scholarly journals 4-aminopyridine – the new old drug for the treatment of neurodegenerative diseases

Pharmacia ◽  
2019 ◽  
Vol 66 (2) ◽  
pp. 67-74
Author(s):  
Ivanka Kostadinova ◽  
Nikolai Danchev
Keyword(s):  
Multiple Sclerosis ◽  
Channel Blocker ◽  
K Channel ◽  
Chemical Agent ◽  
Channel Blockade ◽  
Reversal Agent ◽  
Trade Name ◽  
Pharmacological Data ◽  
The Usa ◽  
The Central Nervous System

In this review are described the preclinical and clinical pharmacological data as well as new therapeutic indications for the use of 4-aminopyridine. 4-aminopyridine is a potassium (K+) channel blocker that has a long history and various application areas. It is a chemical agent developed in 1963 as a bird poison. The first approval for clinical application of 4-aminopyridine was in 70’s in Bulgaria, since anesthetists in that country have confirmed its effect as reversal agent for nondepolarizing myorelaxants. The Bulgarian pharmaceutical company Sopharma commersialized 4-aminopyridine under the trade name Pymadin. Since then 4-aminopyridine was extensively studied and in 2010 is approved in the USA for the treatment of walking disabilities in patients with multiple sclerosis. In recent years, data from clinical trials indicated that K-channel blockade may prove to be an appropriate strategy to overcome disturbances in nerve impulses conduction associated with demyelination of the central nervous system.

Glibenclamide decreases basal coronary blood flow in anesthetized dogs

1992 ◽  
Vol 263 (2) ◽  
pp. H399-H404 ◽  
Author(s):  
Y. Imamura ◽  
H. Tomoike ◽  
T. Narishige ◽  
T. Takahashi ◽  
H. Kasuya ◽  
...  
Keyword(s):  
Blood Flow ◽  
Coronary Blood Flow ◽  
Channel Blocker ◽  
K Channel ◽  
Channel Blockade ◽  
Circumflex Coronary Artery ◽  
Physiological Conditions ◽  
Intracoronary Infusion ◽  
Anesthetized Dogs ◽  
St Elevation

The effects of ATP-sensitive K+ channel blockade on coronary blood flow were studied in 13 anesthetized open-chest dogs. A specific ATP-sensitive K+ channel blocker, glibenclamide, was infused into the left circumflex coronary artery (LCx). Coronary blood flow of LCx and systolic segment shortening at the LCx area were measured. Intracoronary infusion of glibenclamide (0.5, 5, and 50 micrograms.kg-1.min-1) decreased coronary blood flow dose dependently. Glibenclamide at the dose of 50 micrograms.kg-1.min-1 decreased LCx coronary blood flow by 55 +/- 4% (P less than 0.01), which was accompanied by a decrease in percentage segment shortening at the LCx area (P less than 0.01) and ST elevation. When coronary blood flow was maintained at the baseline level by simultaneous infusion of sodium nitroprusside (1-3 micrograms/min ic) or pinacidil (0.3-0.6 mg/min ic), glibenclamide did not alter percentage segment shortening or produced ST elevation. The latter results suggest that glibenclamide decreased coronary blood flow, which secondarily induced myocardial ischemia and dysfunction. Our results suggest that ATP-sensitive K+ channels of coronary arteries are involved in maintaining the level of resting coronary blood flow under physiological conditions in anesthetized dogs.

Modulation of cat antral slow waves by ion substitution, Ca2+ and K+ channel blockade, and ACh stimulation

1992 ◽  
Vol 263 (6) ◽  
pp. G880-G886
Author(s):  
L. M. Renzetti ◽  
M. B. Wang ◽  
J. P. Ryan
Keyword(s):  
Channel Blocker ◽  
Slow Waves ◽  
K Channel ◽  
Plateau Phase ◽  
Channel Blockade ◽  
Plateau Potentials ◽  
Wave Duration ◽  
Plateau Potential ◽  
Ion Substitution ◽  
Circular Layer

