactivation of latent varicella-zoster virus (VZV) can induce herpes zoster (HZ). Ramsay Hunt syndrome (RHS) occurs through the reactivation and proliferation of VZV in the geniculate ganglion, which can lead to vesicular rash in the ear or oral mucosa, accompanied by neurological disorders. Materials and methods: A 50-year-old man sought a remedy for pain in the right ear and face. Within 1 week, all his lower right teeth fell out, and in the following 3 months, his lower right mandibular alveolar bone gradually became necrotic. In the past 20 days, he experienced blister rash, hearing and taste loss, and slight facial paralysis. Results: After ruling out tumors and other infectious diseases, he was diagnosed with trigeminal HZ and RHS. Conclusion: Ramsay Hunt syndrome with tooth loss and alveolar osteonecrosis is rare. It requires long-term treatment of pain, and prevention and treatment of tooth loss and alveolar bone necrosis are difficult and warrant further study.

Overexpression of zinc-α2-glycoprotein suppressed seizures and seizure-related neuroflammation in pentylenetetrazol-kindled rats.

BACKGROUND: Zinc-α2-glycoprotein (ZAG) is a 42-kDa protein reported as an anti-inflammatory adipocytokine. Evidences from clinical and experimental studies revealed that brain inflammation plays important roles in epileptogenesis and seizure. Interestingly, closely relationship between ZAG and many important inflammatory mediators has been proven. Our previous study identified ZAG in neurons and found that ZAG is decreased in epilepsy and interacts with TGFß and ERK. This study aimed to investigate the role of ZAG in seizure and explore its effect on seizure-related neuroinflammation. METHODS: We overexpressed AZGP1 in the hippocampus of rats via adeno-associated virus vector injection and observed their seizure behavior and EEG after pentylenetetrazol (PTZ) kindling. The level of typical inflammation mediators including TNFα, IL-6, TGFß, ERK, and ERK phosphorylation were determined. RESULTS: The overexpression of AZGP1 reduced the seizure severity, prolonged the latency of kindling, and alleviated epileptiform discharges in EEG changes induced by PTZ. Overexpression of AZGP1 also suppressed the expression of TNFα, IL-6, TGFß, and ERK phosphorylaton in PTZ-kindled rats. CONCLUSIONS: ZAG may inhibit TGFß-mediated ERK phosphorylation and inhibit neuroinflammation mediated by TNFα and IL-6, suggesting ZAG may suppress seizure via inhibiting neuroinflammation. ZAG may be a potential and novel therapeutic target for epilepsy.

Resumption of antiplatelet therapy in patients with primary intracranial hemorrhage-benefits and risks: A meta-analysis of cohort studies.

BACKGROUND: Clinical disagreement over antiplatelet (AP) resumption in patients with primary intracranial hemorrhage (ICH) has long existed. This meta-analysis aimed to evaluate the benefits of AP resumption on preventing ischemic or thromboembolic events against its risks of promoting ICH recurrence or hematoma expansion. METHODS: All relevant articles published in Pubmed, EMBASE, the Cochrane Library, and Science Direct from January 1950 to March 2017 were sourced, and the combined relative risk (RR) was calculated. RESULTS: A total of 3648 articles were found, and after screening, 6 cohort studies including 1916 patients were included in this meta-analysis. AP resumption was associated with a decreased risk of ischemic or thromboembolic events (RR, 0.61; 95% confidence interval (CI), 0.48-0.79; P<0.01). There was no significant difference in the risk of ICH recurrence or hematoma expansion between patients with or without AP resumption (RR, 0.84; 95% CI, 0.47-1.51; P=0.56). CONCLUSION: AP resumption in patients with primary ICH reduced the risk of ischemic or thromboembolic events, without significant increase of risk of ICH recurrence or hematoma expansion.

Neuronal zinc-α2-glycoprotein is decreased in temporal lobe epilepsy in patients and rats.

Zinc-α2-glycoprotein (ZAG) is a 42-kDa protein encoded by the AZGP1 gene that is known as a lipid mobilizing factor and is highly homologous to major histocompatibility complex class I family molecules. Recently, transcriptomic research has shown that AZGP1 expression is reduced in the brain tissue of epilepsy patients. However, the cellular distribution and biological role of ZAG in the brain and epilepsy are unclear. Patients with refractory temporal lobe epilepsy (TLE) and brain trauma were included in this study, and pentylenetetrazole (PTZ)-kindled rats were also used. The existence and level of ZAG in the brain were identified using immunohistochemistry, double-labeled immunofluorescence and western blot, and the expression level of AZGP1 mRNA was determined with quantitative real-time polymerase chain reaction (qrt-PCR). To explore the potential biological role of ZAG in the brain, co-immunoprecipitation (Co-IP) of phosphorylated ERK (p-ERK), TGF-ß1 and ZAG was also performed. ZAG was found in the cytoplasm of neurons in brain tissue from both patients and rats. The levels of AZGP1 mRNA and ZAG were lower in refractory TLE patients and PTZ-kindled rats than in controls. In addition, the ZAG level decreased as PTZ kindling continued. Co-IP identified direct binding between p-ERK, TGF-ß1 and ZAG. ZAG was found to be synthesized in neurons, and both the AZGP1 mRNA and ZAG protein levels were decreased in epilepsy patients and rat models. The reduction in ZAG may participate in the pathogenesis and pathophysiology of epilepsy by interacting with p-ERK and TGF-ß1, promoting inflammation, regulating the metabolism of ketone bodies, or affecting other epilepsy-related molecules.

