Curcumin Facilitates Aryl Hydrocarbon Receptor Activation to Ameliorate Inflammatory Astrogliosis.

Curcumin is an anti-inflammatory and neuroprotective compound in turmeric. It is a potential ligand of the aryl hydrocarbon receptor (AhR) that mediates anti-inflammatory signaling. However, the AhR-mediated anti-inflammatory effect of curcumin within the brain remains unclear. We investigated the role of AhR on the curcumin effect in inflammatory astrogliosis. Curcumin attenuated lipopolysaccharide (LPS)-induced proinflammatory IL-6 and TNF-α gene expression in primary cultured rat astrocytes. When AhR was knocked down, LPS-induced IL-6 and TNF-α were increased and curcumin-decreased activation of the inflammation mediator NF-κB p65 by LPS was abolished. Although LPS increased AhR and its target gene CYP1B1, curcumin further enhanced LPS-induced CYP1B1 and indoleamine 2,3-dioxygenase (IDO), which metabolizes tryptophan to AhR ligands kynurenine (KYN) and kynurenic acid (KYNA). Potential interactions between curcumin and human AhR analyzed by molecular modeling of ligand-receptor docking. We identified a new ligand binding site on AhR different from the classical 2,3,7,8-tetrachlorodibenzo-p-dioxin site. Curcumin docked onto the classical binding site, whereas KYN and KYNA occupied the novel one. Moreover, curcumin and KYNA collaboratively bound onto AhR during molecular docking, potentially resulting in synergistic effects influencing AhR activation. Curcumin may enhance the inflammation-induced IDO/KYN axis and allosterically regulate endogenous ligand binding to AhR, facilitating AhR activation to regulate inflammatory astrogliosis.

Intensified treatment of hyperphosphatemia associated with reduction in parathyroid hormone in patients on maintenance hemodialysis.

BACKGROUND: This study investigated the therapeutic effect of intensive phosphorus-lowering therapy on intact-parathyroid hormone (iPTH) levels in hemodialysis patients. METHODS: Ninety-five hemodialysis patients with serum phosphorus ≥1.78 mmol/L and iPTH ≥300 pg/dL were apportioned to either the treatment or control group (n = 43 and 52, respectively) based on patient commitment to treatment. The treatment group was given phosphorus-lowering therapies with phosphate binders (lanthanum, sevelamer or/and calcium reagent) combined with dietary phosphate restriction and intensified hemodialysis. The control individuals were given low doses of calcium agents, if serum calcium was <2.54 mmol/L. Percent changes in serum phosphorus and iPTH levels were compared between the two groups. In addition, based on the time required to achieve >20% decrease in serum phosphorus, the patients in the treatment group were further stratified as rapid responders (≤2 months; 27 patients) or slow responders (>2 months; 16 patients) and percent changes in iPTH were compared. RESULTS: Serum phosphorus and iPTH levels decreased from baseline in the treatment group (-24.08 ± 1.93% and -9.92 ± 3.70%, respectively) but increased in the control group (22.00 ± 3.63% and 104.21 ± 23.89%; both p < .001). In the rapid responders subgroup, the iPTH decreased (-16.93 ± 3.49%), but in the slow responders subgroup the iPTH increased slightly (0.68 ± 7.37%, p < .05). CONCLUSIONS: For these patients on maintenance hemodialysis, intensive treatment of hyperphosphatemia was associated with a decrease in iPTH levels, especially for those who had achieved substantial reduction in serum phosphorus within 2 months.

Astrocytic GAP43 Induced by the TLR4/NF-κB/STAT3 Axis Attenuates Astrogliosis-Mediated Microglial Activation and Neurotoxicity.

