Effects Of Α7 nAChR Agonists Research Articles

The neuroprotective effects of activated \u03b17 nicotinic acetylcholine receptor against mutant copper\u2013zinc superoxide dismutase 1-mediated toxicity

Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease characterized by the selective and progressive loss of motor neurons. Although many drugs have entered clinical trials, few have shown effectiveness in the treatment of ALS. Other studies have shown that the stimulation of α7 nicotinic acetylcholine receptor (nAChR) can have neuroprotective effects in some models of neurodegenerative disease, as well as prevent glutamate-induced motor neuronal death. However, the effect of α7 nAChR agonists on ALS-associated mutant copper–zinc superoxide dismutase 1 (SOD1) aggregates in motor neurons remains unclear. In the present study, we examined whether α7 nAChR activation had a neuroprotective effect against SOD1G85R-induced toxicity in a cellular model for ALS. We found that α7 nAChR activation by PNU282987, a selective agonist of α7 nAChR, exhibited significant neuroprotective effects against SOD1G85R-induced toxicity via the reduction of intracellular protein aggregates. This reduction also correlated with the activation of autophagy through the AMP-activated protein kinase (AMPK)–mammalian target of rapamycin (mTOR) signaling pathway. Furthermore, the activation of α7 nAChRs was found to increase the biogenesis of lysosomes by inducing translocation of the transcription factor EB (TFEB) into the nucleus. These results support the therapeutic potential of α7 nAChR activation in diseases that are characterized by SOD1G85R aggregates, such as ALS.

α7 nicotinic receptor agonist and positive allosteric modulators differently improved schizophrenia-like cognitive deficits in male rats

The majority of schizophrenia patients have cognitive deficits as a separate symptom cluster independent of positive or negative symptoms. Current medicines, unfortunately, cannot provide clear benefits for cognitive symptoms in patients. Recent findings showed decreased α7 nicotinic acetylcholine receptor (nAChR) expressions in subjects with schizophrenia. α7 nAChR full/partial agonists and positive allosteric modulators (PAMs) may be valuable drug candidates to treat cognitive deficits of disease. This study comparatively investigated the effect of α7 nAChR agonist (A-582941), type I PAM (CCMI), type II PAM (PNU-120596), and the antipsychotic drug (clozapine) on behavioral, molecular, and immunohistochemical parameters in a subchronic MK-801 model of schizophrenia in male rats. Novel object recognition (NOR) and Morris water maze (MWM) tests were performed to evaluate recognition and spatial memories, respectively. Gene and protein expressions of parvalbumin, glutamic acid decarboxylase-67 (GAD67), and α7 nAChR were examined in the rats' hippocampal tissue. The subchronic MK-801 administration produced cognitive deficits in the NOR and MWM tests. It also decreased the protein and gene expressions of parvalbumin, GAD67, and α7 nAChR in the hippocampus. Clozapine, A-582941, and PNU-120596 but not CCMI increased the parvalbumin and α7 nAChR expressions and provided benefits in recognition memory. Interestingly, clozapine and CCMI restored the MK-801 induced deficits on GAD1 expression and spatial memory while A-582941 and PNU-120596 were ineffective. These results indicated that α7 nAChR agonist, type I and type II PAMs may provide benefits in different types of cognitive deficits rather than a complete treatment in schizophrenia.

Alpha 7 nicotinic receptor agonist and positive allosteric modulators improved social and molecular deficits of MK-801 model of schizophrenia in rats

Schizophrenia is a common psychiatric disease that cannot be fully treated with current antipsychotic drugs. It has shown that glutamatergic NMDA receptor antagonists such as MK-801 cause schizophrenia-like phenotype in rodents. Recent studies indicated that α7 nicotinic acetylcholine receptor (nAChR) deficits contribute to schizophrenia. Enhancing its activity with agonist or positive allosteric modulators (PAMs) may be a valuable approach for treatment. The certain intracellular pathways such as Akt/Glycogen synthase kinase 3 beta (GSK-3β) and phosphodiesterase-4 (PDE-4)/cAMP are associated with the pathogenesis of schizophrenia. In this study, we examined the effect of α7 nAChR agonists and PAMs on the behavioral and molecular phenotype of schizophrenia in the subchronic MK-801 administered rats. Social interaction, the levels of α7 nAChR, and related intracellular pathways (cAMP, PDE4A, PDE4D, p-Akt/Akt, p-GSK-3β/GSK-3β) were measured by behavioral or ELISA and western blot tests. Subchronic MK-801 administration decreased the following behaviors and increased the avoiding behaviors. However, only α7 nAChR agonist (A-582941) increased the following behavior while α7 nAChR agonist, PAMs (CCMI and PNU-120596), and clozapine decreased the avoiding behavior compared to MK-801. For molecular parameters, MK-801 administration decreased the α7 nAChR, p-Akt/Akt, p-GSK-3β/GSK-3β expressions, and cAMP levels while it increased PDE4A, PDE4D expressions in the prefrontal cortex. Besides, MK-801 decreased the α7 nAChR, p-GSK-3β/GSK-3β expressions in the hippocampus. We found clozapine, α7 nAChR agonists, and PAMs reversed the molecular deficits induced by MK-801. Herein, we showed that prefrontal cortex is more sensitive to the devastating effects of subchronic MK-801 administration, especially for PDE4, in rats. In addition to clozapine, α7 nAChR agonists and PAMs found to be beneficial on both social and molecular deficits induced by MK-801 in rats. We suggested that α7 nAChR agonists and PAMs might be valuable approaches to treat negative symptoms of schizophrenia when unmet needs and current limitations considered in this pathology.

