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Механистическая и структурная основа канала Kv ингибируется с помощью 4-аминопиридина.

Ингибирование каналов Kv с помощью 4-аминопиридина (4AP) улучшает моторную функцию при множественном склерозе, повышая нейронную активность. Механизм сдерживания и структурная основа 4AP, связывающая каналы Kv, остаются неясными. Здесь мы определили структуру мутатата Shaker V369I-I372L-S376T (ILT), примыкающего к 4AP на 3,3a, показав, что 4AP связывается с закрытым состоянием канала. Эта структура не совместима с механизмом открытых каналов. Эксперименты в области электрофизиологии показывают, что 4AP связывается даже тогда, когда внутриклеточный доступ к поре блокирован, что говорит о том, ч

Совпадение в аннотации оригинала
Inhibition of Kv channels by 4-aminopyridine (4AP) improves motor function in multiple sclerosis by enhancing neuronal excitability. The mechanism of inhibition and the structural basis of 4AP binding to Kv channels remain unclear. Here, we determined the structure of the Shaker V369I-I372L-S376T (ILT) mutant bound to 4AP at 3.3Å, demonstrating that 4AP bind…

Antagonism of xylazine and ketamine anesthesia by 4-aminopyridine and yohimbine in geldings.

Thirty-six fasted, mixed horse breed geldings (6 groups of 6 animals each) were anesthetized with xylazine and ketamine, and when maximally sedated, were given 1 of the following antagonists: saline solution, 4-aminopyridine (4-AP), small-dose yohimbine, large-dose yohimbine, 4-AP plus low-dose yohimbine, or 4-AP plus high-dose yohimbine. Measured data included mean standing time (MST), heart rate, respiratory rate, rectal temperature, and mean total recovery time ( MTRT ). Emergence phenomena were also observed and recorded as smooth, fairly smooth, fairly rough, or rough. Groups given 4-AP a…

Behavioral and cardiorespiratory responses to 4-aminopyridine in healthy awake horses.

4-Aminopyridine was administered in incremental IV doses to healthy horses to evaluate cardiorespiratory and behavioral effects. Doses of 100 micrograms/kg produced apparent sensory discomfort, manifested by wiggling or curling of the lips and tongue, arching or stretching the neck, snorting, squealing, and coughing. At cumulative dosages of 300 to 500 micrograms/kg, muscle tremors, a stilted gait, and signs of excitement occurred. Once signs of excitement occurred, additional administration of 4-aminopyridine resulted in prolonged excitement consisting of severe muscle tremors and exaggerated…

Effects of 4-aminopyridine on normal and demyelinated mammalian nerve fibres.

We have previously demonstrated that a drug which prolongs action potentials can, like a reduction in temperature, overcome conduction failure in demyelinated nerve fibres. Although the particular substance then used, a scorpion venom, was not a suitable therapeutic agent, we suggested that other drugs, with similar but milder effects on the action potential, might be effective in the symptomatic treatment of multiple sclerosis. We now report some encouraging results obtained with 4-amino-pyridine (4AP), a substance which blocks the voltage-dependent potassium current in squid giant axons. The

Recovery from the lethal effects of saxitoxin: a therapeutic window for 4-aminopyridine (4-AP).

We have shown that saxitoxin (STX) induced lethality can be reversed by 4-AP when it is administered at the time of respiratory arrest [Benton, B. J., Spriggs, D. L., Capacio, B. R. and Chang, F.-C. T. (1995) 4-Aminopyridine antagonizes the lethal effects of saxitoxin (STX) and tetrodotoxin (TTX). International Society of Toxicology, 5th Pan American Symposium on Animal, Plant and Microbial Toxins, Frederick, MD. July/August 1995, p. 217]. The purpose of this study was to determine whether 4-AP's efficacy could be enhanced further when administered at different times relative to STX intoxicati…

4-Aminopyridine in pediatric traumatic spinal cord injury: A case report.

Context: Spinal cord injury (SCI) presents significant challenges due to its debilitating nature and potential complications. While few medications have shown efficacy in improving neurological recovery, 4-Aminopyridine (4-AP), a voltage-gated potassium channel blocker, has been used clinically off-label to improve neurologic function in adults with spinal cord-related paralysis. However, evidence regarding its safety and effectiveness in the pediatric population remains scarce, as it is approved for use in older patients.Findings: This manuscript reports the case of a pediatric patient who su…

4-aminopyridine activates a cholinergic chloride conductance in isolated Helix neurons.

