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Concept: Myasthenia gravis


Opioids are first-line drugs for moderate to severe acute pain and cancer pain. However, these medications are associated with severe side effects, and whether they are efficacious in treatment of chronic nonmalignant pain remains controversial. Medications that act through alternative molecular mechanisms are critically needed. Antagonists of α9α10 nicotinic acetylcholine receptors (nAChRs) have been proposed as an important nonopioid mechanism based on studies demonstrating prevention of neuropathology after trauma-induced nerve injury. However, the key α9α10 ligands characterized to date are at least two orders of magnitude less potent on human vs. rodent nAChRs, limiting their translational application. Furthermore, an alternative proposal that these ligands achieve their beneficial effects by acting as agonists of GABAB receptors has caused confusion over whether blockade of α9α10 nAChRs is the fundamental underlying mechanism. To address these issues definitively, we developed RgIA4, a peptide that exhibits high potency for both human and rodent α9α10 nAChRs, and was at least 1,000-fold more selective for α9α10 nAChRs vs. all other molecular targets tested, including opioid and GABAB receptors. A daily s.c. dose of RgIA4 prevented chemotherapy-induced neuropathic pain in rats. In wild-type mice, oxaliplatin treatment produced cold allodynia that could be prevented by RgIA4. Additionally, in α9 KO mice, chemotherapy-induced development of cold allodynia was attenuated and the milder, temporary cold allodynia was not relieved by RgIA4. These findings establish blockade of α9-containing nAChRs as the basis for the efficacy of RgIA4, and that α9-containing nAChRs are a critical target for prevention of chronic cancer chemotherapy-induced neuropathic pain.

Concepts: Nicotine, Pain, Acetylcholine, Myasthenia gravis, Muscarinic acetylcholine receptor, Nicotinic acetylcholine receptor, Acetylcholine receptor, Dextromethorphan


Although the activity of the nicotinic acetylcholine receptor (nAChR) is exquisitely sensitive to its membrane environment, the underlying mechanisms remain poorly defined. The homologous prokaryotic pentameric ligand gated ion channel, GLIC, represents an excellent model for probing the molecular basis of nAChR sensitivity due to its high structural homology, ease of expression, and amenability to crystallographic analysis. We show here that membrane-reconstituted GLIC exhibits structural and biophysical properties similar to those of membrane-reconstituted nAChR, although GLIC is substantially more thermally stable. GLIC, however, does not possess the same exquisite lipid sensitivity. In particular, GLIC does not exhibit the same propensity to adopt an uncoupled conformation where agonist binding is uncoupled from channel gating. Structural comparisons provide insight into the chemical features that may predispose the nAChR to the formation of an uncoupled state.

Concepts: Receptor, Acetylcholine, Ion channels, Myasthenia gravis, Muscarinic acetylcholine receptor, Nicotinic acetylcholine receptor, Acetylcholine receptor, Ligand-gated ion channel


Neurotransmitter corelease is emerging as a common theme of central neuromodulatory systems. Though corelease of glutamate or GABA with acetylcholine has been reported within the cholinergic system, the full extent is unknown. To explore synaptic signaling of cholinergic forebrain neurons, we activated choline acetyltransferase expressing neurons using channelrhodopsin while recording post-synaptic currents (PSCs) in layer 1 interneurons. Surprisingly, we observed PSCs mediated by GABAA receptors in addition to nicotinic acetylcholine receptors. Based on PSC latency and pharmacological sensitivity, our results suggest monosynaptic release of both GABA and ACh. Anatomical analysis showed that forebrain cholinergic neurons express the GABA synthetic enzyme Gad2 and the vesicular GABA transporter (Slc32a1). We confirmed the direct release of GABA by knocking out Slc32a1 from cholinergic neurons. Our results identify GABA as an overlooked fast neurotransmitter utilized throughout the forebrain cholinergic system. GABA/ACh corelease may have major implications for modulation of cortical function by cholinergic neurons.

