Temporally Decoupled Ammonia Splitting by a Zn-NH3 Battery with an Ammonia Oxidation/Hydrogen Evolution Bifunctional Electrocatalyst as a Cathode.

Ammonia splitting to hydrogen is a decisive route for hydrogen economy but is seriously limited by the complex device and low efficiency. Here, we design and propose a new rechargeable Zn-NH3 battery based on temporally decoupled ammonia splitting to achieve efficient NH3-to-H2 conversion. In this system, ammonia is oxidized into nitrogen during cathodic charging (2NH3 + 6OH- → N2 + 6H2O + 6e-) with external electrical energy conversion and storage, while during cathodic discharging, water is reduced to hydrogen (2H2O + 2e- → H2 + 2OH-) with electrical energy generation. In this loop, continuous and efficient H2 production without separation and purification is achieved. With the help of the ammonia oxidation reaction (AOR) and hydrogen evolution reaction (HER) bifunctional catalyst of Mo2C/NiCu@C, a rechargeable Zn-NH3 battery is realized that exhibits a high NH3-to-H2 FE of 91.6% with outstanding durability for 900 cycles (300 h) at 20 mA/cm2, enabling efficient and continuous NH3-to-H2 conversion.

A multicomponent triformylphoroglucinol-based covalent organic framework for overall hydrogen peroxide photosynthesis.

A multicomponent covalent organic framework (COF-Tfp-BpyDaaq) integrating bipyridine with diaminoanthraquinone through a triformylphoroglucinol linkage was synthesized for the first time as a photocatalyst for overall H2O2 photosynthesis. It exhibits enhanced photo-charge separation and H2O2 production rate over its two-component counterparts, demonstrating the pivotal role of multicomponent synthesis in designing efficient photocatalysts.

Granulin in renal tubular epithelia is associated with interstitial inflammation and activates the TLR9-IFN-α pathway in lupus nephritis.

OBJECTIVE: This study aimed to investigate the possible role of granulin (GRN) in activating the TLR9-IFN-α pathway in renal tubular epithelial cells (RTECs) and explore clues that RTECs regulate the micro-environment of inflammatory response in lupus nephritis (LN). METHODS: Renal sections from 57 LN patients and 30 non-LN patients were sampled for histological study, and GRN overexpression RTECs were applied for cytological study. RESULTS: In the histological study, GRN is highly expressed in LN RTECs with tubulointerstitial inflammation (TII) and well co-localized with TLR9. ROC analysis suggested a potential relationship between GRN expression in RTECs and therapeutic response. Moreover, IFN-α also highly expressed in LN RTECs with TII, and the intensity of IFN-α is positively correlated with the co-localization intensity of GRN and TLR9. In the cytological study, LN serum, especially serum from LN with TII, activates the expression of TLR9 in RTECs, and GRN engages the interaction of TLR9 to activate the expression of IFN-α in RTECs. While TLR9 inhibitors can suppress the expression of IFN-α in RTECs, the degree of inhibition is dose-dependent. CONCLUSION: The expression of GRN in RTECs is associated with interstitial inflammation and therapeutic response. GRN may mediate the activation of the TLR9-IFN-α pathway in RTECs and involve in the micro-environment of inflammatory response in LN.

Translation, cultural adaptation, and validation of the Chinese standardized outcomes in nephrology-hemodialysis fatigue (C-SONG-HD fatigue) scale: a study of Chinese patients undergoing hemodialysis.

OBJECTIVE: This study aimed to translate and culturally adapt the standardized outcomes in nephrology-hemodialysis fatigue (SONG-HD fatigue) scale and to assess the psychometric properties of the Chinese version of the SONG-HD fatigue (C-SONG-HD fatigue) scale. METHODS: Forward and back translations were used to translate the SONG-HD fatigue scale into Chinese. We used the C-SONG-HD fatigue scale to survey Chinese patients undergoing hemodialysis (HD) in China. We examined the distribution of responses and floor and ceiling effects. Cronbach's alpha and McDonald's omega coefficient, intraclass coefficients, and Spearman correlations were used to assess internal consistency reliability, test-retest reliability, and convergent validity, respectively. Responsiveness was also evaluated. RESULTS: In total, 489 participants across southeast China, northwest China, and central China completed the study. The C-SONG-HD fatigue scale had good internal consistency (Cronbach's alpha coefficient 0.861, omega coefficient 0.916), test-retest reliability (intraclass correlation coefficient 0.695), and convergent validity (Spearman correlation 0.691). The analysis of all first-time HD patients did not show notable responsiveness, and only patients with temporary vascular access had good responsiveness with an effect size (ES) of 0.54, a standardized response mean (SRM) of 0.85, and a standard error of measurement (SEM) of 0.77. CONCLUSION: The Chinese version of the SONG-HD fatigue scale showed satisfactory reliability and validity in patients undergoing hemodialysis (HD) in China. It could be used as a tool to measure the fatigue of Chinese HD patients.