Growth-associated protein 43 (GAP43), a protein kinase C (PKC)-activated phosphoprotein, is often implicated in axonal plasticity and regeneration. In this study, we found that GAP43 can be induced by the endotoxin lipopolysaccharide (LPS) in rat brain astrocytes both in vivo and in vitro. The LPS-induced astrocytic GAP43 expression was mediated by Toll-like receptor 4 and nuclear factor-κB (NF-κB)- and interleukin-6/signal transducer and activator of transcription 3 (STAT3)-dependent transcriptional activation. The overexpression of the PKC phosphorylation-mimicking GAP43(S41D) (constitutive active GAP43) in astrocytes mimicked LPS-induced process arborization and elongation, while application of a NF-κB inhibitory peptide TAT-NBD or GAP43(S41A) (dominant-negative GAP43) or knockdown of GAP43 all inhibited astrogliosis responses. Moreover, GAP43 knockdown aggravated astrogliosis-induced microglial activation and expression of proinflammatory cytokines. We also show that astrogliosis-conditioned medium from GAP43 knock-down astrocytes inhibited GAP43 phosphorylation and axonal growth, and increased neuronal damage in cultured rat cortical neurons. These proneurotoxic effects of astrocytic GAP43 knockdown were accompanied by attenuated glutamate uptake and expression of the glutamate transporter excitatory amino acid transporter 2 (EAAT2) in LPS-treated astrocytes. The regulation of EAAT2 expression involves actin polymerization-dependent activation of the transcriptional coactivator megakaryoblastic leukemia 1 (MKL1), which targets the serum response elements in the promoter of rat Slc1a2 gene encoding EAAT2. In sum, the present study suggests that astrocytic GAP43 mediates glial plasticity during astrogliosis, and provides beneficial effects for neuronal plasticity and survival and attenuation of microglial activation. SIGNIFICANCE STATEMENT: Astrogliosis is a complex state in which injury-stimulated astrocytes exert both protective and harmful effects on neuronal survival and plasticity. In this study, we demonstrated for the first time that growth-associated protein 43 (GAP43), a well known growth cone protein that promotes axonal regeneration, can be induced in rat brain astrocytes by the proinflammatory endotoxin lipopolysaccharide via both nuclear factor-κB and signal transducer and activator of transcription 3-mediated transcriptional activation. Importantly, LPS-induced GAP43 mediates plastic changes of astrocytes while attenuating astrogliosis-induced microglial activation and neurotoxicity. Hence, astrocytic GAP43 upregulation may serve to indicate beneficial astrogliosis after CNS injury.

Investigation of optimum N-terminal probrain natriuretic peptide level in patients on maintained hemodialysis.

BACKGROUND: Serum N-terminal probrain natriuretic peptide (NT-proBNP) level is known to be strongly associated with fluid overload, and serves as a guide for fluid management in patients on hemodialysis (HD). This study aimed at investigating the relationship between NT-proBNP level and blood pressure (BP), ultrafiltration/dry weight ratio as well as hemoglobin, and to explore the optimal cutoff point of NT-proBNP level in Chinese patients on HD. METHODS: A total of 306 patients on maintained HD for stage 5 chronic kidney disease (CKD) were included in this prospective study [corrected]. Their average ultrafiltration/dry weight ratio and BP before dialysis were recorded. The serum NT-proBNP, hemoglobin, serum calcium, and phosphorus were detected. The cutoff value for NT-proBNP level was calculated using receiver operating characteristic (ROC) analysis. RESULTS: The high NT-proBNP level was associated with high BP and ultrafiltration/dry weight ratio, and low hemoglobin level. The optimal cutoff point of NT-proBNP level for patients on maintained HD was 5666 pg/mL, with a sensitivity of 78.5%, specificity of 43.9%, and area under the curve (AUC) of 0.703 (<0.001). CONCLUSIONS: NT-proBNP level ≤5666 pg/mL was recommended to achieve the target BP, hemoglobin level, and ultrafiltration/dry weight ratio in patients on maintained HD with an ejection fraction (EF) >50%.

Application of ureterorenoscope and flexible ureterorenoscope lithotripsy in removing calculus from extracorporeal living donor renal graft: a single-center experience.

