Alpha7 Nicotinic Acetylcholine Receptor Agonists Research Articles

Activation of alpha-7 nicotinic acetylcholine receptor by tropisetron mitigates 3-nitropropionic acid-induced Huntington's disease in rats: Role of PI3K/Akt and JAK2/NF-κB signaling pathways

Huntington's disease (HD) is an inheritable autosomal-dominant disorder that targets mainly the striatum. 3-Nitropropionic acid (3-NP) induces obvious deleterious behavioral, neurochemical, and histological effects similar to the symptoms of HD. Our study aimed to examine the neuroprotective activity of tropisetron, an alpha-7 neuronal nicotinic acetylcholine receptor (α-7nAChR) agonist, against neurotoxic events associated with 3-NP-induced HD in rats. Forty-eight rats were randomly allocated into four groups. Group I received normal saline, while Groups II, III and IV received 3-NP for 2 weeks. In addition, Group III and IV were treated with tropisetron 1 h after 3-NP administration. Meanwhile, Group IV received methyllycaconitine (MLA), an α-7nAChR antagonist, 30 min before tropisetron administration. Treatment with tropisetron improved motor deficits as confirmed by the behavioral tests and restored normal histopathological features of the striatum. Moreover, tropisetron showed an anti-oxidant activity via increasing the activities of SDH and HO-1 as well as Nrf2 expression along with reducing MDA level. Tropisetron also markedly upregulated the protein expression of p-PI3K and p-Akt which in turn hampered JAK2/NF-κB inflammatory cascade. In addition, tropisetron showed an anti-apoptotic activity through boosting the expression of Bcl-2 and reducing Bax expression and caspase-3 level. Interestingly, all the aforementioned effects of tropisetron were blocked by pre-administration of MLA, which confirms that such neuroprotective effects are mediated via activating of α-7nAChR. In conclusion, tropisetron showed a neuroprotective activity against 3-NP-induced HD via activating PI3K/Akt signaling and suppressing JAK2/NF-κB inflammatory axis. Thus, repositioning of tropisetron could represent a promising therapeutic strategy in management of HD.

The alpha-7 nicotinic acetylcholine receptor agonist PHA-543613 reduces food intake in male rats

Obesity is a prevalent disease, but effective treatment options remain limited. Agonists of the alpha-7 nicotinic acetylcholine receptor (α7nAChR) promote negative energy balance in mice, but these effects are not well-studied in rats. We tested the hypothesis that central administration of the α7nAChR agonist PHA-543613 (PHA) would decrease food intake and body weight in adult male Sprague Dawley rats. Intracerebroventricular (ICV) PHA administration in chow-fed rats produced a suppression of energy intake and weight gain over 24 h. Next, to evaluate effects of ICV PHA on palatable food intake, rats were maintained on a choice diet of rodent chow and 45 % high fat diet (HFD); under these conditions, ICV PHA produced no significant changes in energy intake from either food, or body weight gain, in the 24 h post-injection. However, when given a choice of chow or a higher-fat 60 % HFD, ICV PHA reduced intake of 60 % HFD, but not chow; body weight gain was also suppressed. Further experiments evaluating conditioned taste avoidance (CTA) and pica in response to ICV PHA suggested that the suppressive food intake and body weight effects after ICV injection of PHA were not due to nausea/malaise. Finally, an operant conditioning study showed that responding on a progressive ratio schedule of reinforcement for high-fat food pellets decreased after ICV PHA. Collectively, these studies show that PHA reduces energy intake under some but not all dietary conditions. Importantly, central PHA decreases both food intake as well as motivation for highly palatable, energy dense foods in rats without inducing nausea/malaise, suggesting that the α7nAChR could be a viable target for developing treatments for obesity.