Clinicopathological characteristics, risk factors and prognostic value of intrarenal vascular lesions in IgA nephropathy.

BACKGROUND: The aim was to study clinicopathological characteristics, risk factors and renal outcome in IgA nephropathy (IgAN) patients with vascular lesions. METHODS: We enrolled a Chinese cohort with 458 biopsy-confirmed primary IgAN patients for a retrospective analysis. They were divided into three groups according to vascular lesions: no vascular lesions (n = 239), arterio-/arteriolosclerosis (n = 181) and microangiopathic lesions (n = 38). The clinicopathological features and renal outcome were recorded. In univariate and multivariate models, association between vascular lesions and renal outcome and vascular lesions associated clinical factors were analyzed. RESULTS: Patients with vascular lesions presented worse clinical characteristics with regard to blood pressure and kidney function, and segmental glomerulosclerosis (S1), tubular atrophy/interstitial fibrosis (T1/2) and lymphocytes and monocytes infiltration were more common. Furthermore, older age, hyperuricemia, proteinuria, global glomerulosclerosis and endocapillary hypercellularity (E1) were more severe in patients with simple arterio-/arteriolosclerosis. By multivariate logistic regression, age, MAP and eGFR were significantly associated with vascular lesions. Vascular lesions, especially arterio-/arteriolosclerosis, were significantly associated with poorer renal survival in IgAN patients, and renal survival was similar whether patients with arterio-/arteriolosclerosis received immunosuppressive therapy. In addition to eGFR, arterio-/arteriolosclerosis, along with arterial intimal fibrosis, was an independent predictor for renal survival in multivariate Cox analyses. CONCLUSION: IgAN patients with vascular lesions, especially with arterio-/arteriolosclerosis, presented more severe clinicopathological features. Renal function, blood pressure and age contributed to distinguishing patients with vascular lesions. Arterio-/arteriolosclerosis lesions were associated with poorer renal survival.

Factors associated with subgroups of fatigue in maintenance hemodialysis patients: a cross-sectional study.

OBJECTIVE: This study aimed to investigate affected factors for subgroups of fatigue and the degree of fatigue in maintenance hemodialysis (MHD) patients. METHODS: This study included 120 MHD patients. Questionnaires, pre- and post-dialysis clinical data, bioimpedance spectroscopy, and ultrasound assessment were involved. RESULTS: The prevalence of fatigue in participants was 83%, including 54% of patients with fatigue worsened by dialysis, 13% with fatigue lessened by dialysis, and 16% with undifferentiated fatigue. Based on multi-nominal logistic regression analysis, age was associated with worsened fatigue by dialysis (odds ratio (OR) = 1.06, 95% confidence interval (CI) 1.01-1.11, p = 0.019), lower post-dialysis phosphorus was associated with lessened fatigue by dialysis (OR = 0.03, 95% CI 0.001-0.981, p = 0.049), and there was an increasing trend of patients experiencing undifferentiated fatigue as the extracellular water / intracellular water (E/I) level increased (p for trend = 0.020). Based on multi-ordinal logistic regression analysis, age was also a significant predictor for more severe fatigue (OR = 1.042, 95% CI 1.008-1.059, p = 0.015). CONCLUSIONS: Different subgroups of fatigue in MHD patients have different affecting factors. Older patients were prone to worsened fatigue by dialysis, patients with lower post-dialysis phosphorus were prone to lessened fatigue by dialysis, and patients with higher E/I levels were prone to undifferentiated fatigue. Meanwhile, older patients are prone to suffer from more severe fatigue. However, more in-depth studies are needed to clarify the pathogenesis of fatigue in MHD patients.