Two distinct slow waves can be recorded from smooth muscle cells on the submucosal border (submucosal cells) and the myenteric border (myenteric cells) in the circular layer of the cat antrum. The present studies examined the effects of decreasing extracellular Na+ ([Na+]o) or Ca2+ concentration ([Ca2+]o), Ca2+ and K+ channel blockade, and acetylcholine (ACh) stimulation on "submucosal" and "myenteric" slow waves using intracellular recording techniques. Decreasing [Na+]o (30 mM) reduced the upstroke depolarization of slow waves from submucosal cells but had no effect on the upstroke depolarization of myenteric cells. Decreasing [Ca2+]o (0.5 mM) decreased the upstroke depolarization in cells from each area. Neither cadmium (200 microM) nor nifedipine (100 microM) had any effect on the upstroke depolarizations from both submucosal and myenteric slow waves. In contrast, nickel (5 mM), a nonselective Ca2+ channel blocker, decreased the upstroke depolarizations of slow waves from submucosal and myenteric cells. Slow waves from myenteric cells normally exhibit a plateau phase of several seconds duration. The amplitude of the plateau potential could be decreased by lowering [Na+]o or [Ca2+]o or by nickel, cadmium or nifedipine. In the presence of 30 mM Na+ slow waves from submucosal cells appeared to develop plateau potentials. K+ channel blockade with tetrabutylammonium (TBA, 5 mM) or cesium (10 mM) increased the upstroke depolarization and delayed membrane repolarization in slow waves from submucosal cells. TBA and cesium also increased the upstroke depolarization from myenteric cells but did not delay membrane repolarization. ACh (1 and 3 microM) caused the generation of plateau potentials in slow waves from submucosal cells and increased slow-wave duration.(ABSTRACT TRUNCATED AT 250 WORDS)

Cold-induced reactivity in multiple sclerosis patients

2017 ◽  
pp. 56-62 ◽  
Author(s):  
Л.И. Герасимова-Мейгал ◽  
И.М. Сиренев
Keyword(s):  
Multiple Sclerosis ◽  
Cold Test ◽  
Typical Feature ◽  
Humid Climate ◽  
Ssr Analysis ◽  
Epidemiological Surveys ◽  
The Central Nervous System ◽  
The Individual ◽  
Hands And Feet ◽  
Multiple Sclerosis Patients

Цель исследования - изучение особенностей восприимчивости пациентов с рассеянным склерозом (РС) к холодовому воздействию с помощью функциональных тестов, характеризующих функцию терморегуляции. Как известно, РС - хроническое прогрессирующее аутоиммунное заболевание центральной нервной системы мультифакториальной природы, более часто встречающееся в регионах с холодным и влажным климатом. Нарушения терморегуляции вследствие автономной дисфункции являются характерным признаком РС, вместе с тем участию холодового фактора в развитии заболевания не придается существенного значения. Методика. Обследовано 32 пациента (17 мужчин и 15 женщин, средний возраст 29,6 ± 4,2 года) с установленным диагнозом: РС ремиттирующе-рецидивирующая форма течения (средняя продолжительность заболевания - 4,2 ± 2,7 года) и 18 практически здоровых лиц группы сравнения. Восприятие холода оценивали с помощью визуально-аналоговой шкалы. Продолжительность холод-индуцированной вазоконстрикции после локального холодового теста изучали по данным инфракрасной термометрии. Вегетативную регуляцию вазомоторных реакций оценивали по результатам анализа вызванных кожных вегетативных потенциалов (ВКВП). Результаты. На основе анализа самооценки восприятия холода у пациентов с РС показана низкая переносимость холодового фактора. При проведении локального холодового теста отмечено замедление восстановления температуры кожи кисти, что характерно для усиления холод-индуцированной вазоконстрикции. В группе пациентов с РС выявлено снижение параметров ВКВП ладоней и стоп, свидетельствующее о дефиците нейрогенного контроля терморегуляционных сосудистых реакций. Заключение. У пациентов с РС выявлены нарушения механизмов терморегуляции при действии холода, что обусловливает высокую индивидуальную восприимчивость к холоду у данной категории лиц. Сопоставление результатов анализа механизмов индивидуальной холод-индуцированной реактивности у пациентов с РС с данными эпидемиологических исследований приводит к заключению о потенциальном модулирующем влиянии холодового фактора на течение РС. The purpose of the present study was focused on the evaluation of the sensitivity to cold in multiple sclerosis (MS) patients by means of functional thermoregulatory based tests. MS is known to be a chronic autoimmune progressive disease of the central nervous system of multifactor origin that is very common in regions with cold and humid climate. Disorder of thermoregulation caused by autonomic dysfunction is a typical feature of MS, however the role of the cold in the disease development is still underestimated. Methods. Thirty two MS patients (17 males, 15 females, mean age 29,6 ± 4,2 years) with the remittent form of the disease (mean disease duration 4,2 ± 2,7 years) and 18 age-matched healthy controls volunteered to participate in this study. Susceptibility to cold was analyzed with the use of visual-analogous scale. The duration of cold-induced vasoconstriction after local cold test was estimated using by infrared thermometry. Autonomic regulation of vasomotor reactions was investigated with the help of the skin sympathetic response (SSR) analysis. Results. The analysis of self-reported perception of the cold in MS patients showed their low tolerance to cold. Slow recovery of the skin temperature of the hand in the local cold test observed in MS patients was considered as the aggravated cold-induced vasoconstriction. The decreased SSR in the hands and feet in MS patients was found that indicates the deficit of the neurogenic control of thermoregulatory vasomotor reactions. Conclusion. The results obtained demonstrate the impairment of thermoregulation under cold in MS patients that leads to higher individual susceptibility to cold of this group. Comparing of the data found in this study on the mechanisms of the individual cold-induced reactivity in MS patients with epidemiological surveys enable to conclude that cold environment has potential modulating effect of on the course of MS.

