SDF-1 and CXCR4 play an important role in adult SVZ lineage cell proliferation and differentiation.

Evidence has shown that stromal cell-derived factor (SDF-1/CXCL12) plays an important role in maintaining adult neural progenitor cells (NPCs). SDF-1 is also known to enhance recovery by recruiting NPCs to damaged regions and recent studies have revealed that SDF-1α exhibits pleiotropism, thereby differentially affecting NPC subpopulations. In this study, we investigated the role of SDF-1 in in vitro NPC self-renewal, proliferation and differentiation, following treatment with different concentrations of SDF-1 or a CXCR4 antagonist, AMD3100. We observed that AMD3100 inhibited the formation of primary neurospheres. However, SDF-1 and AMD3100 exhibited no effect on proliferation upon inclusion of growth factors in the media. Following growth factor withdrawal, AMD3100 and SDF-1 treatment resulted in differential effects on NPC proliferation. SDF-1, at a concentration of 500ng/ml, resulted in an increase in the relative proportion of oligodendrocytes following growth factor withdrawal-induced differentiation. Using CXCR4 knockout mice, we observed that SDF-1 affected NPC proliferation in the sub-ventricular zone (SVZ). We also investigated the occurrence of differential CXCR4 expression at different stages during lineage progression. These results clearly indicate that signaling interactions between SDF-1 and CXCR4 play an important role in adult SVZ lineage cell proliferation and differentiation.

Alleviating neuropathic pain mechanical allodynia by increasing Cdh1 in the anterior cingulate cortex.

BACKGROUND: Plastic changes in the anterior cingulate cortex (ACC) are critical in the pathogenesis of pain hypersensitivity caused by injury to peripheral nerves. Cdh1, a co-activator subunit of anaphase-promoting complex/cyclosome (APC/C) regulates synaptic differentiation and transmission. Based on this, we hypothesised that the APC/C-Cdh1 played an important role in long-term plastic changes induced by neuropathic pain in ACC. RESULTS: We employed spared nerve injury (SNI) model in rat and found Cdh1 protein level in the ACC was down-regulated 3, 7 and 14 days after SNI surgery. We detected increase in c-Fos expression, numerical increase of organelles, swollen myelinated fibre and axon collapse of neuronal cells in the ACC of SNI rat. Additionally, AMPA receptor GluR1 subunit protein level was up-regulated on the membrane through a pathway that involves EphA4 mediated by APC/C-Cdh1, 3 and 7 days after SNI surgery. To confirm the effect of Cdh1 in neuropathic pain, Cdh1-expressing lentivirus was injected into the ACC of SNI rat. Intra-ACC treatment with Cdh1-expressing lentivirus vectors elevated Cdh1 levels, erased synaptic strengthening, as well as alleviating established mechanical allodynia in SNI rats. We also found Cdh1-expressing lentivirus normalised SNI-induced redistribution of AMPA receptor GluR1 subunit in ACC by regulating AMPA receptor trafficking. CONCLUSIONS: These results provide evidence that Cdh1 in ACC synapses may offer a novel therapeutic strategy for treating chronic neuropathic pain.

Blocking PAR2 attenuates oxaliplatin-induced neuropathic pain via TRPV1 and releases of substance P and CGRP in superficial dorsal horn of spinal cord.

Oxaliplatin (OXL) is a third-generation chemotherapeutic agent commonly used to treat metastatic digestive tumors; however, neuropathic pain is one of the main limiting complications of OXL. The purpose of this study was to examine the underlying mechanisms by which neuropathic pain is induced by OXL in a rat model. Our results demonstrated that blocking spinal proteinase-activated receptor 2 (PAR2) and transient receptor potential vanilloid 1 (TRPV1) attenuated pain responses evoked by mechanical stimulation and decreased the releases of substance P and CGRP in the superficial dorsal horn of the spinal cord. The attenuating effect on mechanical pain was significantly smaller in OXL-rats than that in control rats. Blocking PAR2 also attenuated a heightened cold sensitivity evoked by OXL; whereas blocking TRPV1 had little effects on OXL-evoked hypersensitive cold response. Our data also showed that OXL increased the protein expressions of PAR2 and TRPV1 in the superficial dorsal horn. In addition, blocking PAR2 decreased TRPV1 expression in OXL-rats. Overall, our data suggest that upregulated expression of PAR2 in the superficial dorsal horn contributes to mechanical hyperalgesia and cold hypersensitivity; whereas amplified TRPV1 plays a role in regulating mechanical hyperalgesia, but not cold hypersensitivity after administration of OXL. We further suggest that TRPV1 is likely one of the signaling pathways for PAR2 to play a role in regulating OXL-induced neuropathic pain.