Clinicopathological characteristics, risk factors and renal outcome in IgA nephropathy with crescents.

BACKGROUND/AIMS: The aim of the study was to investigate the clinicopathological characteristics, risk factors and renal outcome in IgA nephropathy (IgAN) patients with crescents. METHODS: Four hundred and fifty-eight biopsy-proven primary IgAN patients included between January 2010 and October 2021 for a retrospective analysis were divided into three groups according to crescent score of the updated Oxford classification: C0 group (n = 255), C1 group (n = 187) and C2 group (n = 16). The clinicopathological features and renal outcomes were recorded. In univariate and multivariate models, the association between crescents and renal outcome and C2-associated clinical factors were analyzed. RESULTS: Patients with a higher proportion of crescents presented worse clinical characteristics with regard to kidney function, proteinuria, hematuria, hemoglobin, uric acid, cholesterol, and serum albumin, while global glomerulosclerosis, segmental adhesion, tuft necrosis, segmental glomerulosclerosis (S1), tubular atrophy/interstitial fibrosis (T1/2), and lymphocyte and monocyte infiltration were more severe. By multivariate logistic regression analysis, eGFR (OR 0.981, 95% CI 0.964-0.999, P = 0.039), proteinuria (OR 1.655, 95% CI 1.180-2.321, P = 0.004), and hematuria (OR 4.752, 95% CI 1.426-15.835, P = 0.011) were significantly associated with C2. C2 was significantly associated with poorer renal survival even in patients receiving immunosuppressive therapy. Nevertheless, only eGFR at baseline, rather than crescents, was an independent predictor for renal survival in multivariate Cox analyses. CONCLUSION: IgAN patients with crescents presented more severe clinical and pathological features. Renal function, proteinuria and hematuria contributed to identifying patients with crescents. Crescents were associated with poorer renal survival, even in patients receiving immunosuppressive therapy, but it was not an independent predictor.

Bulleyaconitine A Inhibits Visceral Nociception and Spinal Synaptic Plasticity through Stimulation of Microglial Release of Dynorphin A.

Background: Visceral pain is one of the most common types of pain and particularly in the abdomen is associated with gastrointestinal diseases. Bulleyaconitine A (BAA), isolated from Aconitum bulleyanum, is prescribed in China to treat chronic pain. The present study is aimed at evaluating the mechanisms underlying BAA visceral antinociception. Methods: The rat model of chronic visceral hypersensitivity was set up by colonic perfusion of 2,4,6-trinitrobenzene sulfonic acid (TNBS) on postnatal day 10 with coapplication of heterotypic intermittent chronic stress (HeICS). Results: The rat model of chronic visceral hypersensitivity exhibited remarkable abdominal withdrawal responses and mechanical hyperalgesia in hind paws, which were dose-dependently attenuated by single subcutaneous of administration of BAA (30 and 90 µg/kg). Pretreatment with the microglial inhibitor minocycline, dynorphin A antiserum, and κ-opioid receptor antagonist totally blocked BAA-induced visceral antinociception and mechanical antihyperalgesia. Spontaneous excitatory postsynaptic currents (sEPSCs) in spinal dorsal horn lamina II neurons were recorded by using whole-cell patch clamp. Its frequency (but not amplitude) from TNBS-treated rats was remarkably higher than that from naïve rats. BAA (1 µM) significantly reduced the frequency of sEPSCs from TNBS-treated rats but not naïve rats. BAA-inhibited spinal synaptic plasticity was blocked by minocycline, the dynorphin A antiserum, and κ-opioid receptor antagonist. Dynorphin A also inhibited spinal synaptic plasticity in a κ-opioid receptor-dependent manner. Conclusions: These results suggest that BAA produces visceral antinociception by stimulating spinal microglial release of dynorphin A, which activates presynaptic κ-opioid receptors in afferent neurons and inhibits spinal synaptic plasticity, highlighting a novel interaction mode between microglia and neurons.

Bulleyaconitine A Exerts Antianxiety and Antivisceral Hypersensitivity Effects.

