Substitution therapy for patients with alcohol dependence: Mechanisms of action and efficacy.

New approaches for the treatment of alcohol dependence (AD) may improve patient outcomes. Substitution maintenance therapy is one of the most effective treatment options for opioid and nicotine use disorders. So far, there has been little attention to substitution therapy for the treatment of AD. Here, we explain the mechanistic foundations of alcohol substitution maintenance therapy. Alcohol has many primary targets in the brain (and other organs) and the physical interaction of ethanol molecules with these specific ethanol-sensitive sites on a variety of ionotropic receptors (e.g. GABA-A, NMDA, and nicotinic acetylcholine (nACh) receptors) and ion channels provides the rationale for substitution. As such, a variety of compounds can interact with those ethanol-sensitive sites and can thus substitute for some of the effects of alcohol. For some of these compounds, alcohol discrimination studies have shown their substitution potential. Accordingly, potential substitution treatments include agonists acting at GABA receptors such as sodium oxybate, baclofen and benzodiazepines, NMDA receptor antagonists such as ketamine and memantine, or nAChRs agonists such as varenicline. All these compounds are already approved for other indications and we present clinical evidence for these drugs in the treatment of alcohol withdrawal syndrome (AWS) and in the long-term treatment of AD, and outline future steps for their acceptance as substitution treatment in AD. Finally, we discuss the substitution approach of managed alcohol programs for the most severely affected homeless populations. Results showed that sodium oxybate is probably the closest to a substitution therapy for AD and is already approved for the treatment of AWS and in the long-term treatment of AD in some countries. In conclusion, we argue that better AD treatment can be provided if substitution maintenance treatments for alcohol are implemented at a similar scale as for opioid and nicotine use disorder.

Altered HCAR3 expression may underlying the blunted niacin responses of the psychiatric disorders and the risk of schizophrenia.

AIM: Blunted niacin response (BNR) was an endophenotype of schizophrenia, but the underlying mechanism remains unclarified. The objective of this study was to verify whether genes associated with BNR pathway constitute the genetic basis and the pathological mechanism of BNR phenotypic psychiatric patients. METHODS: Two independent sample sets consisting of 971 subjects were enrolled in this study. A total of 62 variants were genotyped in the discovery set, then the related variants were verified in the verification set. The published PGC GWAS data were used to validate the associations between the variants and psychiatry disorders. RT-PCR analysis, eQTL data, and Dual-Luciferase Reporter experiment were used to investigate the potential molecular mechanisms of the variants underlying BNR. RESULTS: The results showed that two SNPs, rs56959712 in HCAR2 and rs2454721 in HCAR3 were significantly associated with niacin response. The risk allele T of rs2454721 could affect the niacin responses of psychiatric patients through elevated HCAR3 gene expression. These two genes, especially HCAR3, were significantly associated with the risk of schizophrenia, as identified in this study and verified using the published GWAS data. CONCLUSION: HCAR3 is a novel schizophrenia susceptibility gene which is significantly associated with blunted niacin response in schizophrenia. In-depth investigation of HCAR3 is of great significance for uncovering the pathogenesis and propose new therapeutic targets for psychiatric disorders, especially for the BNR subgroup patients.

Competitive inhibition of nicotine acetylcholine receptors using microneedles of nicotine and varenicline for smoking withdrawal therapy.