Expression of 1N3R-Tau isoform inhibits cell proliferation by inducing S phase arrest in N2a cells.

Tau is a microtubule-associated protein implicated in neurodegenerative tauopathies. Six tau isoforms are generated from a single gene through alternative splicing of exons 2, 3 and 10 in human brain. Differential expression of tau isoforms has been detected in different brain areas, during neurodevelopment and in neurodegenerative disorders. However, the biological significance of different tau isoforms is not clear. Here, we investigated the individual effect of six different isoforms of tau on cell proliferation and the possible mechanisms by transient expression of eGFP-labeled tau isoform plasmid in N2a cells. Our study showed the transfection efficiency was comparable between different isoforms of tau by examining GFP expression. Compared with other isoforms, we found expression of 1N3R-tau significantly inhibited cell proliferation by Cell Counting Kit-8 assay and BrdU incorporation. Flow cytometry analysis further showed expression of 1N3R-tau induced S phase arrest. Compared with the longest isoform of tau, expression of 1N3R-tau induced cyclin E translocation from the nuclei to cytoplasm, while it did not change the level of cell cycle checkpoint proteins. These data indicate that 1N3R-tau inhibits cell proliferation through inducing S phase arrest.

[Transplantation of immortalized neural progenitor cells to treat focal cerebral ischemia: experiment with rats].

OBJECTIVE: To investigate the impact of transplantation of immortalized neural progenitor cells (INPCs) into the brain with focal cerebral ischemia and the survival and differentiation thereof. METHODS: Twenty-four male SD rats underwent middle cerebral artery occlusion (MCAO) and were randomly divided into 2 equal groups: INPC group undergoing transplantation of BrdU-labeled INPCs into the penumbra zone in striatum using stereotaxic apparatus 3 days after brain ischemia, and control group undergoing transplantation of PBS. Neurological severity score (NSS) system was used 6 hours, 1 day, and 3 days after MCAO, and 1, 2, 3, and 4 weeks respectively after transplantation. One week after transplantation, 6 animals of each group were randomly chosen and killed with their brains taken out, the rest of the animals were killed four weeks after transplantation. The survival of INPCs in the brain was determined by double immunofluorescent labeling technique with BrdU + NSE or BrdU + GFAP antibody. RESULTS: The NSS values at different time points after transplantation of both groups were all higher than those before MCAO; however, no significant difference in NSS was detected between the two groups. BrdU + GFAP and BrdU + NSE positive astrocytes and neurons were detected in the INPC group by double immunofluorescent labeling technique 1 week and 4 weeks after transplantation. CONCLUSION: INPC can survive in penumbra zone in rats with focal cerebral ischemia and develop into neurons and astrocytes.

[The effect of beating heart intracardiac procedures on postoperative cognitive function and S100b release: analysis of 51 patients].

OBJECTIVE: To investigate the effect of beating heart intracardiac procedures on postoperative cognitive function and S100b release. METHODS: Fifty-one patients, aged 15 - 45, were divided into 2 groups to undergo intracardiac procedures under the conditions of cardiac arrest (n = 29, including 14 isolated valve replacement patients and 14 interauricular or interventricular septum repair patients) or beating heart (n = 23, all undergoing interauricular or interventricular septum repair). Before the operation and 7 days after the operation, a battery of neuropsychological tests, using trail making test, Wechsler memory scale, and Wechsler adult intelligence scale, was conducted. Forty healthy sex and age-matched volunteers underwent the same neuropsychological tests. The cognitive function impairment was evaluated by calculating the modified reliable change indices (MRCI). Cognitive function impairment in 2 or more items of the tests was defined as postoperative cognitive dysfunction (POCD. Blood samples were collected preoperatively and 24 h after cardiac surgery to measure the serum S100b by ELISA. RESULTS: The incidence of POCD in the arrested heart group was 42.9%, not significantly different from that of the beating heart group (34.8%, P > 0.05). The concentration of serum S100b 24 hours after cardiac surgery of the beating heart group was 0.37 +/- 0.17 microg/L, not ignorantly different from that of the arrested heart group (0.35 +/- 0.18 microg/L, P > 0.05). CONCLUSION: Beating heart intracardiac procedures does not decrease the incidence of early cognitive dysfunction after cardiac surgery, and does not reduce the release of S100b.