GTS-21 attenuates ACE/ACE2 ratio and glycocalyx shedding in lipopolysaccharide-induced acute lung injury by targeting macrophage polarization derived ADAM-17

Acute lung injury (ALI) has received considerable attention in intensive care owing to its high mortality rate. It has been demonstrated that the selective alpha7 nicotinic acetylcholine receptor agonist Gainesville Tokushima scientists (GTS)-21 is promising for treating ALI caused by lipopolysaccharides (LPS). However, the precise underlying mechanism remains unknown. This study aimed to investigate the potential efficacy of GTS-21 in the treatment of ALI. We developed mouse models of ALI and alveolar epithelial type II cells (AT2s) injury following treatment with LPS and different polarized macrophage supernatants, respectively. Pathological changes, pulmonary edema, and lung compliance were assessed. Inflammatory cells count, protein content, and pro-inflammatory cytokine levels were analysed in the bronchoalveolar lavage fluid. The expression of angiotensin-converting enzyme (ACE), ACE2, syndecan-1 (SDC-1), heparan sulphate (HS), heparanase (HPA), exostosin (EXT)-1, and NF-κB were tested in lung tissues and cells. GTS-21-induced changes in macrophage polarization were verified in vivo and in vitro. Polarized macrophage supernatants with or without recombination a disintegrin and metalloproteinase-17 (ADAM-17) and small interfering (si)RNA ADAM-17 were used to verify the role of ADAM-17 in AT2 injury. By reducing pathological alterations, lung permeability, inflammatory response, ACE/ACE2 ratio, and glycocalyx shedding, as well as by downregulating the HPA and NF-κB pathways and upregulating EXT1 expression in vivo, GTS-21 significantly diminished LPS-induced ALI compared to that of the LPS group. GTS-21 significantly attenuated macrophage M1 polarization and augmented M2 polarization in vitro and in vivo. The destructive effects of M1 polarization supernatant can be inhibited by GTS-21 and siRNA ADAM-17. GTS-21 exerted a protective effect against LPS-induced ALI, which was reversed by recombinant ADAM-17. Collectively, GTS-21 alleviates LPS-induced ALI by attenuating AT2s ACE/ACE2 ratio and glycocalyx shedding through the inhibition of macrophage M1 polarization derived ADAM-17.

Increased brain cytokine level associated impairment of vigilance and memory in aged rats can be alleviated by alpha7 nicotinic acetylcholine receptor agonist treatment

Age-related neurocognitive disorders are common problems in developed societies. Aging not only affects memory processes, but may also disturb attention, vigilance, and other executive functions. In the present study, we aimed to investigate age-related cognitive deficits in rats and associated molecular alterations in the brain. We also aimed to test the effects of the alpha7 nicotinic acetylcholine receptor (nAChR) agonist PHA-543613 on memory as well as on the sustained attention and vigilance of aged rats. Short- and long-term spatial memories of the rats were tested using the Morris water maze (MWM) task. To measure attention and vigilance, we designed a rat version of the psychomotor vigilance task (PVT) that is frequently used in human clinical examinations. At the end of the behavioral experiments, mRNA and protein expression of alpha7 nAChRs, cytokines, and brain-derived neurotrophic factor (BDNF) were quantitatively measured in the hippocampus, frontal cortex, striatum, and cerebellum. Aged rats showed marked cognitive deficits in both the MWM and the PVT. The deficit was accompanied by increased IL-1beta and TNFalpha mRNA expression and decreased BDNF protein expression in the hippocampus. PHA-543613 significantly improved the reaction time of aged rats in the PVT, especially for unexpectedly appearing stimuli, while only slightly (non-significantly) alleviating spatial memory deficits in the MWM. These results indicate that targeting alpha7 nAChRs may be an effective strategy for the amelioration of attention and vigilance deficits in age-related neurocognitive disorders.