Current strategies for smoking withdrawal conditions involve monotherapy of nicotine and combinational therapy of nicotine with varenicline or bupropion as per the CDC and FDA. The available dosage forms for nicotine are patches, gums, inhalers and nasal sprays, bupropion and varenicline are available in tablet form. This research work focused on developing a microneedle delivery system to deliver combination drug for overcoming the obstacles encountered by oral route of administration of varenicline such as severe side effects (mood swings, agitation, depressed behaviour, seizures, etc), and nicotine therapy challenges such as short half-life, repeated dosing, nausea, and vomiting. The nanoparticles of nicotine prepared by nanoprecipitation method showed particle size PTZ (356.6 ± 65.98), percentage entrapment efficiency (35.55 % ± 0.007), in-vitro drug release (47.89 % ± 0.7) for 72 h. Microneedles showed height (600 µm), width (350 µm), and tip diameter (10 µm). The nanoparticles encapsulated in microneedles showed in-vitro sustained delivery of nicotine (67.00 % ± 4.92) and varenicline (79.78 % ± 1.09) in 48 h. Nicotine released in a sustained manner attaches to the nicotine acetylcholine receptors (nAchR) to release dopamine for controlling the withdrawal challenges such as anxiety, irritability, cravings, disturbed sleep pattern, etc. The varenicline released from microneedles binds to the nAchR and inhibits dopamine release responsible for the euphoric effect induced by nicotine, and thus assists in curbing the nicotine withdrawal symptoms. This combination microneedle system offers prolonged treatment in a single application for smoking withdrawal conditions wherein patients are not in stage of oral dosing because of repeated dosing resulting in adverse effects like seizures, hypertension, sleep disturbances, insomnia, and nausea.

Nicotine addiction: More than just dopamine.

Despite decades of research and anti-tobacco messaging, nicotine addiction remains an important public health problem leading to hundreds of thousands of deaths each year. While fundamental studies have identified molecular, circuit-level and behavioral mechanisms important for nicotine reinforcement and withdrawal, recent studies have identified additional pathways that are important for both nicotine seeking and aversion. In particular, although dopaminergic mechanisms are necessary for nicotine-dependent reward and drug-seeking, novel glutamate and GABA signaling mechanisms in the mesolimbic system have been identified for their contributions to reward-related behaviors. An additional area of active investigation for nicotine addiction focuses on molecular mechanisms in the habenula-interpeduncular pathway driving nicotine aversion and withdrawal. Across all these domains, sex differences in the molecular basis of nicotine-induced behaviors have emerged that identify important new directions for future research. Recent studies reviewed here highlight additional pathways that could provide therapeutic targets for smoking cessation and problematic nicotine vaping.

Therapeutic effect of α7 nicotinic receptor activation after ischemic stroke in rats.

Nicotinic acetylcholine α7 receptors (α7 nAChRs) have a well-known modulator effect in neuroinflammation. Yet, the therapeutical effect of α7 nAChRs activation after stroke has been scarcely evaluated to date. The role of α7 nAChRs activation with PHA 568487 on inflammation after brain ischemia was assessed with positron emission tomography (PET) using [18F]DPA-714 and [18F]BR-351 radiotracers after transient middle cerebral artery occlusion (MCAO) in rats. The assessment of brain oedema, blood brain barrier (BBB) disruption and neurofunctional progression after treatment was evaluated with T2 weighted and dynamic contrast-enhanced magnetic resonance imaging (T2 W and DCE-MRI) and neurological evaluation. The activation of α7 nAChRs resulted in a decrease of ischemic lesion, midline displacement and cell neurodegeneration from days 3 to 7 after ischemia. Besides, the treatment with PHA 568487 improved the neurofunctional outcome. Treated ischemic rats showed a significant [18F]DPA-714-PET uptake reduction at day 7 together with a decrease of activated microglia/infiltrated macrophages. Likewise, the activation of α7 receptors displayed an increase of [18F]BR-351-PET signal in ischemic cortical regions, which resulted from the overactivation of MMP-2. Finally, the treatment with PHA 568487 showed a protective effect on BBB disruption and blood brain vessel integrity after cerebral ischemia.

ONSET-1 Phase 2b Randomized Trial to Evaluate the Safety and Efficacy of OC-01 (Varenicline Solution) Nasal Spray on Signs and Symptoms of Dry Eye Disease.