Here, we reported our clinical application of ureterorenoscope (URS) and flexible URS lithotripsy in stone removal on 10 cases of excised living donor kidney graft. After the extraction of donor kidney by retroperitoneal laparoscopy, the donor graft was perfused with 4 °C HCA solution. Calculus between 2-4 mm were removed intact with lithotomy forceps under direct vision of URS. Larger calculi of >4 mm were fractured with flexible URS combining holmium laser lithotripsy. Fragments of the calculus were extracted with basket extractor and lithotomy forceps. All operations were successful. The operation time was 14-31 min (average 21.2 ± 6.3 min). The kidneys were then transplanted to the recipients using routine procedure. The transplanted kidneys functioned well after transplantation. Gross hematuria resolved 1-4 d after operation (average 2.6 ± 0.9 d). The transplanted kidneys functioned well without early complications such as functional recovery delay and acute graft rejection. The donors and recipients were followed for 12 months. The size of the transplanted kidneys was normal and new stones or urinary obstruction was not seen upon urinary color Doppler ultrasound examination. In conclusion, we believe it is feasible, safe and effective to use URS or flexible URS combining holmium laser lithotripsy on extracorporeal living donor kidney.

Aryl hydrocarbon receptor mediates both proinflammatory and anti-inflammatory effects in lipopolysaccharide-activated microglia.

The aryl hydrocarbon receptor (AhR) regulates peripheral immunity; but its role in microglia-mediated neuroinflammation in the brain remains unknown. Here, we demonstrate that AhR mediates both anti-inflammatory and proinflammatory effects in lipopolysaccharide (LPS)-activated microglia. Activation of AhR by its ligands, formylindolo[3,2-b]carbazole (FICZ) or 3-methylcholanthrene (3MC), attenuated LPS-induced microglial immune responses. AhR also showed proinflammatory effects, as evidenced by the findings that genetic silence of AhR ameliorated the LPS-induced microglial immune responses and LPS-activated microglia-mediated neurotoxicity. Similarly, LPS-induced expressions of tumor necrosis factor α (TNFα) and inducible nitric oxide synthase (iNOS) were reduced in the cerebral cortex of AhR-deficient mice. Intriguingly, LPS upregulated and activated AhR in the absence of AhR ligands via the MEK1/2 signaling pathway, which effects were associated with a transient inhibition of cytochrome P450 1A1 (CYP1A1). Although AhR ligands synergistically enhance LPS-induced AhR activation, leading to suppression of LPS-induced microglial immune responses, they cannot do so on their own in microglia. Chromatin immunoprecipitation results further revealed that LPS-FICZ co-treatment, but not LPS alone, not only resulted in co-recruitment of both AhR and NFκB onto the κB site of TNFα gene promoter but also reduced LPS-induced AhR binding to the DRE site of iNOS gene promoter. Together, we provide evidence showing that microglial AhR, which can be activated by LPS, exerts bi-directional effects on the regulation of LPS-induced neuroinflammation, depending on the availability of external AhR ligands. These findings confer further insights into the potential link between environmental factors and the inflammatory brain disorders.

Initial experience of percutaneous nephrolithotomy combined with retroperitoneal laparoendoscopic single-site partial nephrectomy in one-stage treatment of homolateral renal diseases.

This study investigated the feasibility of percutaneous nephrolithotomy (PCNL) combined with retroperitoneal laparoendoscopic single-site partial nephrectomy (LESS-PN) in one-stage treatment of homolateral renal calculi and tumors. Between October 2010 and July 2014 one-stage PCNL combined LESS-PN surgery was performed in 23 patients with homolateral renal calculi and tumors. Patients included 17 male and 8 female, ranged from 31 to 66 years old with a median age of 42.7. Operative parameters and occurrence rate of complications were recorded. In all cases renal tumors were successfully removed without converting to open surgery. One-stage clearance rate for renal calculi was 21/23 (91.3%), leaving two cases for second-stage operation of flexible ureteroscope lithotomy. The operation time was 95-186 min; average 128 min. Intraoperative blood loss was 40-200 mL; average 130 mL. Median warm ischemia time was 23.8 ± 9.5 min. There were no serious post-operative complications such as massive hemorrhage or urine leakage. Length of stay was 5-7 days, average 6 days. There was no recurrence of renal calculus, renal tumors or ureterostenosis and kidney functions were normal. In conclusion, with good practice, one-stage combined operation of PCNL and retroperitoneal LESS-PN in removing homolateral renal tumors and calculi was safe, feasible and would potentially reduce the operative trauma.