Alpha-7 Nicotinic Acetylcholine Receptor Activation Inhibits Trauma Induced Pronociceptive Autoimmune Responses

Both autonomic nervous system dysfunction and immune system activation are characteristic of chronic pain after limb injuries. Cholinergic agonists reduce immune system activation in many settings. We hypothesized, therefore, that alpha-7 nicotinic acetylcholine receptor (α7nAChR) agonist administration would reduce nociceptive and immune changes after tibia fracture and cast immobilization in mice. Fracture mice were treated with either vehicle, a low (.2 mg/kg) dose, or a high (1 mg/kg) dose of the selective α7nAChR agonist PNU-282987 for 4 weeks. We assessed hindpaw allodynia and weight bearing as behavioral outcomes. The assessment of adaptive immune responses included regional lymph node hypertrophy, germinal center formation, α7nAChR expression, and IgM deposition. Assessment of innate immune system activation focused on IL-1β and IL-6 generation in fractured hindlimb skin. We observed that mechanical allodynia and unweighting were alleviated by PNU-282987 treatment. Drug treatment also reduced popliteal lymph node hypertrophy and germinal center formation. Immunohistochemical studies localized α7nAChR to germinal center B lymphocytes, and this expression increased after fracture. Analysis of fracture limb hindpaw skin demonstrated increased inflammatory mediator (IL-1β and IL-6) levels and IgM deposition, which were abrogated by PNU-282987. Serum analyses demonstrated fracture-induced IgM reactivity against keratin 16, histone 3.2, GFAP, and NMDAR-2B. Administration of PNU-282987 reduced the enhancement of IgM reactivity. Collectively, these data suggest that the α7nAChR is involved in regulating posttraumatic innate and adaptive immune responses and the associated nociceptive sensitization. PerspectiveThese studies evaluate the effects of a selective α7nAChR agonist in a tibial fracture/cast immobilization model of limb pain. Administration of the drug reduced nociceptive and functional changes 4 weeks after injury. These novel findings suggest that well-tolerated α7nAChR agonists may be viable analgesics for chronic pain after limb injuries.

352 Endothelial cells – additional targets for alpha7 nicotinic acetylcholine receptor agonists in the future treatment of skin fibrosis and scleroderma?

352 Endothelial cells – additional targets for alpha7 nicotinic acetylcholine receptor agonists in the future treatment of skin fibrosis and scleroderma?

Discovery of the Nicotinic Receptor Toxin Anabaseine in a Polystiliferan Nemertean.

Nemerteans (also called Nemertines) are a phylum of predominantly marine worms that use toxins to capture prey and to defend themselves against predators. Hoplonemerteans have a proboscis armed with one or more stylets used in prey capture and are taxonomically divided into Order Monostilifera, whose members possess a single large proboscis stylet, and Order Polystilifera, whose members have multiple small stylets. Many monostiliferans contain alkaloidal toxins, including anabaseine, that stimulate and then desensitize nicotinic acetylcholine receptors that are present in all animals. These compounds also interact with pyridyl chemoreceptors in crustaceans, reducing predation and larval settlement. Anabaseine has been a lead compound in the design of alpha7 nicotinic acetylcholine receptor agonists like GTS-21 (also called DMXBA) to treat disorders of cognition such as Alzheimer's disease and schizophrenia. These drug candidates also display anti-inflammatory activities of potential medical importance. Most polystiliferans live deep in open oceans and are relatively inaccessible. We fortunately obtained two live specimens of a large benthic polystiliferan, Paradrepanophorus crassus (Pc), from the coast of Spain. MS and NMR analyses of the Ehrlich's reagent derivative allowed identification of anabaseine. A spectrophotometric assay for anabaseine, also based on its reaction with Ehrlich's reagent, revealed high concentrations of anabaseine in the body and proboscis. Apparently, the biosynthetic mechanism for producing anabaseine was acquired early in the evolution of the Hoplonemertea, before the monostiliferan-polystiliferan divergence.