PURPOSE: The purpose of this trial was to evaluate the safety and efficacy of OC-01 (varenicline solution), a nicotinic acetylcholine receptor agonist nasal spray, on signs and symptoms of dry eye disease. METHODS: A phase 2b, multicenter, randomized, double-masked, vehicle-controlled trial (ONSET-1; NCT03636061) was performed. Patients were aged 22 years or older with a physician's diagnosis of dry eye disease and previous use of artificial tears were randomized 1:1:1:1 to control (vehicle nasal spray twice daily [BID]), OC-01 0.006 mg BID, OC-01 0.03 mg BID, and OC-01 0.06 mg BID. The primary end point was the change in the anesthetized Schirmer test score from baseline to day 28 in the study eye. The secondary end points included the change in the eye dryness score from baseline to day 28. RESULTS: One hundred eighty-two patients were randomized. After 28 days, patients who received OC-01 0.03 or 0.06 mg showed a statistically significant improvement in tear film production relative to vehicle, with least squares mean differences from vehicle of 7.7 mm [95% confidence interval, 3.8-11.7; P < 0.001] with OC-01 0.03 mg and 7.5 mm (95% confidence interval, 3.4-11.6; P < 0.001) with OC-01 0.06 mg. Patients receiving OC-01 0.03 mg showed a significant reduction in the eye dryness score by day 28 versus vehicle (P = 0.021); those receiving the OC-01 0.06 mg dose showed a nonsignificant reduction versus vehicle. OC-01 administration was associated with sneezing (62%-84%) and cough (9%-25%); these were transient and predominantly mild in severity. CONCLUSIONS: OC-01 nasal spray administered BID at 0.03 and 0.06 mg resulted in significant improvements in signs and symptoms of dry eye disease, was well tolerated, and warrants further clinical investigation.

Efficacy and Safety of Single-dose OC-02 (Simpinicline Solution) Nasal Spray on Signs and Symptoms of Dry Eye Disease: The PEARL Phase II Randomized Trial.

PURPOSE: Dry eye disease is a multifactorial disorder that affects the ocular surface, with symptoms including ocular irritation, impaired vision, and pain. Nicotinic acetylcholine receptor (nAChR) agonists are novel treatments for dry eye disease; this study investigates the nAChR agonist OC-02 (simpinicline solution) as an aqueous nasal spray. METHODS: PEARL (Clinical Trial to Evaluate the Efficacy of OC-02 Nasal Spray on Signs and Symptoms of Dry Eye Disease) was a Phase II study that evaluated the efficacy and safety of OC-02 (simpinicline solution) nasal spray (OC-02 SNS) in adult patients with dry eye disease. Patients ≥22 years of age were eligible if they had an Ocular Surface Disease Index score ≥23, corneal fluorescein staining score ≥2 in >1 region or ≥4 for all regions, or Schirmer test score (STS) ≤10 mm; there were no restrictions on eye dryness score (EDS). Patients (N = 165) were randomly assigned 1:1:1:1 to vehicle (control; n = 42) or OC-02 SNS (0.11 mg, 0.55 mg, or 1.1 mg; n = 41 per group) and received a single dose of study drug (100 µL using a nasal spray atomizer) at visit 1 and visit 2 (15-19 days after visit 1). Primary efficacy outcomes were change in the STS from baseline to immediately after treatment administration (visit 1) and change in the EDS from before to 5 minutes after treatment during controlled adverse environment exposure (visit 2). FINDINGS: Baseline demographic and ocular clinical characteristics were similar across all groups. Single-dose OC-02 SNS improved the signs and symptoms of dry eye disease. For the STS, statistically significant and dose-dependent improvements were found from before to after treatment with OC-02 SNS versus vehicle (least-squares mean change from baseline: vehicle, 3.0 mm; 0.11 mg OC-02 SNS, 9.0 mm; 0.55 mg, 17.5 mm; and 1.1 mg, 19.6 mm). For EDS, statistically significant and dose-dependent improvements were found from before to 5 minutes after treatment with higher doses of OC-02 SNS versus vehicle (least-squares mean change from baseline: vehicle, -6.5; 0.11 mg OC-02 SNS, -9.4; 0.55 mg, -17.4; and 1.1 mg, -20.7). OC-02 SNS was well tolerated: only 2 ocular adverse events were reported (eye pruritis and keratitis), and the most common nonocular events were cough and throat irritation. IMPLICATIONS: Single-dose OC-02 SNS over a range of doses immediately and significantly increased tear production and improved eye dryness. Together with previous studies of OC-01 (varenicline solution) nasal spray, our findings suggest that agonist stimulation of nAChRs in the nasal cavity is a valid and effective mechanism to elicit natural tear production in patients with dry eye disease. CLINICALTRIALS: gov identifier: NCT03452397.