N-methyl-D-aspartate receptors mediate epilepsy-induced axonal impairment and tau phosphorylation via activating glycogen synthase kinase-3ß and cyclin-dependent kinase 5.

The mechanism of epilepsy-induced axonal impairment is poorly understood. N-methyl-D-aspartate receptors (NMDARs) play important roles in epilepsy and mediate structural and functional axonal impairment. GSK-3ß and Cdk5 affect axons and are regulated by NMDARs, while their roles in epilepsy-induced axonal impairment are unclear. We demonstrated that axonal impairment is characterized by neurofilament heavy (NFH) reduction, amyloid precursor protein (APP) accumulation, and increased tau phosphorylation accompanied by a decrease of total tau in temporal lobe epilepsy (TLE) patients and pentylenetetrazol (PTZ)-kindled rats. Inhibiting NMDARs using memantine and ifenprodil alleviated NFH reduction and APP accumulation, decreased Cdk5 expression, and inhibited the activity of GSK-3ß in the white matter of PTZ-kindled rats. Inhibiting GSK-3ß and Cdk5 using lithium chloride and roscovitine also alleviated axonal impairment induced by PTZ. Therefore, axonal impairment in TLE may be mediated by NMDAR via GSK-3ß and Cdk5. In addition, inhibiting either NMDARs or GSK-3ß lowered the relative tau phosphorylation level by reversing the decrease of total tau without affecting phosphorylated tau S396 and T231. Meanwhile inhibiting Cdk5 lowered the tau phosphorylation level by reducing phosphorylated tau without affecting total tau, indicating a possible role of GSK-3ß in NMDAR-mediated tau phosphorylation in epilepsy.

Alpha-2-macroglobulin and heparin cofactor II and the vulnerability of carotid atherosclerotic plaques: An iTRAQ-based analysis.

Rupture of carotid atherosclerotic plaque may cause stroke, while few biomarker in clinic can evaluate carotid plaque vulnerability. In this study, we divided the recruited participants into no plaque, stable plaque, and vulnerable plaque group according to carotid ultrasonography, and screened the differentially expressed proteins in plasma of these participants using isobaric tags for relative and absolute quantitation labeling coupled with liquid chromatography-tandem mass spectrometry. 28 proteins were identified differentially expressed, among which alpha-2-macroglobulin (α2M) and heparin cofactor II (HCII) were found to be at hub position in the interactions of these proteins by STRING analysis and were selected for enzyme-linked immunosorbent assay measurement to assess their relevance with carotid plaques vulnerability and diagnostic efficiency. The plasma level of α2M was found positively correlated, while HCII level was negatively correlated with higher vulnerability of carotid plaques. Both proteins were efficient in differentiating stable and vulnerable carotid plaques. These findings provide potential new targets for the research of carotid plaque vulnerability. Plasma α2M and HCII may be potential biomarkers for evaluation of the vulnerability of carotid plaques if further studied.

Silencing Drp1 inhibits glioma cells proliferation and invasion by RHOA/ ROCK1 pathway.

BACKGROUNDS: Dynamin-related protein 1 (Drp1) is a newly discovered therapeutic target for tumor initiation, migration, proliferation, and chemosensitivity. In the present study, we aimed to examine the level of expression and distribution of DRP1 in glioma tissues and explore the concrete mechanism of DRP1 played in glioma. METHODS: Expression of DRP1 in glioma tissues was determined by immunohistochemistry staining. The DRP1 gene was knocked down using small interfering RNA, and was overexpressed using plasmids in glioma cells. To assess changes in cell function, in vitro assays for invasion and growth were applied. Protein expression was tested by using Western-blot method. Variation of F-actin in cells was analyzed using immunofluorescence staining. Interactions between proteins were determined by co-immunoprecipitation. RESULTS: The protein expression levels of DRP1 were significantly increased in glioma tissues compared to the normal brain tissues. Down-regulation of DRP1 decreased cell proliferation and invasion, and inhibited the formation of pseudopodias and microvillis. Moreover, a possible link between DRP1 and RHOA was confirmed when interactions between these two proteins were observed in the cells. CONCLUSIONS: Our results demonstrated that silencing DRP1 regulated the cytoskeleton remodeling through inhibiting RHOA/ROCK1 pathway, and thus decreased the proliferation and invasion of glioma cells.