Background and Purpose: Abnormal activation of the NLRP3 inflammasome in macrophages is closely associated with Ulcerative colitis (UC), and targeting the NLRP3 inflammasome has been proposed as a potential therapeutic approach, but the underlying mechanism by which it regulates intestinal inflammation remains unclear. Anemoside B4 (AB4) has anti-inflammatory activity, but whether it alleviates UC by inhibiting the activation of NLRP3 inflammasome remains unclear. More importantly, the molecular targets of AB4 remain unknown. Experimental Approach: We explored the role of AB4 in the development of dextran sodium sulfate (DSS)-induced colitis in wild-type (WT) mice and its effect on NLRP3 inflammasome. We isolated intestinal macrophages and epithelial cells, and validated them in DSS-induced NLRP3-deficient (NLRP3-/-) mice. The target and molecular mechanism of AB4 were identified in LPS-induced macrophages in vitro and DSS-induced macrophage-specific CD1d depletion (CD1d-/-) mice in vivo. Key Results: This study showed that AB4 had a strong anti-inflammatory effect DSS-induced colitis in WT mice, whereas the protective effects were lost in NLRP3-/- mice. AB4 inhibited the activation of NLRP3 inflammasome in colonic macrophages without affecting intestinal epithelial cells. Mechanistically, AB4 might target CD1d thus reducing the AKT-STAT1-PRDX1-NF-κB signaling pathway, eventually inhibiting the activation of NLRP3 inflammasome. Macrophage-specific CD1d depletion had been shown to reverse the protective effect of AB4. Conclusions and Implications: Our data showed that AB4 attenuated DSS-induced colitis by inhibiting CD1d-dependent NLRP3 inflammasome activation in macrophages. Therefore, as a natural product with high safety index, AB4 might be considered a promising candidate drug for the treatment of colitis.

AKB48 is a synthetic cannabinoid illegally sold for its psychoactive cannabis-like effects that has been associated to several acute intoxications and which effects are poorly known. Using a behavioural, neurochemical and immunohistochemical approach we investigated the pharmaco-toxicological effects, plasma pharmacokinetic and neuroplasticity at cannabinoid CB1 receptor (CB1R) in the cerebellum and cortex induced by repeated AKB48 administration in male and female mice. The effects of AKB48 varied significantly depending on sex and length of treatment. The 1st injection impaired sensorimotor responses and reduced body temperature, analgesia, and breath rate at a greater extent in females than in males, the 2nd injection induced stronger effects in males while the 3rd injection of AKB48 induced weaker responses in both sexes, suggesting the emergence of tolerance. The CB1R antagonist NESS-0327 prevented the effects induced by repeated AKB48, confirming a CB1R-mediated action of the drug. Blood AKB48 levels were higher in females than in males and repeated administration caused a progressive rise of AKB48 content in blood samples of both sexes, suggesting an inhibitory effect on cytochrome activity. Finally, immunohistochemical analysis revealed higher expression of CB1Rs in the cerebellum and cortex of females, and a rapid CB1R downregulation in cerebellar and cortical areas following repeated AKB48 injections, with neuroadaptation occurring generally more rapidly in females than in males. We showed for the first time that AKB48 effects significantly vary with prolonged use and that sex affects the pharmacodynamic/pharmacokinetic responses to its repeated administration, suggesting a sex-tailored approach in managing AKB48-induced intoxication.

Background and Purpose Voltage sensitivity is a common feature of many membrane proteins, including some G-protein coupled receptors (GPCRs). However, the functional consequences of voltage sensitivity in GPCRs are not well understood. Experimental approach In this study, we investigated the voltage sensitivity of the post-synaptic metabotropic glutamate receptor mGlu5 and its impact on synaptic transmission. Using biosensors and electrophysiological recordings in non-excitable HEK293T cells or neurons. Key Results We found that mGlu5 receptor function is optimal at resting membrane potentials. We observed that membrane depolarization significantly reduced mGlu5 receptor activation, Gq-PLC/PKC stimulation, Ca2+ release, and mGlu5 receptor-gated currents through TRPC6 channels or NMDA receptors. Notably, we report a previously unknown activity of the NMDA receptor at the resting potential of neurons, enabled by mGlu5. Conclusions & Implications Our findings suggest that mGlu5 receptor activity is directly regulated by membrane voltage which may have a significant impact on synaptic processes and pathophysiological functions.