Concepts: Nicotine, Neurotransmitter, Acetylcholine, Myasthenia gravis, Muscarinic acetylcholine receptor, Nicotinic acetylcholine receptor, GABAA receptor, Ligand-gated ion channel


Chronic exposure to nicotine upregulates nicotinic acetylcholine receptors (nAChRs), and such upregulation is critical for the development of nicotine dependence in humans and animal models. However, how nicotine upregulates nAChRs is not well understood. Here, we identify a key role for microRNA in regulating nicotine-dependent behavior by modulating nAChR expression in C. elegans. We show that the nAChR gene acr-19 and alg-1, a key Argonaute-family member in the microRNA machinery, are specifically required for nicotine withdrawal response following chronic nicotine treatment. Chronic exposure to nicotine downregulates alg-1, leading to upregulation of acr-19. This effect is mediated by the microRNA miR-238 that recognizes the 3' UTR of acr-19 transcript. Our results unveil a previously unrecognized role for microRNA in nicotine signaling, providing insights into how chronic nicotine administration leads to upregulation of nAChR and ultimately nicotine dependence.

Concepts: Nicotine, Acetylcholine, Myasthenia gravis, Muscarinic acetylcholine receptor, Nicotinic acetylcholine receptor, Acetylcholine receptor, Neuromuscular junction, Alpha-4 beta-2 nicotinic receptor


B cells contribute to multiple aspects of autoimmune disorders and may play a role in triggering disease. Thus, targeting B cells may be a promising strategy for treating autoimmune disorders. Better understanding of the B cell subsets that are responsible for the development of autoimmunity will be critical for developing efficient therapies. Here we have reported that B cells expressing the transcription factor T-bet promote the rapid appearance of autoantibodies and germinal centers in spontaneous murine models of systemic lupus erythematosus (SLE). Conditional deletion of T-bet from B cells impaired the formation of germinal centers and mitigated the development of kidney damage and rapid mortality in SLE mice. B cell-specific deletion of T-bet was also associated with lower activation of both B cells and T cells. Taken together, our results suggest that targeting T-bet-expressing B cells may be a potential target for therapy for autoimmune diseases.

Concepts: Cell nucleus, Rheumatoid arthritis, Systemic lupus erythematosus, Lupus erythematosus, Glomerulonephritis, Autoimmune diseases, Sjögren's syndrome, Myasthenia gravis


Rabies virus induces drastic behaviour modifications in infected hosts. The mechanisms used to achieve these changes in the host are not known. The main finding of this study is that a region in the rabies virus glycoprotein, with homologies to snake toxins, has the ability to alter behaviour in animals through inhibition of nicotinic acetylcholine receptors present in the central nervous system. This finding provides a novel aspect to virus receptor interaction and host manipulation by pathogens in general. The neurotoxin-like region of the rabies virus glycoprotein inhibited acetylcholine responses of α4β2 nicotinic receptors in vitro, as did full length ectodomain of the rabies virus glycoprotein. The same peptides significantly altered a nicotinic receptor induced behaviour in C. elegans and increased locomotor activity levels when injected into the central nervous system of mice. These results provide a mechanistic explanation for the behavioural changes in hosts infected by rabies virus.

Concepts: Nervous system, Neurotransmitter, Acetylcholine, Myasthenia gravis, Muscarinic acetylcholine receptor, Nicotinic acetylcholine receptor, Ligand-gated ion channel, Neuromuscular junction


In this multicenter, double-blind, placebo-controlled, randomized, four way cross-over proof-of-mechanism study, we tested the effect of the positive allosteric α7 nicotinic acetylcholine receptor (nAChR) modulator JNJ-39393406 in a key translational assay (sensory P50 gating) in 39 regularly smoking male patients with schizophrenia. All patients were clinically stable and JNJ-39393406 was administered as an adjunct treatment to antipsychotics. No indication was found that JNJ-39393406 has the potential to reverse basic deficits of information processing in schizophrenia (sensory P50 gating) or has a significant effect on other tested electrophysiological markers (MMN, P300 and quantitative resting EEG). Sensitivity analyses including severity of disease, baseline P50 gating, medication and gene variants of the CHRNA7 gene did not reveal any subgroups with consistent significant effects. It is discussed that potential positive effects in subgroups not present or not large enough in the current study or upon chronic dosing are possible, but unlikely to be developed. This article is part of a Special Issue entitled ‘Cognitive Enhancers’.