Immunomodulation in Multiple Sclerosis by Phytotherapy

2020 ◽  
Vol 16 (1) ◽  
pp. 28-36
Author(s):  
Maryam Bahrami ◽  
Ghasem Mosayebi ◽  
Ali Ghazavi ◽  
Ali Ganji
Keyword(s):  
Multiple Sclerosis ◽  
Nigella Sativa ◽  
Boswellia Serrata ◽  
Immunomodulatory Agents ◽  
Therapeutic Benefits ◽  
Demyelinating Disorder ◽  
Sensory Impairments ◽  
The Central Nervous System ◽  
Pomegranate Peel Extract ◽  
Peel Extract

Multiple sclerosis is a chronic inflammatory and demyelinating disorder of the central nervous system (CNS) that can cause cognition, mobility, and sensory impairments. Studies have shown that the immune system through inflammation and autoreactive T cells are involved in the progression of MS. The present article aimed to review the potent anti-inflammatory, antioxidant, and immunomodulatory agents that could modulate the immune response in MS. In herbal medicine, various medicinal plants including Olive, Silybum marianum, Grape, Pomegranate peel extract, Nigella sativa, Turmeric, Green tea, Aloysia citrodora, Boswellia papyrifera, Boswellia serrata, Ruta graveolens, and Andrographis paniculata are known with therapeutic benefits in MS patients through immunoregulation and reduction of major symptoms.

The Effects of Different Kinds of Nutrition and Functional Foods on Multiple Sclerosis

2020 ◽  
Vol 16 (5) ◽  
pp. 632-637
Author(s):  
Masih Falahatian
Keyword(s):  
Multiple Sclerosis ◽  
Functional Foods ◽  
Fruits And Vegetables ◽  
Salt Intake ◽  
Vegetable Intake ◽  
Dietary Salt ◽  
Negative Effects ◽  
Dietary Salt Intake ◽  
Neuroinflammatory Disease ◽  
The Central Nervous System

It is an assumption that different kinds of nutrition, diet, and functional foods might have different positive or negative effects on multiple sclerosis (MS), a neuroinflammatory disease of the central nervous system (CNS). This brief paper involved a study on various kinds of nutrition including salt, fat, dairy, fruit, and vegetables. At the end of this study, appropriate diets were evaluated for MS patients. Based on previous studies both on animal models and on MS patients, excessive dietary salt intake and animal fat had worsening effects on MS patients but fruit and vegetable intake helped the remission of MS and decreased the risk of developing it. There were, of course, conflicting results in different studies over the role of some nutrition in MS and future studies on larger numbers of cases were required to collect reliable results. As a result, at the end of this study and based on literature, it is suggested that a diet should be programmed by nutritionists containing fewer salt, fat, and dairy intake and more fruits and vegetables for MS patients in order to better management of the disease.