GTS-21, a selective alpha7 nicotinic acetylcholine receptor agonist, ameliorates diabetic nephropathy in Leprdb/db mice

Diabetic nephropathy (DN) is a serious complicating factor in human type 2 diabetes mellitus (T2DM), and it commonly results in end-stage renal disease (ESRD) that requires kidney dialysis. Here, we report that the α7 nicotinic acetylcholine receptor (α7nAChR) agonist GTS-21 exerts a novel anti-inflammatory action to ameliorate DN, as studied using an inbred strain of Leprdb/db mice in which hyperglycemia and obesity co-exist owing to defective leptin receptor (Lepr) signaling. For this analysis, GTS-21 was administered to 10–12 week-old male and female mice as a 4 mg/kg intraperitoneal injection, twice-a-day, for 8 weeks. Kidney function and injury owing to DN were monitored by determination of plasma levels of BUN, creatinine, KIM-1 and NGAL. Histologic analysis of glomerular hypertrophy and mesangial matrix expansion were also used to assess DN in these mice. Concurrently, renal inflammation was assessed by measuring IL-6 and HMGB1, while also quantifying renal cell apoptosis, and apoptotic signaling pathways. We found that Leprdb/db mice exhibited increased markers of BUN, creatinine, NGAL, KIM-1, IL-6, cytochrome C, and HMGB-1. These abnormalities were also accompanied by histologic kidney injury (mesangial matrix expansion and apoptosis). Remarkably, all such pathologies were significantly reduced by GTS-21. Collectively, our results provide new evidence that the α7nAChR agonist GTS-21 has the ability to attenuate diabetes-induced kidney injury. Additional studies are warranted to further investigate the involvement of the vagal cholinergic anti-inflammatory reflex pathway (CAP) in ameliorating diabetic nephropathy.

Functional Changes in the Adult Mouse Retina using an Alpha7 Nicotinic Acetylcholine Receptor Agonist after Blast Exposure

Currently, there is a lack of treatments for retinal neurotrauma. To address this issue, this study uses an alpha7 nAChR agonist, PNU-282987, to determine it effects on functional activity in the retina shortly after a traumatic blast exposure. The objectives of this research include: (1) examination of the cellular and functional damage associated with ocular blast exposure, and (2) evaluation of structural and functional changes that occur post PNU-282987 treatment. Significant ocular blast damage was induced in adult mice after exposure to a single blast of 35 psi to the left eye. Blast-exposed transgenic mice expressing tdTomato Müller glia were treated daily with eyedrops containing PNU-282987 for 4 weeks following the blast exposure. Antibody staining studies in these transgenic mice was conducted to examine lineage tracing and electroretinograms (ERGs) were obtained to examine functional changes. Blast exposure caused a significant loss of cells in all retinal layers after 4 weeks. Immunohistochemical analysis demonstrated tdTomato-positive labeled photoreceptors and retinal ganglion cells in blast-exposed mice treated with PNU-282987. ERG recordings were taken from control animals, from blast-damaged animals and from animals exposed to blast followed by 4 weeks of PNU-282987 treatment. Scotopic ERG recordings from blast-exposed mice had significantly decreased amplitudes of a-wave, b-wave, oscillatory potentials and flicker frequencies, which were prevented after PNU-282987 treatment. In photopic experiments, the PhNR response was reduced significantly after blast exposure but the decrease was prevented after treatment with PNU-282987. These are the first experiments that demonstrate preservation of retinal function after blast exposure using an alpha7 nAChR agonist.

The alpha-7 nicotinic acetylcholine receptor agonist GTS-21 does not affect food intake in rats

