Celebrating the 70 years of pyridostigmine on therapy of Myasthenia Gravis: historical aspects of the preliminary trials

Currently, pyridostigmine bromide is an indispensable anticholinesterase agent used worldwide to treat patients with Myasthenia Gravis (MG). However, pyridostigmine bromide was unsuccessful in its “pioneering trials” to treat a series of MG patients. There are important historical landmarks before pyridostigmine bromide becomes useful, safe and indispensable for MG therapy. After 70 years of these “pioneering trials”, this article reviews some historical aspects related to them, as well as other preliminary trials using pyridostigmine bromide as therapy for MG patients.

Effects of Cholinergic Stimulation with Pyridostigmine Bromide on Chronic Chagasic Cardiomyopathic Mice

The aim of the present study was to assess the effects of an anticholinesterase agent, pyridostigmine bromide (Pyrido), on experimental chronic Chagas heart disease in mice. To this end, male C57BL/6J mice noninfected (control:Con) or chronically infected (5 months) withTrypanosoma cruzi(chagasic:Chg) were treated or not (NT) with Pyrido for one month. At the end of this period, electrocardiogram (ECG); cardiac autonomic function; heart histopathology; serum cytokines; and the presence of blood and tissue parasites by means of immunohistochemistry and PCR were assessed. In NT-Chg mice, significant changes in the electrocardiographic, autonomic, and cardiac histopathological profiles were observed confirming a chronic inflammatory response. Treatment with Pyrido in Chagasic mice caused a significant reduction of myocardial inflammatory infiltration, fibrosis, and hypertrophy, which was accompanied by a decrease in serum levels of IFNγwith no change in IL-10 levels, suggesting a shift of immune response toward an anti-inflammatory profile. Lower nondifferent numbers of parasite DNA copies were observed in both treated and nontreated chagasic mice. In conclusion, our findings confirm the marked neuroimmunomodulatory role played by the parasympathetic autonomic nervous system in the evolution of the inflammatory-immune response toT. cruziduring experimental chronic Chagas heart disease in mice.

Muscarinic regulation of neonatal rat bladder spontaneous contractions

In vitro preparations of whole urinary bladders of neonatal rats exhibit prominent myogenic spontaneous contractions, the amplitude and frequency of which can be increased by muscarinic agonists. The muscarinic receptor subtype responsible for this facilitation was examined in the present experiments. Basal spontaneous contractions in bladders from 1- to 2-wk-old Sprague-Dawley rats were not affected by M2 or M3 receptor antagonists. However, administration of 0.5 μM physostigmine, an anticholinesterase agent that increases the levels of endogenous acetylcholine, or 50–100 nM carbachol, a cholinergic agonist at low concentrations, which did not cause tonic contractions, significantly augmented the frequency and amplitude of spontaneous contractions. Blockade of M2 receptors with 0.1 μM AF-DX 116 or 1 μM methoctramine or blockade of M3 receptors with 50 nM 4-diphenylacetoxy- N-methylpiperidine methiodide or 0.1 μM 4-diphenylacetoxy- N-(2-chloroethyl)piperidine hydrochloride (4-DAMP mustard) reversed the physostigmine and carbachol responses. M2 and M3 receptor blockade did not alter the facilitation of spontaneous contractions induced by 10 nM BAY K 8644, an L-type Ca2+ channel opener, or 0.1 μM iberiotoxin, a large-conductance Ca2+-activated K+ channel blocker. NS-1619 (30 μM), a large-conductance Ca2+-activated K+ channel opener, decreased carbachol-augmented spontaneous contractions. These results suggest that spontaneous contractions in the neonatal rat bladder are enhanced by activation of M2 and M3 receptors by endogenous acetylcholine released in the presence of an anticholinesterase agent or a cholinergic receptor agonist.

Links between multiple chemical sensitivity and asthma in a rat model of cholinergic hypersensitivity: a brief review

Individuals with multiple chemical sensitivity (MCS) also commonly report symptoms of asthma, but, as far as we have been able to determine, no one has yet suggested that an abnormal cholinergic system may provide the link between asthma and MCS. The present brief review provides evidence for such a link by summarizing recent findings in a genetic animal model of cholinergic hyperresponsiveness. The Flinders Sensitive Line (FSL) rats were developed by selective breeding for increased responses to an anticholinesterase agent similar to commonly used organophosphate pesticides. Relative to their control line, the Flinders Resistant Line (FRL) rats, the FSL rats are more sensitive to drugs that stimulate acetylcholine receptors, alcohol, diazepam, and drugs that have a selective effect on dopamine or serotonin receptors. These findings raise the possibility that the FSL rats may resemble individuals with MCS. Hyperresponsiveness of the airways is a hallmark of asthma. The procedure known as whole-body plethysmography, where breathing can be monitored in freely moving animals, was employed to study the FSL and FRL rats. The FSL rats exhibited a greater index of bronchoconstriction than the FRL rats in response to both a cholinergic agonist and an allergen challenge. Thus, the FSL rats are more sensitive both to a variety of drugs unrelated to the cholinergic system and to cholinergic- and allergen-induced bronchoconstriction. An abnormal cholinergic system may therefore contribute to both MCS and asthma.