Application of self-retaining bidirectional barbed absorbable suture in retroperito- neoscopic partial nephrectomy.

OBJECTIVE: To investigate the safety and feasibility of self-retaining bidirectional barbed absorbable suture application in retroperitoneoscopic partial nephrectomy. MATERIALS AND METHODS: From Sep 2011 and Aug 2012, 76 cases of retroperitoneoscopic partial nephrectomy were performed at our hospital. The patients were divided into two groups: self-retaining barbed suture (SRBS) group (n = 36) and non-SRBS group (n = 40). There was no significant difference in age, sex, tumor size and location between the two groups. Clinical data and outcomes were analyzed retrospectively. RESULTS: All 76 cases of retroperitoneoscopic partial nephrectomy were successfully performed, without conversion to open surgery or serious intraoperative complications. In the SRBS group, the suture time, warm ischemia time and operation blood loss were significantly shorter than that of non-SRBS group (p < 0.01), and operation time and hospital stay were shorter than that of non-SRBS group (p < 0.05). CONCLUSIONS: The application of self-retaining bidirectional barbed absorbable suture in retroperitoneoscopic partial nephrectomy could shorten suture time and warm ischemia time, with good safety and feasibility, worthy of being used in clinic.

Identification and interruption of inheritance of familial cryptic translocations: A case report.

BACKGROUND: Cryptic translocations can be identified via genetic analysis of aborted tissues or malformed infants, but it is difficult to deduce the parental origins of the translocations. In the absence of such information, it is not easy to distinguish translocations from normal embryos during pre-implantation genetic testing, that seeks to block familial transmission of translocations. METHODS: Here, we present a new method that detects cryptic translocations and blocks familial transmission thereof. Whole-genome, low-coverage mate-pair sequencing (WGLMPS) revealed chromosome breakpoint sequences, and preimplantation genetic haplotyping (PGH) was then used to discard embryos with cryptic translocations. RESULTS: Cryptic translocations were found in all four families, and familial transmission was successfully blocked in one family. CONCLUSION: Whole-genome, low-coverage mate-pair sequencing combined with preimplantation genetic haplotyping methods powerfully and practically identify cryptic translocations and block familial transmissions.

Combined use of heparin and anisodamine reduces the risk of early thrombosis in native arteriovenous fistula.

The greatest threat of arteriovenous fistula (AVF) is early thrombosis. There remains limited evidence for the use of agents for the prevention of AVF thrombosis. A total of 180 patients with stage 4 or 5 chronic kidney disease were enrolled in the present study. They were expected to have hemodialysis (HD) within the next six months and a planned lower arm AVF is expected to be the primary HD access. They were randomly divided into a control group with 60 patients, a heparin (H) treatment group with 60 patients and a heparin/anisodamine (H/A)-treatment group with 60 patients. The H/A-treatment group was given 50 IU/kg of heparin and 10 mg of anisodamine for seven days after the AVF was generated. The H-treatment group was given 50 IU/kg of heparin for seven days whereas the control group was given no treatment. The diameter and blood flow rate of the AVF were evaluated by color Doppler ultrasound at the fourth week after the operation. Patency rates of AVF were 96.7% in the H/A-treatment group, 86.7% in the H-treatment group (P < 0.05) and 83.3% in the control group (P < 0.05). The present research indicates that combined application of heparin and anisodamine can effectively relieve the vessel spasm that often occurs after establishment of an AVF and reduce the risk of early thrombosis. However, further evidence is required to validate the maintenance of long-term patency of AVF.