Nicotine and opioid co-dependence: Findings from bench research to clinical trials.

Concomitant use of tobacco and opioids represents a growing public health concern. In fact, the mortality rate due to smoking-related illness approaches 50% among SUD patients. Cumulative evidence demonstrates that the vulnerability to drugs of abuse is influenced by behavioral, environmental, and genetic factors. This review explores the contribution of genetics and neural mechanisms influencing nicotine and opioid reward, respiration, and antinociception, emphasizing the interaction of cholinergic and opioid receptor systems. Despite the substantial evidence demonstrating nicotine-opioid interactions within the brain and on behavior, the currently available pharmacotherapies targeting these systems have shown limited efficacy for smoking cessation on opioid-maintained smokers. Thus, further studies designed to identify novel targets modulating both nicotinic and opioid receptor systems may lead to more efficacious approaches for co-morbid nicotine dependence and opioid use disorder.

Expression of a highly antigenic and native-like folded extracellular domain of the human α1 subunit of muscle nicotinic acetylcholine receptor, suitable for use in antigen specific therapies for Myasthenia Gravis.

We describe the expression of the extracellular domain of the human α1 nicotinic acetylcholine receptor (nAChR) in lepidopteran insect cells (i-α1-ECD) and its suitability for use in antigen-specific therapies for Myasthenia Gravis (MG). Compared to the previously expressed protein in P. pastoris (y-α1-ECD), i-α1-ECD had a 2-fold increased expression yield, bound anti-nAChR monoclonal antibodies and autoantibodies from MG patients two to several-fold more efficiently and resulted in a secondary structure closer to that of the crystal structure of mouse α1-ECD. Our results indicate that i-α1-ECD is an improved protein for use in antigen-specific MG therapeutic strategies.

The role of the α7 nicotinic receptor in cognitive processing of persons with schizophrenia.

PURPOSE OF REVIEW: Cognitive abilities are established as major deficits in those with schizophrenia and represent significant impediments toward successful psychosocial functioning within the community. Pharmacological treatments have historically focused on reducing the positive and negative symptoms of schizophrenia, with recent increased attention to developing agents to improve cognition as a treatment outcome. This review will highlight the recent advances in developing agents that act at neuronal α7 nicotinic acetylcholine receptors (nAChRs). RECENT FINDINGS: A number of agents have demonstrated improvements in cognitive deficits in studies using both preclinical and clinical models. Evidence suggests that α7 nAChR activation impacts rule acquisition and initial learning in preclinical models. Preclinical studies indicate improved spatial working memory and reversal of phencyclidine-induced learning and memory deficits. Clinical studies indicate normalization of neuronal default network activity using functional magnetic resonance imaging methods. In addition, research on new agents developed to improve cognition suggests improved cognitive functioning in multiple domains (e.g., attention, memory, executive functioning, sensory gating and overall cognition) and promising safety profiles of additional agents. SUMMARY: Improvements in cognitive functioning within preclinical and clinical studies of schizophrenia are evident through the use of α7 nAChR agonists, while positive allosteric modulators may gain increased attention in the future.

Future of GPR109A agonists in the treatment of dyslipidaemia.