GPR84 was first identified as an open reading frame encoding an orphan Class A G protein coupled receptor in 2001. Gpr84 mRNA is expressed in a limited number of cell types with the highest levels of expression being in innate immune cells, M1 polarised macrophages and neutrophils. The first reported ligands for this receptor were medium chain fatty acids with chain lengths between 9 and 12 carbons. Subsequently a series of synthetic agonists that signal via the GPR84 receptor were identified. Radioligand binding assays and molecular modelling with site-directed mutagenesis suggest the presence of three ligand binding sites on the receptor, but the physiological agonist(s) of the receptor remain unidentified. Here, we review the effects of GPR84 agonists on innate immune cells following a series of chemical discoveries since 2001. The development of highly biased agonists has helped to probe receptor function in vitro, and the challenge remaining is to follow the effects of biased signalling to the physiological functions of innate immune cell types.

Background and Purpose: Transient hypofunction of NMDARs represents a convergence point for the onset and further development of psychiatric disorders, including schizophrenia. Although the cumulative evidence indicates dysregulation of the hippocampal formation in schizophrenia, the integrity of the synaptic transmission and plasticity conveyed by the somatosensorial inputs to the dentate gyrus, the perforant path synapses, have barely been explored in this pathological condition. Experimental Approach: We identified a series of synaptic alterations of the lateral and medial perforant paths, in animals neonatally treated with the NMDAR antagonist MK-801. The dysregulation here reported suggests decreased cognitive performance, for which the dentate gyrus is critical. Key Results: We identified alterations in the synaptic properties of the lateral and medial perforant paths to the dentate gyrus synapses in MK-801-treated animals. Altered glutamate release and decreased synaptic strength precede an impairment in the induction and expression of LTP and cannabinoid 1 receptor (CB1R)-mediated LTD. Remarkably, by inhibiting the degradation of 2-arachidonoylglycerol, the endogenous ligand of the CB1R, we restored the LTD in animals treated with MK-801. Additionally, we show for the first time that spatial discrimination, a cognitive task that requires dentate gyrus integrity, is impaired in animals exposed to transient hypofunction of NMDARs. Conclusion and Implications: Descriptive and mechanistic evidence showing the dysregulation of glutamatergic transmission and synaptic plasticity from the entorhinal cortex to the dentate gyrus is presented. These findings may explain the cellular dysregulations underlying the altered cognitive processing in the dentate gyrus associated with schizophrenia.

Background and Purpose: Although the amphiphilic nature of the widely used antithrombotic drug Ticagrelor is well known, it was never considered as a membranotropic agent, which is able to interact with lipid bilayer in a receptor-independent way. In this work we investigate the influence of Ticagrelor on plasma membrane lipid order in platelets and whether this could modulate affinity of P2Y12 receptor to Ticagrelor. Experimental Approach: Here, we combined fluorescent in situ, in vitro and in silico approaches to probe the interactions between the plasma membrane of platelets and Ticagrelor. The influence of Ticagrelor on the lipid order of the platelets’ plasma membrane and large unilamellar vesicles was studied using advanced fluorescent probe NR12S. Further, the properties of the model lipid bilayers in presence of Ticagrelor were characterized by molecular dynamics simulations. Finally, the influence of an increased lipid order on the dose response of platelets to Ticagrelor was studied. Key Results: Ticagrelor incorporates spontaneously into lipid bilayers and affects the lipid order of the membranes of model vesicles and isolated platelets in non-trivial composition and concentration-dependent manner. We showed that higher plasma membrane lipid order in platelets leads to the lower IC50 for Ticagrelor. It is shown that membrane incorporation of Ticagrelor increases the affinity of the drug to its own therapeutic target, the P2Y12 receptor, by means of increasing the order of the platelet’s plasma membrane. Conclusion and Implications: A novel dual mechanism of Ticagrelor action is suggested that combines direct binding to P2Y12 receptor with simultaneous modulation of receptor’s lipid microenvironment.