Visceral pain is one of the leading causes for abdominal pain in gastroenterological diseases and is still hard to treat effectively. Bulleyaconitine A (BAA) is an aconitine analog and has been used for the treatment of pain. Our previous work suggested that BAA exerted analgesic effects on neuropathic pain through stimulating the expression of dynorphin A in spinal microglia. Here, we investigated the inhibitory effect of BAA on visceral pain and examined whether the expression of dynorphin A in spinal microglia was responsible for its effects. We found that BAA produced significant antivisceral pain effect induced by acetic acid through stimulating dynorphin A expression in spinal microglia. In addition, anxiety and chronic visceral pain are highly prevalent comorbid conditions in clinical research, which is still a problem to be solved. We also aimed to evaluate the effects of BAA on anxiety. A comorbidity model with characteristics of both chronic visceral pain and anxiety was developed by colorectal injection of 2,4,6-trinitrobenzene sulfonic acid and the induction of heterotypic intermittent chronic stress protocol. In comorbid animals, BAA exerted great antianxiety effects. Meanwhile, the antianxiety mechanism of BAA was different with the antivisceral pain mechanism of BAA. In conclusion, our study demonstrated, for the first time, that BAA exerted marked antivisceral pain and antianxiety effects, which expands the analgesic spectrum and clinical application of BAA. Furthermore, it also it provides a better guidance for the clinical use of BAA.

The protective effects of Mogroside V and its metabolite 11-oxo-mogrol of intestinal microbiota against MK801-induced neuronal damages.

RATIONALE: Animal models, notably with non-competitive NMDA receptor antagonist MK801, are commonly used to investigate the mechanisms of schizophrenia and to pursue its mechanism-related drug discoveries. OBJECTIVES: In the current study, we have extensively examined the protective effects of MogrosideV (MogV), a plant-derived three terpene glucoside known to exhibit anti-oxidative and anti-inflammatory activities. METHODS AND RESULTS: Here, we investigated its protective effects against neuronal damages elicited by MK-801 treatment. Our behavioral experimental results showed that MK-801-induced PPI deficits and social withdrawal were prevented by MogV treatment. Moreover, the cellular and neurochemical responses of MK-801 in medial prefrontal cortical cortex (mPFC) were also ameliorated by MogV treatment. Also, profiling metabolites assay through artificial intestinal microbiota was performed to identify bioactive components of MogV. An in vitro study of primary neuronal culture demonstrated that MogV and its metabolite 11-oxo-mogrol treatment prevented the MK-801-induced neuronal damages through the mechanisms of promoting neurite outgrowth, inhibiting cell apoptosis, and [Ca2+]i release. Additionally, 11-oxo-mogrol reversed inactivation of phosphorylation levels of AKT and mTOR induced by MK801. CONCLUSIONS: These results suggest therapeutic potential of MogV for schizophrenia.

Nomograms Predicting Self-Regulated Learning Levels in Chinese Undergraduate Medical Students.

PURPOSE: The purpose of this study was to construct a multi-center cross-sectional study to predict self-regulated learning (SRL) levels of Chinese medical undergraduates. METHODS: We selected medical undergraduates by random sampling from five universities in mainland China. The classical regression methods (logistic regression and Lasso regression) and machine learning model were combined to identify the most significant predictors of SRL levels. Nomograms were built based on multivariable models. The accuracy, discrimination, and generalization of our nomograms were evaluated by the receiver operating characteristic curves (ROC) and the calibration curves and a high quality external validation. RESULTS: There were 2052 medical undergraduates from five universities in mainland China initially. The nomograms constructed based on the non-overfitting multivariable models were verified by internal validation (C-index: learning motivation: 0.736; learning strategy: 0.744) and external validation (C-index: learning motivation: 0.986; learning strategy: 1.000), showing decent prediction accuracy, discrimination, and generalization. CONCLUSION: Comprehensive nomograms constructed in this study were useful and convenient tools to evaluate the SRL levels of undergraduate medical students in China.

Antinociceptive effects of novel epibatidine analogs through activation of α4ß2 nicotinic receptors.