DNA methylation regulates CHRNA7 transcription and can be modulated by valproate

The CHRNA7 gene encoding the α7 nicotinic acetylcholine receptor (nAChR) has repeatedly been linked with schizophrenia and the P50 sensory gating deficit. The α7 nAChR is considered a promising drug target for treatment of cognitive dysfunction in schizophrenia and improves memory and executive functions in patients and healthy individuals. However, clinical trials with pro-cognitive drugs are challenged by large inter-individual response variations and these have been linked to genotypic variations reducing CHRNA7 expression and α7 nAChR function. Genetic variants as well as environmental conditions may cause epigenetic dysregulation and it has previously been found that DNA methylation of a region surrounding the transcription start site of CHRNA7 is important for tissue specific regulation and gene silencing. In the present study we identify two additional regions involved in epigenetic regulation of the CHRNA7 promoter. In human temporal cortex we find large variations in expression of CHRNA7 and establish evidence for a significant correlation with DNA methylation levels of one region. We then establish evidence that genotypic variations can influence methylation levels of the CHRNA7 promoter. Epigenetic dysregulation can be reversed by pharmacological intervention and in HeLa cells. Valproate, a commonly used mood stabiliser, caused demethylation and increased CHRNA7 expression in HeLA cells. Similar demethylation effect and increased CHRNA7 expression was obtained in SH-SY5Y cells stimulated concomitantly with valproate and nicotine. In summary, both genetic and epigenetic information could be useful to predict treatment outcomes in patients and epigenetic modulation may serve as a mechanism for potentiating the effects of α7 nAChR agonists.

Effect of α7nAChR agonists on acute lung injury caused by cardiopulmonary bypass in rats

Objective To evaluate the effect of α7 nicotinic acetylcholine receptor(α7nAChR) agonists on lung injury caused by cardiopulmonary bypass (CPB) in rats. Methods Eighteen healthy clean-grade adult male Sprague-Dawley rats, weighing 350-400 g, were divided into 3 groups (n=6 each) using a random number table method: sham operation group (group S), CPB group and α7nAChR agonist PHA568487 group (group PHA). The rats underwent no CPB and were mechanically ventilated for 60 min in group S. PHA568487 0.8 mg/kg (diluted to 2 ml in normal saline) was intraperitoneally injected at 30 min before CPB, and then CPB was performed for 60 min in group PHA.Normal saline 2 ml was intraperitoneally injected at 30 min before CPB, and then CPB was performed for 60 min in group CPB.Blood samples were collected from the internal jugular vein for determination of serum interleukin-6 (IL-6) and tumor necrosis factor-alpha (TNF-α) concentrations by enzyme-linked immunosorbent assay.Lung tissues were obtained for microscopic examination of the pathologic changes and for determination of wet/dry weight ratio (W/D ratio) and matrix metalloproteinase-9 (MMP-9) expression (by Western blot). Results Compared with group S, the W/D ratio and serum concentrations of TNF-α and IL-6 were significantly increased, and the expression of MMP-9 was up-regulated in CPB and PHA groups (P<0.05). Compared with group CPB, the W/D ratio and serum concentrations of TNF-α and IL-6 were significantly decreased, the expression of MMP-9 was down-regulated (P<0.05), and the pathological changes of lung tissues were significantly attenuated in group PHA (P<0.05). Conclusion α7nAChR agonists can reduce the acute lung injury caused by CPB in rats, and the mechanism may be related to down-regulating MMP-9 expression and inhibiting systemic inflammatory responses. Key words: Cholinergic agonists; Cardiopulmonary bypass; Respiratory distress syndrome, adult

Alpha7 nAChR Agonists for Cognitive Deficit and Negative Symptoms in Schizophrenia: A Meta-analysis of Randomized Double-blind Controlled Trials.