Background and Purpose: Traumatic brain injury (TBI) remains a major public health concern worldwide with unmet effective treatment. Stimulator of Interferon Genes (STING) protein and its downstream type-I Interferon (IFN) signaling are now appreciated to be involved in TBI pathogenesis. Compelling evidence have shown that STING and type-I IFNs are key in mediating detrimental neuroinflammatory response after TBI, exacerbating outcome. Therefore, pharmacological inhibition of STING presents a viable therapeutic opportunity in combating the detrimental neuroinflammatory response after TBI. Experimental Approach: This study investigated the neuroprotective effects of the small-molecule STING inhibitor C-176 in the controlled-cortical impact (CCI) mouse model of TBI in 10–12-week-old male mice. 30-minutes post-CCI surgery, a single 750nmol dose of C-176 or saline (vehicle) was administered intravenously. Analysis was conducted 2h- and 24h-post TBI. Key Results: Mice administered C-176 had significantly smaller cortical lesion area when compared to vehicle-treated mice 24h post-TBI. Quantitative temporal gait analysis conducted using DigiGait™ showed C-176 administration attenuated TBI-induced impairments in gait symmetry, stride frequency and forelimb stance width. C-176-treated mice displayed a significant reduction in striatal gene expression of pro-inflammatory cytokines TNF-α, IL-1β and CXCL10 compared to their vehicle-treated counterparts 2h post-TBI. Conclusion and Implications: This study demonstrates the neuroprotective activity of C-176 in ameliorating acute neuroinflammation and preventing white matter neurodegeneration post-TBI. This study highlights the therapeutic potential of small-molecule inhibitors targeting STING for the treatment of trauma induced inflammation and neuroprotective potential.

Background and Purpose L-type amino acid (AA) transporters LAT1 (SLC7A5) and LAT2 (SLC7A8) facilitate the bidirectional transport of branched and aromatic AA across the plasma membrane. While LAT1 is overexpressed in different tumour cells and it is dedicated to deliver AA into growing cells, LAT2 facilitates the transcellular AA transport at biological barriers. Data on dynamic AA transport by LAT1/2 in physiological media are widely lacking and the impact of LAT1-selective inhibitors and mutations on the cellular metabolome is unknown. Experimental Approach The human MDST8 cell line lacking LAT1/2 expression was employed to generate transiently and stably expressing MDST8-LAT1 and MDST8-LAT2 cells. Together with the HT-29 cell line, we depicted metabolic signatures mediated by LAT1 and LAT2 using LC-ESI-MS/MS and characterized potent LAT1/2 inhibitors for their selectivity and mode of action. Moreover, LAT1 mutations associated with autism spectrum disorder (ASD) were functionally evaluated. Key Results LAT1 and LAT2 expression induced the expression of 4F2hc and facilitated differential cellular metabolomic signatures in MDST8 cells. The LAT1(A246V) mutation showed overall reduced aromatic AA uptake and profound alterations of intracellular metabolites and biochemical processes. The equipotent LAT1 inhibitors JPH203 and JX-078 showed intriguing differences on metabolomic effects, uncovering their distinct mode of action. Conclusion and Implications Our study demonstrates that SLC7A transporters mediate differential dynamic cellular AA changes under physiological conditions and reports the broad effects of one human LAT1 mutation associated with ADS. Moreover, the characterization of biased LAT1 inhibitors challenges current concepts about transporter pharmacology and has implications for drug discovery.

Objective: Our study aimed to explore the mechanism network that TLR2/AP-1 combined with SOX10 to activate the MAPK pathway via CTGF in Dox-induced myocardial injury. Methods: Rats with Dox-induced myocardial injury were treated with a TLR2 inhibitor or CTGF silencing lentiviral vector. H9c2 cells were treated with genetic vectors or MAPK pathway activators. Cardiac function was tested using echocardiography and serum markers. H&E, sirius red, and TUNEL staining were used to detect myocardial pathological changes, collagen accumulation, and apoptosis. Western blot was used to detect proteins related to cardiac hypertrophy, fibrosis, apoptosis, and MAPK pathway. H9c2 cell injury was assessed by testing cell viability, LDH release, and mitochondrial membrane potential. Results: TLR2 and CTGF were highly expressed in patients with heart failure, and Dox treatment further increased their expression. Inhibiting TLR2 or silencing CTGF improved cardiac function and reduced myocardial fibrosis and apoptosis in Dox-treated rats. Silencing TLR2 alleviated Dox-induced H9c2 cell injury, which was nullified by CTGF overexpression. TLR2 activated AP-1, which cooperated with SOX10 to promote CTGF transcription. MAPK activation aggravated H9c2 cells against Dox-induced injury. Conclusions: TLR2 activates AP-1 which cooperates with SOX10 to promote CTGF transcription and subsequently activate the MAPK pathway, thereby stimulating Dox-induced myocardial injury.