Obesity is a prevalent disease, but effective treatments remain limited. Agonists of the alpha-7 nicotinic acetylcholine receptor (α7nAChR) promote negative energy balance in mice, but these effects are not well-studied in rats. We tested the hypothesis that the α7nAChR agonist GTS-21 would decrease food intake and body weight in adult male Sprague Dawley rats. Contrary to our hypothesis, acute systemic administration of GTS-21 produced no significant effects on chow or high-fat diet (HFD) intake. Acute intracerebroventricular (ICV) GTS-21 also had no impact on chow intake, and actually increased body weight at the highest dose tested. Previous studies suggest that GTS-21 engages the food intake-suppressive glucagon-like peptide-1 (GLP-1) system in mice. As there are known species differences in GLP-1 physiology between mice and rats, we tested the ability of GTS-21 to elicit GLP-1 secretion in rats. Our results showed that plasma levels of total GLP-1 in rats were not significantly altered by peripheral GTS-21 injection. These results represent an advance in understanding how α7nAChR activation impacts energy balance control in rodents and suggest that there may be important differences between rats and mice in the ability of GTS-21/α7nAChR activation to increase secretion of GLP-1.

Transcriptome Changes in Retinal Pigment Epithelium Post-PNU-282987 Treatment Associated with Adult Retinal Neurogenesis in Mice.

PNU-282987, a selective alpha7 nicotinic acetylcholine receptor agonist, has previously been shown to have both neurogenic and broad regenerative effects in the adult murine retina. The objective of this study was to assay the molecular mechanism by which PNU-282987 promotes the production of Muller-derived progenitor cells through signaling via the resident retinal pigment epithelium. These Muller-derived progenitor cells generate a myriad of differentiated neurons throughout the retina that have previously been characterized by morphology. Herein, we demonstrate that topical application of PNU-282987 stimulates production of functional neurons as measured by electroretinograms. Further, we examine the mechanism of how this phenomenon occurs through activation of this atypical receptor using a transcriptomic approach isolated retinal pigment epithelium activated by PNU-282987 and in whole retina. We provide evidence that PNU-282987 causes a bi-modal signaling event in which early activation primes the retina with an inflammatory response and developmental signaling cues, followed by an inhibition of gliotic mechanisms and a decrease in the immune response, ending with upregulation of genes associated with specific retinal neuron generation. Taken together, these data provide evidence that PNU-282987 activates the retinal pigment epithelium to signal to Muller glia to produce Muller-derived progenitor cells, which can differentiate into new, functional neurons in adult mice. These data not only increase our understanding of how adult mammalian retinal regeneration can occur, but also provide therapeutic promise for treating functional vision loss.

The alpha-7 nicotinic acetylcholine receptor agonist GTS-21 engages the glucagon-like peptide-1 incretin hormone axis to lower levels of blood glucose in db/db mice.

To establish if alpha-7 nicotinic acetylcholine receptor (α7nAChR) agonist GTS-21 exerts a blood glucose-lowering action in db/db mice, and to test if this action requires coordinate α7nAChR and GLP-1 receptor (GLP-1R) stimulation by GTS-21 and endogenous GLP-1, respectively. Blood glucose levels were measured during an oral glucose tolerance test (OGTT) using db/db mice administered intraperitoneal GTS-21. Plasma GLP-1, peptide tyrosine tyrosine 1-36(PYY1-36), glucose-dependent insulinotropic peptide (GIP), glucagon, and insulin levels were measured by ELISA. A GLP-1R-mediated action of GTS-21 that is secondary to α7nAChR stimulation was evaluated using α7nAChR and GLP-1R knockout (KO) mice, or by co-administration of GTS-21 with the dipeptidyl peptidase-4 inhibitor, sitagliptin, or the GLP-1R antagonist, exendin (9-39). Insulin sensitivity was assessed in an insulin tolerance test. Single or multiple dose GTS-21 (0.5-8.0mg/kg) acted in a dose-dependent manner to lower levels of blood glucose in the OGTT using 10-14 week-old male and female db/db mice. This action of GTS-21 was reproduced by the α7nAChR agonist, PNU-282987, was enhanced by sitagliptin, was counteracted by exendin (9-39), and was absent in α7nAChR and GLP-1R KO mice. Plasma GLP-1, PYY1-36, GIP, glucagon, and insulin levels increased in response to GTS-21, but insulin sensitivity, body weight, and food intake were unchanged. α7nAChR agonists improve oral glucose tolerance in db/db mice. This action is contingent to coordinate α7nAChR and GLP-1R stimulation. Thus α7nAChR agonists administered in combination with sitagliptin might serve as a new treatment for type 2 diabetes.