The Role of NMDA Receptor Partial Antagonist, Carbamathione, as a Therapeutic Agent for Transient Global Ischemia.

Carbamathione (Carb), an NMDA glutamate receptor partial antagonist, has potent neuroprotective functions against hypoxia- or ischemia-induced neuronal injury in cell- or animal-based stroke models. We used PC-12 cell cultures as a cell-based model and bilateral carotid artery occlusion (BCAO) for stroke. Whole-cell patch clamp recording in the mouse retinal ganglion cells was performed. Key proteins involved in apoptosis, endoplasmic reticulum (ER) stress, and heat shock proteins were analyzed using immunoblotting. Carb is effective in protecting PC12 cells against glutamate- or hypoxia-induced cell injury. Electrophysiological results show that Carb attenuates NMDA-mediated glutamate currents in the retinal ganglion cells, which results in activation of the AKT signaling pathway and increased expression of pro-cell survival biomarkers, e.g., Hsp 27, P-AKT, and Bcl2 and decreased expression of pro-cell death markers, e.g., Beclin 1, Bax, and Cleaved caspase 3, and ER stress markers, e.g., CHOP, IRE1, XBP1, ATF 4, and eIF2α. Using the BCAO animal stroke model, we found that Carb reduced the brain infarct volume and decreased levels of ER stress markers, GRP 78, CHOP, and at the behavioral level, e.g., a decrease in asymmetric turns and an increase in locomotor activity. These findings for Carb provide promising and rational strategies for stroke therapy.

Clinical application of percutaneous nephrolithotomy in a patient with kyphoscoliosis.

This case report describes the performance of ultrasound-guided percutaneous nephrolithotomy in a 50-year-old woman who had scoliosis with kyphosis and a history of tuberculosis of the lumbar spine. The operation was performed with the patient under general anesthesia and in the prone position. Residual stones were found in the right lower kidney calyx postoperatively, resulting in a second-phase surgery using the same approach 2 weeks later. All stones were successfully removed during the second surgery. No complications occurred in either operation, and the patient recovered well. This study suggests that ultrasound-guided percutaneous nephrolithotomy is a safe and effective approach in treating renal calculi in patients with scoliosis.

Dextromethorphan Dampens Neonatal Astrocyte Activation and Endoplasmic Reticulum Stress Induced by Prenatal Exposure to Buprenorphine.

Prenatal exposure to buprenorphine renders offspring vulnerable to cerebral impairments. In this study, our data demonstrate, for the first time, that prenatal exposure to buprenorphine escalates astrocyte activation concurrent with indications of endoplasmic reticulum (ER) stress in the hippocampi of neonates, and this can be prevented by the coadministration of dextromethorphan with buprenorphine. Furthermore, dextromethorphan can inhibit the accumulation of GPR37 in the hippocampus of newborns caused by buprenorphine and is accompanied by the proapoptotic ER stress response that involves the procaspase-3/CHOP pathway. Primary astrocyte cultures derived from the neonates of the buprenorphine group also displayed aberrant ER calcium mobilization and elevated basal levels of cyclooxygenase-2 (COX-2) at 14 days in vitro while showing sensitivity to lipopolysaccharide-activated expression of COX-2. Similarly, these long-lasting defects in the hippocampus and astrocytes were abolished by dextromethorphan. Our findings suggest that prenatal exposure to buprenorphine might instigate long-lasting effects on hippocampal and astrocytic functions. The beneficial effects of prenatal coadministration of dextromethorphan might be, at least in part, attributed to its properties in attenuating astrocyte activation and hippocampal ER stress in neonates.

Knockdown of the aryl hydrocarbon receptor attenuates excitotoxicity and enhances NMDA-induced BDNF expression in cortical neurons.