Background and Purpose: The holotoxin A1, isolated from Apostichopus japonicus, has shown potent antifungal activities with unclear mechanism and efficacy against candidiasis. This study aimed to reveal the antifungal effects and mechanism of holotoxin A1 against Candida albicans in vitro and in candidiasis murine models for the first time. Experimental Approach: The antifungal effect of holotoxin A1 against C. albicans was tested in vitro. To explore the antifungal mechanism of holotoxin A1, the transcriptome, ROS levels, and mitochondrial function of C. albicans was evaluated. The oropharyngeal and intra-abdominal candidiasis mouse models were used to verify the effectiveness and systematic toxicity in vivo. Key Results: Holotoxin A1 was a potent fungicide against C. albicans SC5314, clinical strains and drug-resistant strains. Holotoxin A1 inhibited the oxidative phosphorylation and induced oxidative damage by increasing intracellular accumulation of ROS in C. albicans. Holotoxin A1 caused the disfunction of mitochondria by depolarizing the mitochondrial membrane potential and reducing the production of ATP. Holotoxin A1 directly inhibited the enzymatic activity of mitochondrial complex I (CI) and antagonized with the rotenone, an inhibitor of CI, against C. albicans. Meanwhile, the CI subunit NDH51 null mutants showed the decreased susceptibility to holotoxin A1. Furthermore, holotoxin A1 significantly reduced fungal burden and infections with no significant systemic toxicity in oropharyngeal and intra-abdominal candidiasis murine models. Conclusions and Implications: Holotoxin A1 was a promising candidate for the development of novel antifungal drug against both oropharyngeal and intra-abdominal candidiasis, especially caused by the drug resistant strains.

Background and purpose: Hypertension increases the risk for cognitive impairment and promotes vascular and renal inflammation. We tested if immune cell infiltration occurs in the brain during hypertension and if it is associated with cognitive impairment. Experimental approach: Male C57Bl/6 mice were administered vehicle, angiotensin II (0.7 mg/kg/d S.C.) or aldosterone (0.72 mg/kg/d S.C.) via osmotic minipumps. A subset of mice also received hydralazine (50 mg/kg) in their drinking water after minipump implantation. We measured systolic blood pressure, markers of inflammation, working memory and transcriptomic changes in the brain. Key results: Administration of angiotensin II or aldosterone increased blood pressure and promoted blood-brain barrier dysfunction, leukocyte accumulation and impairment of working memory in mice. When co-administered with angiotensin II, hydralazine prevented the development of these changes. In a separate cohort of mice in which angiotensin II-induced changes were first established, intervention with hydralazine lowered blood pressure but did not reverse brain inflammation or cognitive impairment. Finally, angiotensin II infusion altered the transcriptomic profile of the whole brain, as well as specifically within the hippocampus, and co-treatment with hydralazine modulated these changes. Conclusion and implications: Experimental hypertension leads to brain inflammation and impaired working memory. Cognitive impairment that develops during hypertension can be inhibited, but not readily reversed, by anti-hypertensive therapy.

Background and Purpose Metabotropic Glutamate Receptors (mGlu) regulate multiple functions in the nervous systems and are involved in multiple disorders. However, selectively targeting individual mGlu subtypes with spatiotemporal precision is still an unmet need. Photopharmacology can address this concern by means of photoswitchable compounds such as Optogluram, which is a positive allosteric modulator (PAM) of mGlu4 that enables to optically control physiological responses with a high precision. However, Optogluram is not fully selective and finding mGlu4 PAMs with subtype selectivity may be complicated. Experimental Approach New photoswitchable analogues of Optogluram were synthesised with the aim of obtaining photoswitchable PAMs selective for mGlu4 receptor and with improved photoisomerization properties. The photopharmacological profiles of these new compounds were assessed using spectroscopy, functional IP and cAMP assays and computational modelling. Key Results Optogluram-2 emerged as a new photoswitchable PAM for mGlu4 receptor and offered improved photoswitching properties and was selective for mGlu4. Optogluram-2 had activity as both PAM and allosteric agonist. The π-π stacking of the thiazole ring in the allosteric pocket of mGlu6 is hypothesised to be responsible of the mGlu4 selectivity. Conclusion and Implications. The enhanced photoswitching behaviour and improved selectivity of Optogluram-2 makes it an excellent candidate to study the role of mGlu4 with a high spatiotemporal precision that only photopharmacology can offer. Indeed, the use of Optogluram-2 in tissues where mGlu4 can be co-expressed with other mGlu receptors will help to unravel the complexity of mGlu receptors in neural transmission, pinpointing the role of mGlu4 in such systems.