Primary involvement of K+ conductance in membrane resonance of trigeminal root ganglion neurons

1988 ◽  
Vol 59 (1) ◽  
pp. 77-89 ◽  
Author(s):  
E. Puil ◽  
B. Gimbarzevsky ◽  
I. Spigelman
Keyword(s):  
Electrical Properties ◽  
Channel Blocker ◽  
Complex Impedance ◽  
Membrane Potentials ◽  
K Channel ◽  
Bathing Medium ◽  
Trigeminal Root ◽  
Membrane Resonance ◽  
Ganglion Neurons ◽  
Impedance Magnitude

1. The complex impedances and impedance magnitude functions were obtained from neurons in in vitro slices of trigeminal root ganglia using frequency-domain analyses of intracellularly recorded voltage responses to specified oscillatory input currents. A neuronal model derived from linearized Hodgkin-Huxley-like equations was used to fit the complex impedance data. This procedure yielded estimates for membrane electrical properties. 2. Membrane resonance was observed in the impedance magnitude functions of all investigated neurons at their initial resting membrane potentials and was similar to that reported previously for trigeminal root ganglion neurons in vivo. Tetrodotoxin (10(-6) M), a Na+-channel blocker, applied in the bathing medium for 20 min produced only minor changes, if any, in the resonance, although gross impairment of Na+-spike electrogenesis was apparent in most of the neurons. Brief applications (1-5 min) of a K+-channel blocker, tetraethylammonium (TEA; 10(-2) M), increased the impedance magnitude and abolished, in a reversible manner, the resonant behavior. In all cases, the resonant frequency was decreased by TEA administration prior to total blockade of resonance. 3. The TEA-induced blockade of resonance was associated with decreases in the estimates of the membrane conductances, without significant alterations of input capacitance. A particularly large decrease was observed in Gr, the time-invariant resting conductance that includes a lumped leak conductance component. The voltage- and time-dependent conductance, GL, and associated relaxation time constant, tau u, also declined progressively during administration of TEA. 4. Systematic variations in the membrane potentials of trigeminal root ganglion neurons were produced by intracellular injections of long-lasting step currents with superposition of the oscillatory current stimuli, in order to assess the effects of TEA on the relationship of the electrical properties to the membrane potential. Applications of TEA led to a depolarizing shift in the dependence of the membrane property estimates, suggesting voltage-dependence of the effects of TEA on presumed K+ channels in the membrane. 5. These data suggest a primary involvement of K+ conductance in the genesis of membrane resonance. This electrical behavior or its ionic mechanism is a major modulator of the subthreshold electrical responsiveness of trigeminal root ganglion neurons.

scholarly journals Multiple Sclerosis Biomarker Discoveries by Proteomics and Metabolomics Approaches

2021 ◽  
Vol 16 ◽  
pp. 117727192110133
Author(s):  
Ameneh Jafari ◽  
Amirhesam Babajani ◽  
Mostafa Rezaei-Tavirani
Keyword(s):  
Multiple Sclerosis ◽  
Complex Disease ◽  
Biomarker Discovery ◽  
Response To Treatment ◽  
Inflammatory Disorder ◽  
Protein Marker ◽  
Complex Disorders ◽  
New Information ◽  
The Central Nervous System ◽  
Monitoring Treatment

Multiple sclerosis (MS) is an autoimmune inflammatory disorder of the central nervous system (CNS) resulting in demyelination and axonal loss in the brain and spinal cord. The precise pathogenesis and etiology of this complex disease are still a mystery. Despite many studies that have been aimed to identify biomarkers, no protein marker has yet been approved for MS. There is urgently needed for biomarkers, which could clarify pathology, monitor disease progression, response to treatment, and prognosis in MS. Proteomics and metabolomics analysis are powerful tools to identify putative and novel candidate biomarkers. Different human compartments analysis using proteomics, metabolomics, and bioinformatics approaches has generated new information for further clarification of MS pathology, elucidating the mechanisms of the disease, finding new targets, and monitoring treatment response. Overall, omics approaches can develop different therapeutic and diagnostic aspects of complex disorders such as multiple sclerosis, from biomarker discovery to personalized medicine.