NMDA receptors play dual and opposing roles in neuronal survival by mediating the activity-dependent neurotrophic signaling and excitotoxic cell death via synaptic and extrasynaptic receptors, respectively. In this study, we demonstrate that the aryl hydrocarbon receptor (AhR), also known as the dioxin receptor, is involved in the expression and the opposing activities of NMDA receptors. In primary cultured cortical neurons, we found that NMDA excitotoxicity is significantly enhanced by an AhR agonist 2,3,7,8-tetrachlorodibenzo-p-dioxin, and AhR knockdown with small interfering RNA significantly reduces NMDA excitotoxicity. AhR knockdown also significantly reduces NMDA-increases intracellular calcium concentration, NMDA receptor expression and surface presentation, and moderately decreases the NMDA receptor-mediated spontaneous as well as miniature excitatory post-synaptic currents. However, AhR knockdown significantly enhances the bath NMDA application- but not synaptic NMDA receptor-induced brain-derived neurotrophic factor (BDNF) gene expression, and activating AhR reduces the bath NMDA-induced BDNF expression. Furthermore, AhR knockdown reveals the calcium dependency of NMDA-induced BDNF expression and the binding activity of cAMP-responsive element binding protein (CREB) and its calcium-dependent coactivator CREB binding protein (CBP) to the BDNF promoter upon NMDA treatment. Together, our results suggest that AhR opposingly regulates NMDA receptor-mediated excitotoxicity and neurotrophism possibly by differentially regulating the expression of synaptic and extrasynaptic NMDA receptors.

Mechanism of neuroprotective function of taurine.

Taurine has potent protective function against glutamate-induced neuronal injury presumably through its function in regulation of intracellular free calcium level, [Ca2+]i. In this communication, we report that taurine exerts its protective function through one or more of the following mechanisms: 1. Inhibition of glutamate-induced calcium influx through L-, N- and P/Q-type voltage-gated calcium channels and NMDA receptor calcium channel; 2. Attenuation of glutamate-induced membrane depolarization; 3. Prevention of glutamate-induced apoptosis via preventing glutamate-mediated down-regulation of Bcl-2; 4. Prevention of cleavage of Bcl-2 by calpain. This action of taurine is due to its inhibition on glutamate induced calpain activation. Based on these observations, we propose that taurine protects neurons against glutamate-induced neurotoxicity in part, by preventing glutamate-induced membrane depolarization, elevation of [Ca2+]i, activation of calpain, reduction of Bcl-2 and apoptosis.

[Outcomes of renal transplantation with donor kidneys with multiple arteries].

OBJECTIVE: To compare the outcomes of renal transplantation with donor kidneys with multi-branched renal arteries. METHODS: The data about operation time, volume of intra-operational blood loss, postoperative complications, and post-operational renal function status of 251 recipients of donor kidneys with single-branched renal artery (Group A), 12 recipients of donor kidneys with double-branched renal arteries the diameter of one of which was < 2 mm or the estimated blood supply areas of one of which were < 10% (Group B), and 35 recipients of donor kidneys with renal arteries with 2 or more than 2 branches (Group C). RESULTS: The operation time was (115 +/- 34) min in Group A and was (120 +/- 31) min in Group B, both shorter than that of Group C [(133 +/- 55) min], however, not significantly. There were not significant differences in the intra-operational volume of blood loss, 1-year survival rate of patient/transplanted kidney, and post-operational creatinine level among these three groups. The complication rate was 7.6% (19/251) in Group A, 16.7% (2/12) in Group B, and 11.4% in Group C (4/35). CONCLUSION: There are not significant differences in the intra-operational status and post-operational outcomes among the operations of renal transplantation with donor kidneys with different amounts of renal arteries.

Correction to: Soluble Epoxide Hydrolase Inhibition Attenuates Excitotoxicity Involving 14,15-Epoxyeicosatrienoic Acid-Mediated Astrocytic Survival and Plasticity to Preserve Glutamate Homeostasis.

The original version of this article unfortunately contained a mistake. The authors observed inadvertent error in Fig. 7d, in which the image of the GFAP/DAPI in the WT saline treated mice was rotated left 90-degree by mistake. The corrected representative image is given below.