The GPCR signalling cascade is a key pathway responsible for the signal transduction of a multitude of physical and chemical stimuli, including light, odorants, neurotransmitters, and hormones. Understanding the structural and functional properties of the GPCR cascade requires direct observation of signalling processes in high spatial and temporal resolution with minimal perturbation to endogenous systems. Optical microscopy and spectroscopy techniques are uniquely suited to this purpose because they excel at multiple spatial and temporal scales and can be used in living objects. Here, we review recent developments in microscopy and spectroscopy technologies which enable new insights into GPCR signalling. We focus on advanced techniques with high spatial and temporal resolution, single-molecule methods, labelling strategies, and approaches suitable for endogenous systems and large living objects. This review aims to assist researchers in choosing appropriate microscopy and spectroscopy approaches for a variety of applications in the study of cellular signalling.

Inflammation is a physiological response composed by well-defined and overlapping events that can eliminate pathogens and reestablish homeostasis of tissues. Physiological systems have an elastic capacity to deal with numerous perturbations. Infection may lead to inflammation, tissue damage and disease as consequence of breakdown of tissue resilience. The resolutive phase is a sine qua non condition to achieve homeostasis after acute inflammation. Exuberant or chronic inflammation occurs in diverse infectious diseases. Pro-resolving molecules may be useful for the treatment of certain infections, as these molecules modulate the immune response and avoid the exacerbated/misplaced inflammation unleashed by microbes. Some pro-resolving molecules may also favour pathogen clearance, in addition to decreasing tissue damage. In this review, we discuss the endogenous role and the therapeutic potential of the most relevant pro-resolving molecules in the context of bacterial and viral infections.

Accumulating studies in recent years have revealed that airway remodeling is involved in the occurrence, development, and treatment sensitivity of asthma. Airway epithelial cells (AECs) regulate the activation of epithelial-mesenchymal trophic units (EMTUs) during airway remodeling through secretion of a series of signaling mediators. However, the major trigger and the intrinsic pathogenesis of airway remodeling is still obscure. Here, we show that the expression of CTSK in airway epithelia increased significantly along with the development of airway remodeling in HDM-stressed asthma model. Increased secretion of CTSK from airway epithelia induced the activation of EMTU through the activation of PAR2-mediated pathway. We found that CTSK is a potential biomarker of airway remodeling for asthma patients that can reflect the degree of airway remodeling and the severity of asthma. Blockade of CTSK inhibits EMTU activation and alleviate airway remodeling effectively that is an effective intervention target of airway remodeling. Thus, our findings provide that CTSK is a potential biomarker for airway remodeling which may also be a useful target for the targeted intervention of airway remodeling in asthma patients.

Background and Purpose: In major depressive disorder (MDD), exploration of biomarkers will be helpful in diagnosing the disorder as well as in choosing a treatment, and predicting the treatment response. Currently, tRNA-derived small ribonucleic acids (tsRNAs) have been established as promising non-invasive biomarker candidates that may enable a more reliable diagnosis or monitoring of various diseases. Herein, we aimed to explore tsRNA expression together with functional activities in MDD development. Experimental Approach: Serum samples were obtained from patients with MDD and healthy controls, and small RNA sequencing (RNA-Seq) was used to profile tsRNA expression. Dysregulated tsRNAs in MDD were validated by quantitative real-time polymerase chain reaction (qRT-PCR). The diagnostic utility of specific tsRNAs and the expression of these tsRNAs after antidepressant treatment was analyzed. Key Results: In total, 38 tsRNAs were significantly differentially expressed in MDD samples relative to healthy individuals (34 upregulated and 4 downregulated). qRT-PCR was used to validate the expression of six tsRNAs that were upregulated in MDD (tiRNA-1:20-chrM. Ser-GCT, tiRNA-1:33-Gly-GCC-1, tRF-1:22-chrM.Ser-GCT, tRF-1:31-Ala-AGC-4-M6, tRF-1:31-Pro-TGG-2, and tRF-1:32-chrM. Gln-TTG). Interestingly, serum tiRNA-Gly-GCC-001 levels exhibited an area under the ROC curve of 0.844. Moreover, tiRNA-Gly-GCC-001 is predicted to suppress brain-derived neurotrophic factor (BDNF) expression. Furthermore, significant tiRNA-Gly-GCC-001 downregulation was evident following an eight-week treatment course and served as a promising baseline predictor of patient response to antidepressant therapy. Conclusion and Implications: Our current work firstly found that tiRNA-Gly-GCC-001 is a promising MDD biomarker candidate that can predict patient responses to antidepressant therapy.