Isolated Helix neurons were internally perfused under voltage-clamp, with drugs applied by the 'concentration clamp' which allowed an extremely rapid switching of the external solution. 4-Aminopyridine (4-AP) at more than 3 X 10(-4) M induced a chloride current (ICl) which could be blocked by D-tubocurarine. Acetylcholine (ACh) also induced ICl which was similarly blocked. Simultaneous application of 4-AP and ACh resulted in potentiation of ICl over the sum of respective currents. When preceded by either one, the other ICl was reduced in size, showing cross-desensitization. These data indicate…

Тематическая доставка 4-аминопиридина усиливает процесс регенерации кожи в обожженных ранах.

Обжигающие раны представляют собой обычное травматическое повреждение, которое ухудшает клеточную функцию и затрудняет процесс выздоровления, часто приводящее к значительным потерям кожи. Хотя автологический пересадка кожи считается золотым стандартом для обработки ожогов, ее широкое применение ограничено из-за заболеваемости на местах у доноров и потребности в больших количествах тканей. Традиционные повязки и методы лечения ран часто не обеспечивают полного выздоровления. Поскольку первоначально УЛХ одобрило лечение множественных склерозов, было также продемонстрировано, что 4-аминопиридин (

Совпадение в аннотации оригинала
Burn wounds are a common traumatic injury that impair cellular function and hinder the healing process, often resulting in significant skin … s often fail to ensure complete recovery. Being initially FDA-approved to treat multiple sclerosis, 4-aminopyridine (4-AP) has also been shown to accelerate burn wound closure by transforming keratinocytes and fibroblasts when administered systemically. However, prolonged systemic use of 4-AP can lead to significant side effects. In this study, we aimed to repurp …

Pharmacological inhibition of brain carbonic anhydrase protects against 4-aminopyridine seizures.

The effects of the inhibition of carbonic anhydrase on the manifestation of tonic-clonic seizures were investigated in freely-moving rats. 4-Aminopyridine, a specific blocker of the neuronal K+ channels was used to produce generalized convulsions. After pretreatment of adult male rats with 20 or 40 mg/kg acetazolamide, 3, 5, 7 or 9 mg/kg 4-aminopyridine was injected intraperitoneally and the latencies of the symptoms were measured. Pharmacological inhibition of brain carbonic anhydrase significantly increased the latency of onset of seizures. Bolus administration of acetazolamide decreased the…

4-Aminopyridine Promotes BMP2 Expression and Accelerates Tibial Fracture Healing in Mice.

BACKGROUND: Delayed bone healing is common in orthopaedic clinical care. Agents that alter cell function to enhance healing would change treatment paradigms. 4-aminopyridine (4-AP) is a U.S. Food and Drug Administration (FDA)-approved drug shown to improve walking in patients with chronic neurological disorders. We recently showed 4-AP's positive effects in the setting of nerve, wound, and even combined multi-tissue limb injury. Here, we directly investigated the effects of 4-AP on bone fracture healing, where differentiation of mesenchymal stem cells into osteoblasts is crucial. METHODS: All…

Mortality with brainstem seizures from focal 4-aminopyridine-induced recurrent hippocampal seizures.

OBJECTIVE: Sudden unexplained death in epilepsy is the leading cause of death in young adult epilepsy patients, typically occurring during the early postictal period, presumably resulting from brainstem and cardiorespiratory dysfunction. We hypothesized that ictal discharges in the brainstem disrupt the cardiorespiratory network, causing mortality. To study this hypothesis, we chose an animal model comprising focal unilateral hippocampal injection of 4-aminopyridine (4-AP), which produced focal recurrent hippocampal seizures with secondary generalization in awake, behaving rats. METHODS: We s…

4-Aminopyridine promotes functional recovery and remyelination in acute peripheral nerve injury.

Traumatic peripheral nerve damage is a major medical problem without effective treatment options. In repurposing studies on 4-aminopyridine (4-AP), a potassium channel blocker that provides symptomatic relief in some chronic neurological afflictions, we discovered this agent offers significant promise as a small molecule regenerative agent for acute traumatic nerve injury. We found, in a mouse model of sciatic crush injury, that sustained early 4-AP administration increased the speed and extent of behavioral recovery too rapidly to be explained by axonal regeneration. Further studies demonstra…

Effects of cholinergic drugs and 4-aminopyridine on cat ciliary muscle contractility.