Alpha-7 nicotinic acetylcholine receptor agonist alleviates psoriasis-like inflammation through inhibition of the STAT3 and NF-\u03baB signaling pathway

Psoriasis is a chronic inflammatory cutaneous disease; it has been discovered that stimulation of the nervous system increases susceptibility to psoriasis. Although the cholinergic anti-inflammatory pathway, which is mediated by the alpha-7 nicotinic acetylcholine receptor (α7nAChR), is critical for controlling multiple types of inflammation, its expression pattern and pathogenesis function in psoriatic lesioned skin tissue are unknown. We hereby analyzed the expression of α7nAchR in human and mouse psoriatic skin tissue. In vivo, PNU-282987 or Methyllycaconitine, a specific agonist or antagonist of α7nAchR, were administered to imiquimod (IMQ)-induced psoriatic mouse models. The macroscopic appearance and histopathological features of the psoriatic mice skin were evaluated. In addition, cell proliferation and differentiation markers were investigated. The level of pro-inflammatory cytokines released from the lesioned skin, as well as the activation of the relevant signaling pathways, were measured. Our findings indicated that psoriatic lesional skin expressed an increased level of α7nAChR, with its tissue distribution being primarily in skin keratinocytes and macrophages. In an IMQ-induced murine psoriasis model, α7nAChR agonist PNU-282987 treatment alleviated psoriasis-like inflammation by down-regulating the expression of multiple types of pro-inflammatory mediators and normalized keratinocyte proliferation and differentiation, whereas α7nAChR antagonist treatment exacerbated its effect. Mechanically, we observed that activation of the α7nAChR inhibited the activation of the STAT3 and NF-κB signaling pathways in in vitro cultured HaCaT cells induced by Th17-related cytokine IL-6/IL-22 or Th1-related cytokine TNF-α. Taken together, these findings demonstrate that attenuation of psoriatic inflammation via the cholinergic anti-inflammatory pathway is dependent on α7nAChR activation.

Cholinergic anti-inflammatory pathway and COVID-19.

The cholinergic anti-inflammatory pathway (CAP) first described by Wang et al, 2003 has contemporary interest arising from the COVID-19 pandemic. While tobacco smoking has been considered an aggravating factor in the severity of COVID-19 infections, it has been suggested by some that the nicotine derived from tobacco could lessen the severity of COVID-19 infections. This spotlight briefly describes the CAP and its potential role as a therapeutic target for the treatment of COVID-19 infections using vagus nerve stimulation or selective alpha7 nicotinic acetylcholine receptor agonists.

Potentiation of cognitive enhancer effects of Alzheimer’s disease medication memantine by alpha7 nicotinic acetylcholine receptor agonist PHA-543613 in the Morris water maze task

RationaleThere are controversial pieces of evidence whether combination therapies using memantine and cholinesterase inhibitors are beneficial over their monotreatments. However, results of preclinical studies are promising when memantine is combined with agonists and allosteric modulators of the alpha7 nicotinic acetylcholine receptor (nAChR).ObjectivesHere, we tested the hypothesis that cognitive enhancer effects of memantine can be potentiated through modulating alpha7 nAChRs in a scopolamine-induced amnesia model.MethodsMonotreatments, as well as co-administrations of selective alpha7 nicotinic acetylcholine receptor agonist PHA-543613 and memantine were tested in the Morris water maze task in rats. The efficacy of the co-administration treatment was observed on different domains of spatial episodic memory.ResultsLow dose of memantine (0.1 mg/kg) and PHA-543613 (0.3 mg/kg) successfully reversed scopolamine-induced short-term memory deficits both in monotreatments and in co-administration. When recall of information from long-term memory was tested, pharmacological effects caused by co-administration of subeffective doses of memantine and PHA-543613 exceeded that of their monotreatments.ConclusionOur results further support the evidence of beneficial interactions between memantine and alpha7 nAChR ligands and suggest a prominent role of alpha7 nAChRs in the procognitive effects of memantine.