Decreased aortic compliance is a precursor to numerous cardiovascular diseases. Compliance is regulated by the rigidity of the aortic wall and the vascular smooth muscle cells (VSMCs) within it. Extracellular matrix stiffening, observed during ageing, reduces compliance and contributes to hypertension. In response to increased rigidity, VSMCs generate enhanced contractile forces that result in VSMC stiffening and a further reduction in compliance. Due to a lack of suitable in vitro models, the mechanisms driving VSMC response to matrix rigidity remain poorly defined. Human aortic-VSMCs were seeded onto polyacrylamide hydrogels whose rigidity mimicked either healthy or aged/diseased aortae. VSMC response to contractile agonist stimulation was measured through changes in cell area and volume. VSMCs were pre-treated with pharmacological agents prior to agonist stimulation to identify regulators of VSMC hypertrophy. VSMCs undergo a differential response to contractile agonist stimulation based on matrix rigidity. On pliable matrices, VSMCs contract, decreasing in cell area. Meanwhile, on rigid matrices VSMCs undergo a hypertrophic response, increasing in area and volume. Piezo1 mediated calcium influx drives VSMC hypertrophy by promoting microtubule destabilisation. Pharmacological stabilisation of microtubules or blocking calcium influx prevented VSMC hypertrophy on rigid matrices whilst maintaining contractility on pliable matrices. In response to extracellular matrix rigidity, VSMCs undergo a hypertrophic response driven by piezo1-mediated microtubule destabilisation. Pharmacological targeting of this response blocks matrix rigidity induced VSMC hypertrophy whilst VSMC contractility on healthy mimicking matrices is unimpeded. Through delineating this rigidity-induced mechanism, we identify novel targets whose pharmacological inhibition may prove beneficial against VSMC-driven cardiovascular disease.

Background and Purpose Asthma is characterized by airway inflammation, mucus hypersecretion and airway hyperresponsiveness (AHR). The activation of cholinergic anti‐inflammatory pathway (CAP) through nicotinic agents has been shown to control experimental asthma. Yet, the effects of vagus nerve stimulation (VNS)-induced CAP on allergic inflammation remain unknown. Experimental Approach BALB/c mice were sensitized and challenged with house dust mite (HDM) extract, and treated with active VNS (5Hz, 0.5 ms, 0.1 mA). Bronchoalveolar lavage (BAL) fluid was assessed for total and differential cell counts and cytokine levels. Lungs were examined by histopathology and electron microscopy. AHR in response to methacholine was also measured. Key Results In the HDM mouse asthma model, active but not sham VNS reduced BAL fluid total and differential cell counts, blocked mucus hypersecretion and suppressed choline acetyltransferase (ChAT) expression in bronchial epithelial cells. Besides, active VNS also abated HDM-induced elevation of type 2 cytokines IL-4 and IL-5. Furthermore, goblet cell hyperplasia and collagen deposition were diminished in VNS-treated mice. Mechanistically, VNS was found to block the phosphorylation of transcription factor STAT6 and the level of IRF4 in total lung lysates. Finally, VNS abrogated methacholine-induced AHR in asthma mice. Therapeutic effects of VNS were abolished by prior administration with α-bungarotoxin, a specific inhibitor of α7 nicotinic receptors (α7nAChR). Conclusion Our data revealed the protective effects of VNS on various clinical features in allergic airway inflammation model. VNS, a clinically approved therapy for depression and epilepsy, appears to be a promising new strategy for controlling allergic asthma through α7nAChR.