BackgroundPrevious clinical trials of α7-nicotinic acetylcholine receptor agonists (α7-nAChR agonists) showed mixed results in treating the cognitive and negative symptoms of schizophrenia.AimsTo assess the efficacy and safety of α7-nAChR agonists in treating the cognitive and negative symptoms in schizophrenia.MethodsA literature search was conducted to identify randomized double-blind placebo-controlled trials for schizophrenia published before May 26, 2017, by searching PubMed, Embase, ClinicalTrials.gov, the Cochrane Library and the Chinese language databases CNKI, Wanfang, and VIP Data. The effects of α7-nAChR agonists were evaluated for overall cognitive function and negative symptoms by calculating standard mean difference (SMDs) between active drugs and placebo added to antipsychotics.Results8 studies with low bias were included. We found no statistically significant effects of α7 nAChR agonists on the overall cognitive function (SMD=-0.10[-0.46, 0.25], I2 =88%) and negative symptoms (SMD=0.13 [-0.04, 0.30], I2 =64%) in patients with schizophrenia. Sensitivity analysis showed these results to be firm. And this drug is generally safe and well tolerated with no significant difference from placebo based on adverse events (RR=1.02, [0.85, 1.23]) and dropouts (RR=1.04, [0.61, 1.78]) data. Evidence based on outcomes from the meta-analysis was rated as ‘moderate’ as per the GRADE guidelines.Conclusionα7-nAChR agonists may not be effective in reversing overall cognitive impairments and negative symptoms in patients with schizophrenia as adjunctive therapies.

Alpha-7 nicotinic agonists for cognitive deficits in neuropsychiatric disorders: A translational meta-analysis of rodent and human studies

Cognitive dysfunction in schizophrenia (SCZ) and Alzheimer's disease (AD) is a major driver of functional disability but is largely unresponsive to current therapeutics. Animal models of cognitive dysfunction relevant to both disorders suggest the α7 nicotinic acetylcholine receptor (nAChR) may be a promising drug development target, with multiple clinical trials subsequently testing this hypothesis in individuals with SCZ and AD. However, the translational value of rodent cognitive tasks for predicting the overall efficacy of this therapeutic target in clinical trials is unknown. To compare effect sizes between rodent and human studies, we searched PubMed and the Cochrane Library for all randomized, placebo-controlled trials of compounds with pharmacological activity at the α7 nAChR for treatment of cognitive dysfunction in SCZ and AD and identified 18 studies comprising 2670 subjects treated with eight different compounds acting as full or partial agonists. Cognitive outcomes were standardized, and random-effects meta-analyses revealed no statistically significant effects of α7 nAChR agonists on overall cognition or any of eight cognitive subdomains when all doses were included (Range of all cognitive outcomes: Cohen's d=−0.077 to 0.12, negative favoring drug). In contrast, analysis of 29 rodent studies testing the same α7 agonists revealed large effect sizes in multiple commonly used preclinical behavioral tests of cognition (Range: d=−1.18 to – 0.73). Our results suggest that targeting the α7 nAChR with agonists is not a robust treatment for cognitive dysfunction in SCZ or AD and necessitate a better understanding of the translational gap for therapeutics targeting the α7 nAChR.

Effect of α7nAChR agonists on brain injury induced by cardiopulmonary bypass in rats