The study of α4ß2 nicotinic receptors has provided new indications in the treatment of pain. Efforts have been made to explore new α4ß2 nicotinic receptor agonists, including TC-2559, as antinociceptive drugs. In this study, we discovered a set of novel epibatidine analogs with strong binding affinities to the α4ß2 nicotinic receptors. Among these compounds, C-159, C-163, and C-9515 attenuated formalin-induced nociceptive responses in mice; C-9515 caused the most potent analgesic effect, which was blocked by mecamylamine, a non-selective nicotinic receptor antagonist. Furthermore, C-9515 potently inhibited chronic constriction injury (CCI)-induced neuropathic pain in rats, which was sensitive to DHßE, a selective α4ß2 subtype antagonist, indicating that its analgesic effect was mediated by the activation of the α4ß2 nicotinic receptors. In conclusion, the epibatidine analog C-9515 was found to be a potent α4ß2 nicotinic receptor agonist with potent analgesic function, which demonstrated potential for the further exploration of its druggability.

Ketamine Protects Gamma Oscillations by Inhibiting Hippocampal LTD.

NMDA receptors have been widely reported to be involved in the regulation of synaptic plasticity through effects on long-term potentiation (LTP) and long-term depression (LTD). LTP and LTD have been implicated in learning and memory processes. Besides synaptic plasticity, it is known that the phenomenon of gamma oscillations is critical in cognitive functions. Synaptic plasticity has been widely studied, however it is still not clear, to what degree synaptic plasticity regulates the oscillations of neuronal networks. Two NMDA receptor antagonists, ketamine and memantine, have been shown to regulate LTP and LTD, to promote cognitive functions, and have even been reported to bring therapeutic effects in major depression and Alzheimer's disease respectively. These compounds allow us to investigate the putative interrelationship between network oscillations and synaptic plasticity and to learn more about the mechanisms of their therapeutic effects. In the present study, we have identified that ketamine and memantine could inhibit LTD, without impairing LTP in the CA1 region of mouse hippocampus, which may underlie the mechanism of these drugs' therapeutic effects. Our results suggest that NMDA-induced LTD caused a marked loss in the gamma power, and pretreatment with 10 µM ketamine prevented the oscillatory loss via its inhibitory effect on LTD. Our study provides a new understanding of the role of NMDA receptors on hippocampal plasticity and oscillations.

Homeostatic competition between phasic and tonic inhibition.

The GABAA receptors are the major inhibitory receptors in the brain and are localized at both synaptic and extrasynaptic membranes. Synaptic GABAA receptors mediate phasic inhibition, whereas extrasynaptic GABAA receptors mediate tonic inhibition. Both phasic and tonic inhibitions regulate neuronal activity, but whether they regulate each other is not very clear. Here, we investigated the functional interaction between synaptic and extrasynaptic GABAA receptors through various molecular manipulations. Overexpression of extrasynaptic α6ß3δ-GABAA receptors in mouse hippocampal pyramidal neurons significantly increased tonic currents. Surprisingly, the increase of tonic inhibition was accompanied by a dramatic reduction of the phasic inhibition, suggesting a possible homeostatic regulation of the total inhibition. Overexpressing the α6 subunit alone induced an up-regulation of δ subunit expression and suppressed phasic inhibition similar to overexpressing the α6ß3δ subunits. Interestingly, blocking all GABAA receptors after overexpressing α6ß3δ receptors could not restore the synaptic GABAergic transmission, suggesting that receptor activation is not required for the homeostatic interplay. Furthermore, insertion of a gephyrin-binding-site (GBS) into the α6 and δ subunits recruited α6(GBS)ß3δ(GBS) receptors to postsynaptic sites but failed to rescue synaptic GABAergic transmission. Thus, it is not the positional effect of extrasynaptic α6ß3δ receptors that causes the down-regulation of phasic inhibition. Overexpressing α5ß3γ2 subunits similarly reduced synaptic GABAergic transmission. We propose a working model that both synaptic and extrasynaptic GABAA receptors may compete for limited receptor slots on the plasma membrane to maintain a homeostatic range of the total inhibition.

Omega-3 polyunsaturated fatty acid supplementation improves neurologic recovery and attenuates white matter injury after experimental traumatic brain injury.