Concepts: Nicotine, Acetylcholine, Myasthenia gravis, Muscarinic acetylcholine receptor, Nicotinic acetylcholine receptor, Acetylcholine receptor, Alpha-7 nicotinic receptor, CHRNA7


Fatigue is commonly reported in many neurologic illnesses, including multiple sclerosis, Parkinson disease, myasthenia gravis, traumatic brain injury, and stroke. Fatigue contributes substantially to decrements in quality of life and disability in these illnesses. Despite the clear impact of fatigue as a disabling symptom, our understanding of fatigue pathophysiology is limited and current treatment options rarely lead to meaningful improvements in fatigue. Progress continues to be hampered by issues related to terminology and assessment. In this article, we propose a unified taxonomy and a novel assessment approach to addressing distinct aspects of fatigue and fatigability in clinical and research settings. This taxonomy is based on our current knowledge of the pathophysiology and phenomenology of fatigue and fatigability. Application of our approach indicates that the assessment and reporting of fatigue can be clarified and improved by utilizing this taxonomy and creating measures to address distinct aspects of fatigue and fatigability. We review the strengths and weaknesses of several common measures of fatigue and suggest, based on our model, that many research questions may be better addressed by using multiple measures. We also provide examples of how to apply and validate the taxonomy and suggest directions for future research.

Concepts: Better, Traumatic brain injury, Neurology, Parkinson's disease, Dementia, Myasthenia gravis, Post-concussion syndrome, IP address


Introduction: Determination of acetylcholinesterase and butyrylcholinesterase activity has become an important tool in drug design and discovery as well as in medicine and toxicology. There are a large number of compounds that are able to modulate cholinesterase activity. These compounds can be used for pharmacological management of various disorders (e.g., Alzheimer’s disease, myasthenia Gravis). Moreover, organophosphate poisoning is frequently diagnosed via a cholinesterase activity assay. This broad variety of methods has been developed over the past decades for cholinesterase activity quantification. Areas covered: This review provides a summary of the methods that are based on specific properties of cholinesterases and their interactions with native or artificial substrates. The authors also aim to provide an overview of different techniques used for the determination of quantitative cholinesterase activity. Specifically, the authors describe and discuss the manometric, potentiometric, titrimetric, photometric, fluorometric, and radioisotopic methods. Expert opinion: Existing methods are able to cover most of the problems that arise during cholinesterase activity determination. Colorimetry according to Ellman has proved to be the most useful and versatile approach. It may be used in various protocols for the determination of pesticide or nerve agent exposure or for the development of new drugs. Its possible improvement lies in optimization of hemoglobin-rich samples. The progress of the most common methods (including Ellman) depends on miniaturization and modern physical platforms (e.g., optical fibers, chip methods, or nanotechnologies).

Concepts: Pharmacology, Drug, Acetylcholine, Sarin, Myasthenia gravis, Acetylcholinesterase, Acetylcholinesterase inhibitor, Cholinesterase


Alpha-7 nicotinic acetylcholine receptor (α7 nAChR) agonists attenuate pain and inflammation in preclinical models. This study tested whether systemic delivery of an α7 nAChR agonist attenuates neuropathic pain and associated immune-mediated pro-inflammation. Hind paw response thresholds to mechanical stimuli in male Sprague Dawley rats were assessed before and after sciatic chronic constriction injury (CCI) or sham surgery. Osmotic mini-pumps containing TC-7020, an α7 nAChR selective agonist, were implanted 10 to 14 days after surgery. TC-7020 (1, 3, and 10 mg/kg/d; s.c.) significantly attenuated CCI-induced allodynia, which lasted through 2 weeks of test compound administration. Spinal cords were collected after 2 weeks and processed for microglial and astrocyte activation markers within the ipsilateral L4-L6 dorsal horn. In addition, ipsilateral L4-5 dorsal root ganglia (DRGs) were processed for neuronal injury and satellite cell activation markers. CCI-induced central glial cell activation markers were not suppressed by TC-7020, even though TC-7020 is mildly blood-brain barrier permeable. However, TC-7020 downregulated the integrated density of activation transcription factor 3 (ATF3) but not the number of ATF positive cells. TC-7020 also downregulated phosphorylated extracellular signal kinase (p-ERK) and satellite cell activation in the CCI-affected DRGs. Therefore, systemic α7 nAChR agonist may be effective in treating neuropathic pain via reducing neuronal injury and immune cells activation occurring in the periphery. PERSPECTIVE: These studies demonstrated that TC-7020, an alpha7 nicotinic acetylcholine receptor agonist with partial blood-brain barrier permeability, reversed neuropathic pain in rats, likely via attenuation of inflammation in the DRG and/or the site of sciatic injury.

Concepts: Nicotine, Agonist, Acetylcholine, Myasthenia gravis, Muscarinic acetylcholine receptor, Nicotinic acetylcholine receptor, Acetylcholine receptor, Alpha-7 nicotinic receptor