Abnormal blood lipids are the major modifiable risk factor underlying the development of cardiovascular disease. Niacin has a profound ability to reduce low-density lipoprotein-C, very low-density lipoprotein-C and triglycerides and is the most effective pharmacological agent to increase high-density lipoprotein-C. Recently, the receptor for niacin, GPR109A, was discovered. GPR109A in the adipocyte mediates a niacin-induced inhibition of lipolysis, which could play a crucial part in its role as a lipid-modifying drug. GPR109A in epidermal Langerhans cells mediates flushing, an unwanted side effect of niacin therapy. For the past decade, the functions of GPR109A have been studied and full or partial agonists have been developed in an attempt to achieve the beneficial effects of niacin while avoiding the unwanted flushing side effect. This review presents what is known to date about GPR109A biology and function and the future of GPR109A as a pharmacological target.

Nicotine restores endothelial dysfunction caused by excess sFlt1 and sEng in an in vitro model of preeclamptic vascular endothelium: a possible therapeutic role of nicotinic acetylcholine receptor (nAChR) agonists for preeclampsia.

OBJECTIVE: In this study we tested the hypothesis that nicotine restores proangiogenic functions to endothelial cells pretreated with soluble fms-like tyrosine kinase 1 and/or soluble endoglin. STUDY DESIGN: Wound healing assay and tube formation assay were performed using human umbilical vein endothelial cells treated with nicotine (10(-9) to 10(-6) M), and with various combinations of soluble fms-like tyrosine kinase 1 (100 ng/mL), soluble endoglin (100 ng/mL), and nicotine (10(-7) M). Enzyme-linked immunosorbent assay was performed to measure vascular endothelial growth factor, placental growth factor, and transforming growth factor-beta1 concentrations in the conditioned media treated with nicotine (10(-9) to 10(-6) M). RESULTS: Nicotine significantly facilitated endothelial migration and tube formation. By contrast, soluble fms-like tyrosine kinase 1 and/or soluble endoglin suppressed these endothelial functions. Nicotine restored these soluble fms-like tyrosine kinase 1 and/or soluble endoglin-reduced endothelial functions. Placental growth factor, but not transforming growth factor-beta1, production was significantly stimulated by the presence of nicotine. Vascular endothelial growth factor was undetectable. CONCLUSION: Our results suggest a possible mechanism for the protective effects of cigarette smoking against preeclampsia, thus proposing a therapeutic potential of nicotine or other nicotinic acetylcholine receptor agonists for preeclampsia.

Reduced affective symptoms during tobacco dependence treatment with varenicline.

BACKGROUND: The nicotinic acetylcholine receptor partial agonist varenicline has been shown to be effective in the treatment of tobacco dependence, but has been reported to induce exacerbations of psychiatric symptoms in subjects with pre-existing psychiatric disorders. CASE DESCRIPTION: We report a tobacco-dependent patient who developed depression and suicidal tendencies during several cessation attempts, but was finally able to stay nicotine-abstinent by taking varenicline. CONCLUSION: In this case varenicline did not lead to exacerbation but appeared to improve the affective symptoms.

Antigen-specific apheresis of human anti-acetylcholine receptor autoantibodies from myasthenia gravis patients' sera using Escherichia coli-expressed receptor domains.

Myasthenia gravis (MG) is an autoimmune disease usually caused by autoantibodies against the muscle nicotinic acetylcholine receptor (nAChR), found at the neuromuscular junction. Current treatments for the disease, including plasmapheresis, are not antigen-specific, and thus often cause severe side effects. The development and implementation of new therapeutic approaches for the disease attain particular importance, since the number of diagnosed myasthenic patients has increased considerably. In order to develop an antigen-specific approach for the selective depletion of anti-nAChR autoantibodies from MG patients' sera, we have expressed the extracellular domains (ECDs) of all human muscle nAChR subunits in E. coli. These recombinant proteins were immobilized on CNBr-Sepharose and used in immunoadsorption assays with MG sera. We showed that, despite being purified from E. coli under denaturing conditions, these recombinant ECDs could be successfully used as immunoadsorbents with a comparable efficiency to the corresponding ECDs produced in water-soluble form in the yeast Pichia pastoris. The high yield of the ECDs, the stability of the constructed ECD resins and the high selectivity for anti-nAChR antibodies increase the therapeutic potential of the system.