Dietary supplementation with omega-3 (ω-3) fatty acids is a safe, economical mean of preventive medicine that has shown protection against several neurologic disorders. The present study tested the hypothesis that this method is protective against controlled cortical impact (CCI). Indeed, mice fed with ω-3 polyunsaturated fatty acid (PUFA)-enriched diet for 2 months exhibited attenuated short and long-term behavioral deficits due to CCI. Although ω-3 PUFAs did not decrease cortical lesion volume, these fatty acids did protect against hippocampal neuronal loss after CCI and reduced pro-inflammatory response. Interestingly, ω-3 PUFAs prevented the loss of myelin basic protein (MPB), preserved the integrity of the myelin sheath, and maintained the nerve fiber conductivity in the CCI model. ω-3 PUFAs also directly protected oligodendrocyte cultures from excitotoxicity and blunted the microglial activation-induced death of oligodendrocytes in microglia/oligodendrocyte cocultures. In sum, ω-3 PUFAs elicit multifaceted protection against behavioral dysfunction, hippocampal neuronal loss, inflammation, and loss of myelination and impulse conductivity. The present report is the first demonstration that ω-3 PUFAs protect against white matter injury in vivo and in vitro. The protective impact of ω-3 PUFAs supports the clinical use of this dietary supplement as a prophylaxis against traumatic brain injury and other nervous system disorders.

Serum peptidome profiling for identifying pathological patterns in patients with primary nephrotic syndrome.

BACKGROUND: Renal biopsy is necessary for diagnosing the pathological changes of primary nephrotic syndrome (NS). However, it is invasive, time-consuming and can not be performed frequent on the same patient. Thus, development of a non-invasive and rapid diagnostic method may improve clinical patient management. METHODS: Proteomic tool magnetic bead-based matrix-assisted laser desorption/ionization time-of-flight mass spectrometry (MB-based MALDI TOF MS) was applied to serum to determine peptidome patterns that are characteristic of different pathological changes. RESULTS: Serum specimen from 114 patients with NS (62 were minimal change disease (MCD), 30 were membranous nephropathy (MN), and 22 were focal segmental glomerulosclerosis (FSGS)) and 60 normal individuals were analyzed using MB-based MALDI TOF MS. The peptidome pattern was generated by genetic algorithms using a training set of 31 MCD, 15 MN, 11 FSGS and 30 normal individuals and was validated by an independent testing set of the remaining samples. The serum peptidome pattern, based on a panel of 14 peaks, accurately recognized samples from MCD, MN, FSGS and healthy control with sensitivities of 93.5%, 86.7%, 63.6% and 90.0%, and specificities of 98.2%, 94.4%, 100% and 89.5%, respectively. Moreover, one peptide from peptidome pattern was identified by liquid chromatography tandem mass spectrometry (LC MS/MS) as fibrinogen A. CONCLUSION: Detection of the serum peptidome pattern is a rapid, non-invasive, high-throughout, and reproducible method for identifying the pathological patterns of patients with nephrotic syndrome.

Proteomic profiling identifies haptoglobin as a potential serum biomarker for steroid-resistant nephrotic syndrome.

BACKGROUND: Long-term outcomes for patients with adult idiopathic nephrotic syndrome correlate closely with steroid responsiveness. The aim of this prospective study was to evaluate the difference in serum proteomes between steroid-sensitive nephrotic syndrome (SSNS) and steroid-resistant nephrotic syndrome (SRNS) patients and identify potential biomarkers for the prediction of SRNS. METHODS: We performed a gel-based proteomic study of serum obtained from SRNS and SSNS patients and healthy controls at the time of presentation (n = 6 for each group). Proteins from the serum samples were separated using 2-D electrophoresis, digested in-gel and subjected to MALDI-TOF-MS/MS analysis. Further validation was performed utilizing Western blot and ELISA. The sensitivities and specificities of the candidate proteins for predicting SRNS were determined using receiver operating characteristic curves. RESULTS: Thirteen differentially expressed proteins were identified as haptoglobin (Hp) with different isoelectric points and molecular weights. Western blot and ELISA analysis of samples from 146 subjects (healthy controls = 52, SSNS = 54, SRNS = 40) showed a markedly increased level of Hp in the serum, but not urine, of SRNS compared to SSNS patients. The optimal serum cutoff level of Hp was set at ≥1,279 µg/ml using the receiver operating characteristic curve. The sensitivity and specificity for predicting SRNS were 85.0 and 96.3%, respectively. CONCLUSIONS: This study provides a novel overview of the difference in serum proteomes of SSNS and SRNS patients. Serum Hp may be a useful predictive biomarker for steroid therapy efficacy in the treatment of idiopathic nephrotic syndrome.