Soluble Epoxide Hydrolase Inhibition Attenuates Excitotoxicity Involving 14,15-Epoxyeicosatrienoic Acid-Mediated Astrocytic Survival and Plasticity to Preserve Glutamate Homeostasis.

Astrocytes play pivotal roles in regulating glutamate homeostasis at tripartite synapses. Inhibition of soluble epoxide hydrolase (sEHi) provides neuroprotection by blocking the degradation of 14,15-epoxyeicosatrienoic acid (14,15-EET), a lipid mediator whose synthesis can be activated downstream from group 1 metabotropic glutamate receptor (mGluR) signaling in astrocytes. However, it is unclear how sEHi regulates glutamate excitotoxicity. Here, we used three primary rat cortical culture systems, neuron-enriched (NE), astrocyte-enriched glia-neuron mix (GN), and purified astrocytes, to delineate the underlying mechanism by which sEHi and 14,15-EET attenuate excitotoxicity. We found that sEH inhibitor 12-(3-adamantan-1-yl-ureido)-dodecanoic acid (AUDA) and 14,15-EET both attenuated N-methyl-D-aspartate (NMDA)-induced neurite damage and cell death in GN, not NE, cortical cultures. The anti-excitotoxic effects of 14,15-EET and AUDA were both blocked by the group 1 mGluR5 antagonist 2-methyl-6-(phenylethynyl)pyridine (MPEP), as were their protective effects against NMDA-disrupted perineuronal astrocyte processes expressing glutamate transporter-1 (GLT-1) and subsequent glutamate uptake. Knockdown of sEH expression also attenuated NMDA neurotoxicity in mGluR5- and GLT-1-dependent manners. The 14,15-EET/AUDA-preserved astroglial integrity was confirmed in glutamate-stimulated primary astrocytes along with the reduction of the c-Jun N-terminal kinase 1 phosphorylation, in which the 14,15-EET effect is mGluR5-dependent. In vivo studies validated that sEHi and genetic deletion of sEH (Ephx2-KO) ameliorated excitotoxic kainic acid-induced seizure, memory impairment, and neuronal loss while preserving GLT-1-expressing perineuronal astrocytes in hippocampal CA3 subregions. These results suggest that 14,15-EET mediates mGluR5-dependent anti-excitotoxicity by protecting astrocytes to maintain glutamate homeostasis, which may account for the beneficial effect of sEH inhibition in excitotoxic brain injury and diseases.

Neuronal activity enhances aryl hydrocarbon receptor-mediated gene expression and dioxin neurotoxicity in cortical neurons.

The aryl hydrocarbon receptor (AhR) is a ligand-activated transcription factor activated by dioxin and polyaromatic hydrocarbons. Recent studies have revealed that AhR activity in central neurons depends on the NMDA receptor. In this study, we investigated how the neuronal activity influence AhR-mediated dioxin-responsive gene expression and neurotoxicity. Our results show that activation of AhR by the selective agonist 2,3,7,8-tetrachlorodibenzo-p-dioxin induced dioxin-responsive gene expression and calcium entry, which were attenuated by AhR small interfering RNA, the NMDA receptor channel blocker MK801, and the action potential blocker tetrodotoxin (TTX). In addition, AhR-mediated gene expression was enhanced in neurons during synaptogenesis (10 days in vitro) compared with younger neurons (4 days in vitro), as was sensitivity to TTX and MK801. Furthermore, TTX and MK801 differentially affected the association of AhR and its transcriptional co-activator cAMP-responsive-element binding protein with the cytochrome P450 1A1 (cyp1A1) gene enhancer. Calcium/calmodulin-dependent protein kinase IV, the cAMP-responsive-element binding protein activating enzyme, was also activated by 2,3,7,8-tetrachlorodibenzo-p-dioxin in an activity-dependent manner. Finally, we found that neuronal susceptibility to dioxin insult was also maturation and activity-dependent. Together, the results suggest that neuronal activity may facilitate AhR-mediated calcium signaling, which in turn enhances AhR-mediated gene regulation and mediated maturation-dependent dioxin neurotoxicity.