Novel pharmacological approaches for treating tobacco dependence and withdrawal: current status.

Increasing the diversity and availability of medications for the treatment of tobacco dependence and/or withdrawal, to aid in the achievement of smoking cessation, is crucial to meet the diverse needs of tobacco users. Despite a general awareness that smoking is harmful and widespread interest in smoking cessation, nearly 50 million adults in the US and 1.3 billion worldwide continue to smoke. Nicotine replacement therapies are effective in the treatment of tobacco dependence and withdrawal, but do not meet the needs of all tobacco users. Improvement of tobacco dependence and/or withdrawal treatments is likely to rely on novel pharmacological approaches that include new chemical entities and new formulations of current drugs. In addition, new indications for treating tobacco dependence and withdrawal show promise for reducing tobacco use and associated disease. This article focuses on a range of novel pharmacological approaches for the treatment of tobacco dependence and/or withdrawal, including oral and pulmonary nicotine delivery and the following non-nicotinic medications: antidepressants, an alpha4beta2 nicotine partial agonist, an alpha2-noradrenergic agonist, cytochrome P450 (CYP) 2A6 inhibitors, opioid antagonists and GABAergic medications. In addition to existing medications, this article addresses novel medications in the clinical development stage and those that have been evaluated previously. Novel medications in the clinical development stage include at least three nicotine vaccines and the cannabinoid receptor acting drug rimonabant. Medications evaluated previously include lobeline, mecamylamine and an anticholinergic drug regimen comprising atropine, scopolamine and chlorpromazine. Having not been approved by major drug regulatory authorities for the treatment of tobacco dependence and/or withdrawal, these medications have been evaluated in an experimental capacity.

A longer course of varenicline therapy improves smoking cessation rates.

Smoking exerts strong dose-dependent increases in cardiovascular risk and mortality, and quitting can profoundly decrease these risks. Varenicline attenuates nicotine addiction by reducing withdrawal symptoms and cravings. A meta-analysis performed addressed whether a longer duration of varenicline is associated with better abstinence rates than shorter courses of treatment. For this meta-analysis, a literature search was performed to identify randomized controlled trials investigating the efficacy of the smoking cessation agent varenicline. The association between abstinence and duration of treatment was analyzed using fixed-effect meta-regression. Five randomized controlled trials were identified and included in this meta-analysis. A highly significant relationship (P<.001) was found between the length of exposure to varenicline and abstinence rate. Cessation rates were approximately twice as high with varenicline treatment of 24 weeks compared to 6 weeks. In conclusion, a meta-analysis of randomized controlled trials suggests that longer duration of varenicline therapy improves long-term abstinence rates.

Extracellular domains of the beta, gamma and epsilon subunits of the human acetylcholine receptor as immunoadsorbents for myasthenic autoantibodies: a combination of immunoadsorbents results in increased efficiency.

Myasthenia gravis (MG) is usually caused by autoantibodies against the human muscle acetylcholine receptor (AChR). Plasmapheresis offers a therapeutic option, but, as well as removing the pathogenic anti-AChR autoantibodies, it non-specifically removes indispensable immunoglobulins. An attractive alternative to plasmapheresis would be the extracorporeal specific removal of the autoantibodies using AChR-based immunoadsorbents. Previously, we used the N-terminal extracellular domain (ECD) of the AChR alpha subunit to immunoadsorb anti-alpha subunit autoantibodies from MG sera. In this study, we immobilised the beta -, gamma- and epsilon-AChR ECDs on Sepharose and tested them as immunoadsorbents on 50 MG sera. A given ECD removed a different percentage of autoantibodies from different sera and different ECDs removed different percentages from the same serum; on average, the beta-, gamma- and epsilon-ECDs removed 22%, 20% and 15.5% of the autoantibodies, respectively. Immunoadsorption was completed in 3 min, 1 mug of ECD removed approximately 2 pmol of autoantibodies, and the immunoadsorbent could be recycled approximately 4 times. The combined use of two (alpha+gamma) or four (alpha+beta+gamma+epsilon) ECDs in a single immunoadsorbent resulted in much higher (often additive) immunoadsorption. These results show that MG sera have autoantibodies against several AChR subunits, and suggest that the combined use of all AChR ECDs could provide the basis for a novel, antigen-specific therapy for MG.