Enhanced inhibitory synaptic transmission in the spinal dorsal horn mediates antinociceptive effects of TC-2559.

BACKGROUND: TC-2559 is a selective α4ß2 subtype of nicotinic acetylcholine receptor (nAChR) partial agonist and α4ß2 nAChR activation has been related to antinociception. The aim of this study is to investigate the analgesic effect of TC-2559 and its underlying spinal mechanisms. RESULTS: 1) In vivo bioavailability study: TC-2559 (3 mg/kg) had high absorption rate in rats with maximal total brain concentration reached over 4.6 µM within first 15 min after administration and eliminated rapidly with brain half life of about 20 min after injection. 2) In vivo behavioral experiments: TC-2559 exerts dose dependent antinociceptive effects in both formalin test in mice and chronic constriction injury (CCI) model in rats by activation of α4ß2 nAChRs; 3) Whole-cell patch-clamp studies in the superficial dorsal horn neurons of the spinal cord slices: perfusion of TC-2559 (2 µM) significantly increased the frequency, but not amplitude of spontaneous inhibitory postsynaptic currents (sIPSCs). The enhancement of sIPSCs was blocked by pre-application of DHßE (2 µM), a selective α4ß2 nicotinic receptor antagonist. Neither the frequency nor the amplitude of spontaneous excitatory postsynaptic currents (sEPSCs) of spinal dorsal horn neurons were affected by TC-2559. CONCLUSIONS: Enhancement of inhibitory synaptic transmission in the spinal dorsal horn via activation of α4ß2 nAChRs may be one of the mechanisms of the antinociceptive effects of TC-2559 on pathological pain models. It provides further evidence to support the notion that selective α4ß2 subtype nAChR agonist may be developed as new analgesic drug for the treatment of neuropathic pain.

Activation of presynaptic alpha7 nicotinic receptors evokes an excitatory response in hippocampal CA3 neurones in anaesthetized rats: an in vivo iontophoretic study.

BACKGROUND AND PURPOSE: alpha7 Nicotinic receptors have been suggested to play an important role in hippocampal learning and memory. However, the direct action of this receptor subtype on hippocampal pyramidal neurones in vivo has not yet been fully investigated. The availability of selective agonists for alpha7 receptors [AR-R17779 and (R)-(-)-5'-phenylspiro[1-azabicyclo[2.2.2] octane-3,2'-(3'H)furo[2,3-b]pyridine (PSAB-OFP)] has now allowed this role to be investigated. EXPERIMENTAL APPROACH: Single-cell extracellular recordings were made from hippocampal CA3 pyramidal neurones in anaesthetized rats. The effects of nicotine, AR-R17779 and PSAB-OFP, applied either systemically or iontophoretically, were studied on the activity of these neurones. KEY RESULTS: Intravenous injection of cumulative doses of nicotine and PSAB-OFP induced dose-related, significant increases in neuronal firing in the majority of neurones tested. This excitation could be inhibited by intravenous administration of methyllycaconitine (MLA), a selective alpha7 nicotinic receptor antagonist. Furthermore, iontophoretic application of nicotine, AR-R17779 and PSAB-OFP each evoked current-dependent excitation of most CA3 pyramidal neurones studied, and this excitation was antagonized by co-iontophoretic application of MLA. In addition, the excitation induced by iontophoretic application of nicotine, AR-R17779 or PSAB-OFP was also blocked by co-iontophoretic application of either 6,7-dinitroquinoxaline-2,3-dione (DNQX) or D(2)-2-amino-5-phosphonopentanoate (D-AP5), selective N-methyl-D-aspartic acid (NMDA) and non-NMDA receptor antagonists respectively. CONCLUSIONS AND IMPLICATIONS: CA3 pyramidal neurones are modulated by activation of presynaptic alpha7 nicotinic receptors, which, at least in part, enhances glutamate release onto post-synaptic (RS)-alpha-amino-3-hydroxy-5-methyl-4-isoxazole proprionic acid and NMDA receptors on these CA3 neurones. This mechanism probably contributes to the effects of nicotine on hippocampal learning and memory.