Objective To evaluate the effect of α7 nicotinic acetylcholine receptor (α7nAChR) agonists on brain injury induced by cardiopulmonary bypass (CPB) in rats. Methods Seventy-two pathogen-free adult male Sprague-Dawley rats, weighing 350-450 g, were randomly divided into 3 groups (n=24 each) using a random number table: sham operation group (group S), CPB group, and α7nAChR agonist PHA568487 group (group PHA). The rats underwent no CPB and were mechanically ventilated for 60 min in group S. CPB was performed for 60 min in CPB and PHA groups.At 30 min before CPB, PHA568487 0.8 mg/kg was injected intraperitoneally in group PHA, and the equal volume of normal saline was given in group CPB.Before CPB (T0), immediately after termination of CPB (T1), and at 2 and 6 h after operation (T2, 3), 6 rats were sacrificed, and blood samples were collected from the internal jugular vein for determination of serum S100β protein, interleukin-6 (IL-6) and tumor necrosis factor-alpha (TNF-α) concentrations by enzyme-linked immunosorbent assay.Hippocampal tissues were obtained and stained with haematoxylin and eosin for microscopic examination of the pathologic changes and for detection of apoptosis in hippocampal neurons (by TUNEL) and caspase-3 expression (by immunohistochemistry). Results Compared with group S, the concentrations of serum S100β protein, TNF-α and IL-6 were significantly increased, the number of apoptotic neurons was significantly increased, and the expression of caspase-3 was significantly up-regulated at T1-T3 (P<0.05), and the pathologic changes of hippocampal tissues were obvious in CPB and PHA groups.Compared with group CPB, the concentrations of serum S100β protein, TNF-α and IL-6 were significantly decreased, the number of apoptotic neurons was significantly reduced, and the expression of caspase-3 was significantly down-regulated at T1-T3 (P<0.05), and the pathologic changes of hippocampal tissues were significantly attenuated in group PHA. Conclusion α7nAChR agonists can reduce the brain injury induced by CPB in rats, and the mechanism may be related to inhibition of systemic inflammatory responses and apoptosis in hippocampal neurons. Key words: Cholinergic agonists; Cardiopulmonary bypass; Brain injuries

Selective activation of α7 nicotinic acetylcholine receptors augments hippocampal oscillations

Neural α7 nicotinic acetylcholine receptors (α7 nAChRs) emerged as a potential pharmacologic target for treating cognitive deficits in schizophrenia and Alzheimer’s disease. Experiments modeling these dysfunctions, as well as clinical evidence, demonstrate the relatively consistent procognitive effects of α7 nAChR agonists. One preclinical observation supporting the procognitive role of α7 nAChRs is their ability to modulate neuronal network oscillations closely associated with learning and memory, especially hippocampal oscillations. Due to the high degree of structural similarity between α7 nACh and 5-HT receptors, the majority of α7 nAChR agonists to date also act as 5-HT3 antagonists. To address this confounding property and determine the relevance of α7 nAChR agonist binding to 5-HT3 receptors in modulating hippocampal activity, we tested two well-described α7 nAChR agonists, PNU-282987 and FRM-17874, in mice lacking α7 nAChRs (α7 knock-out, α7KO) using the brainstem simulation-elicited hippocampal theta oscillation assay. Under urethane anesthesia both agonists at equivalent doses demonstrated efficacy in wild-type (WT) mice, significantly enhancing theta power and theta phase-gamma amplitude coupling as compared to saline treated control mice. These effects are comparable to those seen with drugs clinically used to treat Alzheimer’s disease. Although α7KO mice showed no alterations in elicited hippocampal oscillations, both α7 nAChR agonists failed to enhance theta power or theta phase – gamma amplitude coupling in these mice. Our findings demonstrate that selective activation of α7 nAChRs can modulate hippocampal oscillation, and these receptors are the primary targets of the tested agonists, PNU-282987 and FRM-17874 and likely underlies their observed procognitive activity.

Hippocampal network dynamics in response to α7 nACh receptors activation in amyloid-β overproducing transgenic mice

Amyloid-β (Aβ) peptide overproduction is one of the pathomechanisms contributing to Alzheimer's disease (AD). Agonists of α7 nicotinic acetylcholine receptors (α7 nAChRs) are under development as symptomatic treatments for AD, and clinical findings suggest that α7 nAChR agonists may improve cognitive functions in AD patients. However, interactions between Aβ and α7 nAChRs have been observed, implying that high levels of Aβ may modify the effects of α7 nAChR agonists. Therefore, we tested the α7 nAChR agonist FRM-17874, an analogue of encenicline, in 8-month-old Aβ overproducing 5xFAD mice in an in vivo neurophysiological assay with a high construct and predictive validity for testing procognitive drugs. By recording changes in brainstem-stimulation–elicited hippocampal oscillations, we identified previously undescribed neurophysiological impairments in 5xFAD mice, including significantly decreased power of theta and gamma oscillations and theta-phase–gamma-amplitude coupling. Compared with their saline controls, systemically administered FRM-17874 significantly increased stimulation-induced theta power by 30% in both 5xFAD and wild-type mice. However, FRM-17874 did not impact gamma oscillation or theta-phase–gamma-amplitude coupling in either wild type or 5xFAD mice, and it did not eliminate the significant differences in these parameters between the 2 groups.