The selective alpha7 nicotinic acetylcholine receptor agonist AR-R17779 does not affect ischemia-reperfusion brain injury in mice.

Inflammation plays a central role in stroke-induced brain injury. The alpha7 nicotinic acetylcholine receptor (α7nAChR) can modulate immune responses in both the periphery and the brain. The aims of the present study were to investigate α7nAChR expression in different brain regions and evaluate the potential effect of the selective α7nAChR agonist AR-R17779 on ischemia–reperfusion brain injury in mice. Droplet digital PCR (ddPCR) was used to evaluate the absolute expression of the gene encoding α7nAChR (Chrna7) in hippocampus, striatum, thalamus and cortex in adult, naïve mice. Mice subjected to transient middle cerebral artery occlusion (tMCAO) or sham surgery were treated with α7nAChR agonist AR-R17779 (12 mg/kg) or saline once daily for 5 days. Infarct size and microglial activation 7 days after tMCAO were analyzed using immunohistochemistry. Chrna7 expression was found in all analyzed brain regions in naïve mice with the highest expression in cortex and hippocampus. At sacrifice, white blood cell count was significantly decreased in AR-R17779 treated mice compared with saline controls in the sham groups, although, no effect was seen in the tMCAO groups. Brain injury and microglial activation were evident 7 days after tMCAO. However, no difference was found between mice treated with saline or AR-R17779. In conclusion, α7nAChR expression varies in different brain regions and, despite a decrease in white blood cells in sham mice receiving AR-R17779, this compound does not affect stroke-induced brain injury.

Nicotine Alleviates Cortical Neuronal Injury by Suppressing Neuroinflammation and Upregulating Neuronal PI3K-AKT Signaling in an Eclampsia-Like Seizure Model.

Our previous studies showed that treatment with alpha7 nicotinic acetylcholine receptor (α7nAChR) agonist nicotine could alleviate systemic inflammation and reduce neuronal loss in the hippocampus and seizure severity in eclampsia. In this study, we further investigated whether there is also neuronal damage in the cortex after eclamptic seizure, elucidated the potential mechanisms underlying the neuroprotective roles of nicotine in eclampsia. Retrospective analysis of MRI data of severe preeclampsia (SPE) patients was conducted. A preeclampsia model was established by lipopolysaccharide injection (PE group), and pentylenetetrazol was used to induce eclamptic seizure (E group). α7nAChR agonist nicotine and its antagonist (α-BGT) and PI3K inhibitor wortmannin were used for drug administration. Neuronal damage was detected by Nissl staining, and changes in neuroinflammation, neuronal apoptosis, α7nAChR expression, and PI3K-AKT signaling on cortical neurons were detected by immunohistochemistry and western blotting. MRI images showed that most abnormal signals from the brain of SPE patients were located in the cortex. The neuron survival ratio was lower in the cortex than in the hippocampus within the E group; such ratios in the cortex were significantly lower in the E and PE groups compared with those of the control group. Nicotine markedly decreased the production of inflammatory cytokines and microglial activation in the cortex of the E group. Moreover, nicotine increased p-AKT levels and decreased cleaved caspase-3 levels in cortical neurons. Treatment with α-BGT reversed effects of nicotine. Wortmannin also blocked the anti-neuronal apoptosis action of nicotine. Our results suggest that nicotine protects against neuronal injury in the cortex following eclampsia possibly by inhibiting neuroinflammation and activating neuronal PI3K-AKT pathway.

ICH3, a selective alpha7 nicotinic acetylcholine receptor agonist, modulates adipocyte inflammation associated with obesity.

