Neuroprotection of quercetin on central neurons against chronic high glucose through enhancement of Nrf2/Glo-1 mediated by phosphorylation regulation

OBJECTIVE To investigate the neuroprotective effects of quercetin on central neurons against chronic high glucose in central neurons,in relation to Nrf2/ARE/Glo-1 activation.METHODS SH-SY5Y cells were cultured with high glucose(HG,70 mmol·L^(-1)),4-fold of the normal glucose(17.5 mmol·L^(-1)).Quercetin was set three concentrations(5,10,20μmol·L^(-1)),with Nrf2 activator sulforaphane(SFN)as a positive group(2.5μmol·L^(-1)).After 72 h,cells were collected for glyoxalase 1(Glo-1)activity and GSH level were by spectrophotometry;advanced glycation end-products(AGEs)as well as nuclear Nrf2 and p-Nrf2 levels by immunofluorescence;Glo-1,γ-glutamycysteine synthase(γ-GCS),Nrf2 and p-Nrf2 protein levels by Western blotting,and Glo-1 andγ-GCS m RNA levels by real-time qP CR.RESULTS Quercetin increased the cell viability of SH-SY5Y cells,and upregulated the levels of Glo-1 activity,protein,and m RNA in SH-SY5Y cells cultured with HG,accompanied by the elevated levels of glutathione,a cofactor of Glo-1 activity,and the reduced levels of AGEs.Meanwhile,quercetin could increase p-Nrf2 and Nrf2 levels in nucleus as well as p-Nrf2 levels in cytosol of SH-SY5Y cells exposed to chronic HG,accompanied by the elevated protein expression and m RNA levels ofγ-GCS,a known target gene of Nrf2/ARE signaling.Moreover,a PKC activator or a p38MAPK inhibitor pretreatment could significantly increase the protein expression ofγ-GCS in HG condition,but an alkylating agent for sulfydryl of cysteine in Keap 1,a negative regulator of Nrf2,pretreatment only showed an increased tendency ofγ-GCS protein,compared with without pretreatment;however,after pretreatment with those tool drugs,co-treatment with quercetin and HG had similar results to those of single tool drug pretreatment followed by HG exposure.CONCLUSION Firstly,quercetin can enhance Glo-1 function in central neurons,which is mediated by activation of Nrf2/ARE pathway,then exerts the neuroprotection against HG induced damage;moreover,PKC and p38 MAPK pathways may be involved in Nrf2 inactivation in chronic HG condition.

Volume transmission and receptor-receptor interactions in heteroreceptor complexes:understanding the role of new concepts for brain communication

The discovery of the central monoamine neurons not only demonstrated novel types of brain stem neurons forming global terminal networks all over the brain and the spinal cord,but also to a novel type of communication called volume transmission.It is a major mode of communication in the central nervous system that takes places in the extracellular fluid and the cerebral spinal fluid through diffusion and flow of molecules,like neurotransmitters and extracellular vesicles.The integration of synaptic and volume transmission takes place through allosteric receptor-receptor interactions in heteroreceptor complexes.These heterocomplexes represent major integrator centres in the plasma membrane and their protomers act as moonlighting proteins undergoing dynamic changes and their structure and function.In fact,we propose that the molecular bases of learning and memory can be based on the reorganization of multiples homo and heteroreceptor complexes into novel assembles in the post-junctional membranes of synapses.

Planning for selective amygdalohippocampectomy involving less neuronal fiber damage based on brain connectivity using tractography

Temporal lobe resection is an important treatment option for epilepsy that involves removal of potentially essential brain regions. Selective amygdalohippocampectomy is a widely performed temporal lobe surgery. We suggest starting the incision for selective amygdalohippocampectomy at the inferior temporal gyrus based on diffusion magnetic resonance imaging（MRI） tractography. Diffusion MRI data from 20 normal participants were obtained from Parkinson＇s Progression Markers Initiative（PPMI） database（www.ppmi-info.org）. A tractography algorithm was applied to extract neuronal fiber information for the temporal lobe, hippocampus, and amygdala. Fiber information was analyzed in terms of the number of fibers and betweenness centrality. Distances between starting incisions and surgical target regions were also considered to explore the length of the surgical path. Middle temporal and superior temporal gyrus regions have higher connectivity values than the inferior temporal gyrus and thus are not good candidates for starting the incision. The distances between inferior temporal gyrus and surgical target regions were shorter than those between middle temporal gyrus and target regions. Thus, the inferior temporal gyrus is a good candidate for starting the incision. Starting the incision from the inferior temporal gyrus would spare the important（in terms of betweenness centrality values） middle region and shorten the distance to the target regions of the hippocampus and amygdala.