The vagus nerve and the nicotinic anti-inflammatory pathway.

Physiological anti-inflammatory mechanisms are selected by evolution to effectively control the immune system and can be exploited for the treatment of inflammatory disorders. Recent studies indicate that the vagus nerve (which is the longest of the cranial nerves and innervates most of the peripheral organs) can modulate the immune response and control inflammation through a 'nicotinic anti-inflammatory pathway' dependent on the alpha7-nicotinic acetylcholine receptor (alpha7nAChR). Nicotine has been used in clinical trials for the treatment of ulcerative colitis, but its clinical applications are limited by its unspecific effects and subsequent toxicity. This article reviews recent advances supporting the therapeutic potential of selective nicotinic agonists in several diseases. Similar to the development of alpha- and beta-agonists for adrenoceptors, selective agonists for alpha7nAChR could represent a promising pharmacological strategy against infectious and inflammatory diseases.

Nicotinic acetylcholine receptors as targets for antidepressants.

While the monoamine deficiency hypothesis of depression is still most commonly used to explain the actions of antidepressant drugs, a growing body of evidence has accumulated that is not adequately explained by the hypothesis. This article draws attention to contributions from another apparently common pharmacological property of antidepressant medications--the inhibition of nicotinic acetylcholine receptors (nAChR). Evidence is presented suggesting the hypercholinergic neurotransmission, which is associated with depressed mood states, may be mediated through excessive neuronal nicotinic receptor activation and that the therapeutic actions of many antidepressants may be, in part, mediated through inhibition of these receptors. In support of this hypothesis, preliminary evidence is presented suggesting that the potent, centrally acting nAChR antagonist, mecamylamine, which is devoid of monoamine reuptake inhibition, may reduce symptoms of depression and mood instability in patients with comorbid depression and bipolar disorder. If this hypothesis is supported by further preclinical and clinical research, nicotinic acetylcholine receptor antagonists may represent a novel class of therapeutic agents for treating mood disorders.

Oral administration of a dual analog of two myasthenogenic T cell epitopes down-regulates experimental autoimmune myasthenia gravis in mice.

Myasthenia gravis (MG) and experimental autoimmune MG (EAMG) are T cell-regulated, antibody-mediated autoimmune diseases. The major autoantigen in MG is the nicotinic acetylcholine receptor (AChR). Two peptides, representing sequences of the human AChR alpha-subunit, p195-212 and p259-271, were previously shown to be immunodominant T cell epitopes in MG patients as well as, respectively, in SJL and BALB/c mice. A dual analog (termed Lys-262-Ala-207) composed of the tandemly arranged two single amino acid analogs of p195-212 and p259-271 was shown to inhibit, in vitro and in vivo, MG-associated autoimmune responses. Furthermore, the dual analog could down-regulate myasthenogenic manifestations in mice with EAMG that was induced by inoculation of a pathogenic T cell line. In the present study, the ability of the dual analog to treat EAMG induced in susceptible C57BL/6 mice by native Torpedo AChR was evaluated. Mice that were diagnosed to have clinical symptoms of EAMG were treated with the dual analog by oral administration, 500 microg per mouse three times a week for 5-8 weeks. Treatment with the dual analog down-regulated the clinical manifestations of the ongoing disease as assessed by the clinical score, grip strength (measured by a grip strength meter), and electromyography. The effects on the clinical EAMG correlated with a reduced production of anti-AChR antibody as well as a decrease in the secretion of interleukin-2 and, more dramatically, interferon-gamma, in response to AChR triggering. Thus, the dual analog is an efficient immunomodulator of EAMG in mice and might be of specific therapeutic potential for MG.