Glutamate and nicotinic receptor interactions in working memory: importance for the cognitive impairment of schizophrenia

This article reaches across disciplines to correlate results in molecular, cellular, behavioral, and clinical research to develop a more complete picture of how working memory (WM) functions. It identifies a new idea that deserves further investigation. NMDA glutamate receptors (NMDAR) are critical for memory function. NMDAR inhibition effectively reproduces principal manifestations of schizophrenia (SP), such as WM impairment and GABAergic deficit (mainly reduction of glutamic acid decarboxylase 67 (GAD67) and parvalbumin (PV) content). Nicotine and selective α7 nicotinic acetylcholine receptor (nAChR) agonists reduce WM impairments in patients with SP and reverse WM deficits in animals treated with NMDAR antagonists. The mechanism of this effect is unknown. Importantly, WM recovery occurs even before restoration of NMDAR blockade-induced molecular alterations, including reduced GAD67 in interneurons. Our insight into the cognitive-enhancing effect of α7 nAChR agonists, particularly in the animal models of SP, combines reviews of recent findings on glutamate and nicotinic receptor expression in the neuronal circuits involved in WM, the properties of these receptors, their implication in WM regulation, generation of rhythmic neuronal activity, resulting in a proposed hypothesis for further investigations. We suggest that (1) cortical/hippocampal interneurons, particularly PV positive, play a crucial role in WM and that impairment of these cells in SP could be behind the WM deficit; (2) activation of α7 nAChRs could restore calcium signaling and intrinsic properties of these interneurons, and associated with these events, computational capacity, gamma rhythmic activity, and WM would also be restored.

Selective nicotinic receptor antagonists: effects on attention and nicotine-induced attentional enhancement

The question of the subtype(s) of the nicotinic acetylcholine receptor (nAChR) mediating the attention-enhancing effects of nicotine is still unsettled. While early studies pointed towards subtypes other than the homomeric α7 nAChR, pro-cognitive effects of α7 nAChR agonists have since been demonstrated. This study tested whether the performance-enhancing effects of nicotine in a rodent model of attention could be reversed by the α4β2, α4β4, α3β2, and α2β2 nAChR antagonist dihydro-β-erythroidine (DHβE), or the α7 antagonist methyllycaconitine (MLA). In repeated tests, 12 rats trained to perform the 5-choice serial reaction time task were systemically injected with nicotine or vehicle in the presence of increasing doses of DHβE or MLA. DHβE did not antagonize the attention-enhancing effects of nicotine reflected by measures of accuracy and omission errors, suggesting that its previously reported antagonism of nicotine effects on latency and anticipatory responses specifically reflected the stimulant effects of nicotine. MLA dose-dependently reversed the reduction in omission errors by nicotine. In the absence of nicotine, low doses of MLA (0.4 and 1.3 mg/kg) not previously tested on attention improved response accuracy, resulting in an inverted U-shape dose-response function. nAChR subtypes involved in the performance-enhancing effects of nicotine appear to vary depending on the function assessed. Our findings suggest a greater involvement of α7 nAChRs in the effects of nicotine on attention than first suggested by preclinical studies, with different optimal receptor tones for aspects of stimulus detection and response readiness to task stimuli.

Cognitive Improvement by Activation of &amp;#945;7 Nicotinic Acetylcholine Receptors: From Animal Models to Human Pathophysiology

Agonists and positive allosteric modulators of the alpha(7) nicotinic acetylcholine receptor (nAChR) are currently being developed for the treatment of cognitive disturbances in patients with schizophrenia or Alzheimer's disease. This review describes the neurobiological properties of the alpha nAChR and the cognitive effects of alpha(7) nAChR activation, focusing on the translational aspects in the development of these drugs. The functional properties and anatomical localization of the alpha(7) nAChR makes it well suited to modulate cognitive function. Accordingly, systemic administration of alpha(7) nAChR agonists improves learning, memory, and attentional function in variety of animal models, and pro-cognitive effects of alpha(7) nAChR agonists have recently been demonstrated in patients with schizophrenia or Alzheimer's disease. The alpha(7) nAChR desensitizes rapidly in vitro, and this has been a major concern in the development of alpha(7) nAChR agonists as putative drugs. Our review of the existing literature shows that development of tolerance to the behavioral effects of alpha(7) nAChR agonists does not occur in animal models or humans. However, the long-term memory-enhancing effects seen in animal models are not mimicked in healthy humans and schizophrenic patients, where attentional improvement predominates. This discrepancy may result from inherent differences in testing methods or from species differences in the level of expression of alpha(7) nAChRs in limbic brain regions, and may hamper preclinical evaluation of alpha(7) nAChR activation. It is therefore important to consider the translational power of the animal models used before entering into a clinical evaluation of the pro-cognitive effects of alpha(7) nAChR activation.