scholarly journals Made to Measure: Patient-Tailored Treatment of Multiple Sclerosis Using Cell-Based Therapies

2021 ◽  
Vol 22 (14) ◽  
pp. 7536
Author(s):  
Inez Wens ◽  
Ibo Janssens ◽  
Judith Derdelinckx ◽  
Megha Meena ◽  
Barbara Willekens ◽  
...  
Keyword(s):  
Multiple Sclerosis ◽  
Autoimmune Diseases ◽  
Stromal Cells ◽  
Mononuclear Cells ◽  
Treatment Options ◽  
Cell Types ◽  
Peripheral Blood Mononuclear ◽  
Tailored Treatment ◽  
Key Issues ◽  
The Central Nervous System

Currently, there is still no cure for multiple sclerosis (MS), which is an autoimmune and neurodegenerative disease of the central nervous system. Treatment options predominantly consist of drugs that affect adaptive immunity and lead to a reduction of the inflammatory disease activity. A broad range of possible cell-based therapeutic options are being explored in the treatment of autoimmune diseases, including MS. This review aims to provide an overview of recent and future advances in the development of cell-based treatment options for the induction of tolerance in MS. Here, we will focus on haematopoietic stem cells, mesenchymal stromal cells, regulatory T cells and dendritic cells. We will also focus on less familiar cell types that are used in cell therapy, including B cells, natural killer cells and peripheral blood mononuclear cells. We will address key issues regarding the depicted therapies and highlight the major challenges that lie ahead to successfully reverse autoimmune diseases, such as MS, while minimising the side effects. Although cell-based therapies are well known and used in the treatment of several cancers, cell-based treatment options hold promise for the future treatment of autoimmune diseases in general, and MS in particular.

Arabidopsis AtCNGC10 rescues potassium channel mutants of E. coli, yeast and Arabidopsis and is regulated by calcium/calmodulin and cyclic GMP in E. coli

2005 ◽  
Vol 32 (7) ◽  
pp. 643 ◽  
Author(s):  
Xinli Li ◽  
Tamás Borsics ◽  
H. Michael Harrington ◽  
David A. Christopher
Keyword(s):  
Channel Blocker ◽  
K Channel ◽  
Structure Characteristic ◽  
Dependent Manner ◽  
Wild Type ◽  
Yeast Saccharomyces Cerevisiae ◽  
E Coli ◽  
Diverse Species ◽  
The Family ◽  
Low K

We have isolated and characterised AtCNGC10, one of the 20 members of the family of cyclic nucleotide (CN)-gated and calmodulin (CaM)-regulated channels (CNGCs) from Arabidopsis thaliana (L.) Heynh. AtCNGC10 bound CaM in a C-terminal subregion that contains a basic amphiphillic structure characteristic of CaM-binding proteins and that also overlaps with the predicted CN-binding domain. AtCNGC10 is insensitive to the broad-range K+ channel blocker, tetraethylammonium, and lacks a typical K+-signature motif. However, AtCNGC10 complemented K+ channel uptake mutants of Escherichia coli (LB650), yeast (Saccharomyces cerevisiae CY162) and Arabidopsis (akt1-1). Sense 35S-AtCNGC10 transformed into the Arabidopsis akt1-1 mutant, grew 1.7-fold better on K+-limited medium relative to the vector control. Coexpression of CaM and AtCNGC10 in E. coli showed that Ca2+ / CaM inhibited cell growth by 40%, while cGMP reversed the inhibition by Ca2+ / CaM, in a AtCNGC10-dependent manner. AtCNGC10 did not confer tolerance to Cs+ in E. coli, however, it confers tolerance to toxic levels of Na+ and Cs+ in the yeast K+ uptake mutant grown on low K+ medium. Antisense AtCNGC10 plants had 50% less potassium than wild type Columbia. Taken together, the studies from three evolutionarily diverse species demonstrated a role for the CaM-binding channel, AtCNGC10, in mediating the uptake of K+ in plants.

Sign in / Sign up

Export Citation Format

Share Document