The effects of some cholinergic agents and 4-aminopyridine (4-AP) on neurally mediated contractions of in vitro cat ciliary muscle preparations were studied. The contractile response to trains of stimuli was enhanced by eserine and completely blocked by tetrodotoxin or atropine. Low concentrations of carbachol did not modify muscle resting tension but clearly attenuated contractile response to electrical stimuli, while higher concentrations increased the resting tonus leading to contracture which did not respond to further stimulation. 4-AP is known to be a potassium-channel blocking drug that…

Noradrenergic modulation of 4-aminopyridine-induced acetylcholine release from rat cerebral cortex.

The noradrenergic influence on cortical acetylcholine (ACh) release was investigated by the cortical cup technique in urethane anaestetized rats treated with 4-aminopyridine (4-AP). The following results were obtained: 1) The increase in ACh release induced by 4-AP (3 mg/kg i.p.) was strongly potentiated by pretreatment with -methyl-p-tyrosine (alpha-MPT) which inhibits catecholamine biosynthesis or by N-(2-chloroethyl)-N-ethyl-bromobenzylamine (DSP4) bringing about a selective degeneration of noradrenergic fibres. Neither pretreatment enhanced the spontaneous ACh output. 2) Pretreatment with …

4-aminopyridine-loaded topical gel for promoting skin regeneration in burn injuries.

Burn wounds are a common traumatic injury that impair cellular function and hinder the healing process, often resulting in significant skin loss. While autologous skin grafting is considered the gold standard for treating burns, its widespread use is limited due to donor site morbidity and the requirement for large amounts of tissue. Traditional wound dressings and treatments often fail to ensure complete recovery. Being initially FDA-approved to treat multiple sclerosis, 4-aminopyridine (4-AP) has also been shown to accelerate burn wound closure by modulating keratinocytes and fibroblasts whe…

Protective effects of 4-aminopyridine in experimental optic neuritis and multiple sclerosis.

Chronic disability in multiple sclerosis is linked to neuroaxonal degeneration. 4-aminopyridine (4-AP) is used and licensed as a symptomatic treatment to ameliorate ambulatory disability in multiple sclerosis. The presumed mode of action is via blockade of axonal voltage gated potassium channels, thereby enhancing conduction in demyelinated axons. In this study, we provide evidence that in addition to those symptomatic effects, 4-AP can prevent neuroaxonal loss in the CNS. Using in vivo optical coherence tomography imaging, visual function testing and histologic assessment, we observed a reduc…

4-Aminopyridine attenuates muscle atrophy after sciatic nerve crush injury in mice.

INTRODUCTION: We recently demonstrated the beneficial effects of 4-aminopyridine (4-AP), a potassium channel blocker, in enhancing remyelination and recovery of nerve conduction velocity and motor function after sciatic nerve crush injury in mice. Although muscle atrophy occurs very rapidly after nerve injury, the effect of 4-AP on muscle atrophy and intrinsic muscle contractile function is largely unknown. METHODS: Mice were assigned to sciatic nerve crush injury and no-injury groups and were followed for 3, 7, and 14 days with/without 4-AP or saline treatment. Morphological, functional, and…

Pulmonary arterial hypertension in patient treated for multiple sclerosis with 4-aminopyridine.

4-Aminopyridine (4-AP) is a recent treatment indicated to improve walking in patient with multiple sclerosis. We report the first case of pulmonary arterial hypertension (PAH) that we attribute to the use of 4-AP. A 64-year-old woman with multiple sclerosis presented with dyspnea. After excluding other secondary causes of pulmonary hypertension, a diagnosis of severe PAH due to 4-AP was made based on right heart catheterization. History revealed that the dyspnea began with the initiation of 4-AP. After discontinuation of 4-AP therapy and initiation of ambrisentan and tadalafil, dyspnea and pul…

4-aminopyridine restores vertical and horizontal neural integrator function in downbeat nystagmus.

Downbeat nystagmus (DBN), the most common form of acquired fixation nystagmus, is often caused by cerebellar degeneration, especially if the vestibulo-cerebellum is involved. The upward ocular drift in DBN has a spontaneous and a vertical gaze-evoked component. Since cerebellar involvement is suspected to be the underlying pathomechanism of DBN, we tested in 15 patients with DBN whether the application of the potassium-channel blocker 4-aminopyridine (4-AP), which increases the excitability of cerebellar Purkinje cells as shown in animal experiments, reduces the vertical ocular drift leading t…