The alpha7 nicotinic acetylcholine receptor (α7nAChR), involved in the modulation of inflammation and insulin sensitivity, is downregulated in white adipose tissue (WAT) of obese patients. This study aims to test the ability of a selective synthetic α7nAChR agonist, the spirocyclic Δ2-isoxazoline derivative (R)-(-)-ICH3 (ICH3), to counteract acute inflammation and obesity-associated modifications in WAT. We employed the LPS-septic shock murine model, human primary adipocytes and diet-induced obese (DIO) mice. Inflammatory factor expression was assessed by ELISA and quantitative real-time PCR. Flow cytometry was employed to define WAT inflammatory infiltrate. Insulin signaling was monitored by quantification of AKT phosphorylation. In the septic shock model, ICH3 revealed antipyretic action and reduced the surge of circulating cytokines. In vitro, ICH3 stimulation (10µM) preserved viability of human adipocytes, decreased IL-6 mRNA (P < 0.05) and blunted LPS-induced peak of TNFα (P < 0.05) and IL-6 (P < 0.01). Chronic administration of ICH3 to DIO mice was associated with lower numbers of CD8+ T cells (P < 0.05) and to changed WAT expression of inflammatory factors (Hp, P < 0.05; CD301/MGL1, P < 0.01; Arg-1, P < 0.05). As compared to untreated, ICH3 DIO mice exhibited improved insulin signaling in the skeletal muscle (P < 0.01) mirrored by an improved response to glucose load (ipGTT: P < 0.05 at 120min). We proved that ICH3 is an anti-inflammatory drug, able to reduce inflammatory cytokines in human adipocytes and to blunt the effects of obesity on WAT inflammatory profile, on glucose tolerance and on tissue insulin sensitivity.

P.689 Cognitive enhancers in schizophrenia: A meta-analysis of Alpha-7 nicotinic acetylcholine receptor agonists for cognitive deficits and negative symptoms

P.689 Cognitive enhancers in schizophrenia: A meta-analysis of Alpha-7 nicotinic acetylcholine receptor agonists for cognitive deficits and negative symptoms

Cognitive Enhancer Effects of Low Memantine Doses Are Facilitated by an Alpha7 Nicotinic Acetylcholine Receptor Agonist in Scopolamine-Induced Amnesia in Rats.

Alpha7 nicotinic acetylcholine receptors (nAChRs) play an important role in learning and memory and are promising targets for pharmacological cognitive enhancement. Memantine, an approved substance for Alzheimer’s disease treatment, is an antagonist of the N-Methyl-D-aspartate receptor (NMDAR) and also acts as an alpha7 nAChR antagonist. Here, we tested the interaction between an alpha7 nAChR agonist (PHA-543613) and memantine. Efficacy of memantine, PHA-543613, and their co-administration were investigated on the spatial working memory of rats using the spontaneous alternation paradigm in T-maze. Scopolamine-induced transient amnesia was used to model cognitive impairment. First, the dose-response relationship was assessed for memantine, and its lowest effective dose was found to be 0.1 mg/kg. Then, co-administration treatments with subeffective doses of the alpha7 nAChR agonist PHA-543613 and different doses of memantine were tested. The co-administration of subeffective drug doses significantly improved memory performance of the rats and reversed scopolamine-induced deficits. Interestingly, a higher than effective (0.3 mg/kg) dose of memantine did not increase performance in monotreatment, only in co-administration with PHA-543613. However, the co-administration of PHA-543613 did not further increase the efficacy of the previously effective monotreatment doses of memantine. Thus, the efficacy of memantine monotreatment and its co-administration with PHA-543613 converged to create a common ceiling effect, with an additive interaction found in the behavioral effects. These results suggest that memantine and PHA-543613 may exert their cognitive enhancer effects on the same target, possibly on the alpha7 nAChRs. Results also suggest possible benefits of a combination therapy with memantine and alpha7 nAChR agonists.