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A centro-symmetric crystal of 4-aminopyridinium 2-chloro-5-nitrobenzoate (4A2Cl5NB) has been grown by the slow evaporation method, and its molecular structure has been confirmed by powder X-ray diffraction using GSAS software; Hirshfeld surface analysis has been carried out to analyze the intermolecular interaction through hydrogen bonding in the molecular structure; and vibration frequencies have been assigned by FTIR spectral studies. UV visible absorption occurs at the lower cut-off wavelength of 266 nm, and the optical band gap was found to be Eg = 4.1 eV. A broad emission band was observed at 482 nm in the luminescence spectrum. Thermo-gravimeter and differential thermal (TG–DTA) analysis were carried out. Micro-hardness studies of grown crystals are discussed. A dielectric study reveals a low dielectric constant and loss at higher frequencies, attesting to nonlinear optical activity. Cyclic Volta-metric studies were also analyzed. The second harmonic generation efficiency of the (4A2Cl5NB) crystal is 4.8 times superior to that of the KDP crystal. [ABSTRACT FROM AUTHOR]

4-Aminopyridine, a small molecule has attracted considerable interest within the neuroscience and pharmacology communities owing to its capacity to augment neural transmission. Over the course of time, scientists have come to acknowledge the potential of this phenomenon in augmenting synaptic transmission and mitigating neurological disorders. The transition from its fortuitous revelation to its intentional medicinal application has facilitated the progress of neuroscience investigations. The investigation conducted on the physicochemical features of analogues of 4-aminopyridine has yielded significant findings on their many attributes, including solubility, propensity for lipid interactions, and affinity for selective receptor binding. The mechanism of action entails the inhibition of voltage-gated potassium channels, resulting in the elongation of action potentials and heightened release of neurotransmitters. This, in turn, facilitates enhanced neuronal signalling. The recent emergence of nanoformulations has significantly transformed the administration and therapeutic capabilities of 4-aminopyridine. Formulations utilizing nanotechnology exhibit enhanced drug stability, precise control over release kinetics, and improved bioavailability. These technological advancements have created novel opportunities for the implementation of personalized medicine and targeted therapies within the field of neurology. This comprehensive review provides an overview of the historical context, structural analogues, physicochemical characteristics, and therapeutic effects of 4-aminopyridine on neural transmission. Additionally, this study emphasizes the potential of nanoformulations in improving the effectiveness of 4-aminopyridine – based treatments and suggests a promising outlook for their application in neurological disorders. Ongoing scientific investigation and advancement in this domain are imperative for fully harnessing the capabilities of 4-aminopyridine and its derivatives in the field of neurotherapeutics. [ABSTRACT FROM AUTHOR]

Various pharmacological blockers targeting K+ channel have been identified to be related to the treatment of Parkinson's disease (PD). Previous studies showed that 4-Aminopyridine (4-AP), a wide-spectrum K+ channel blocker, was able to attenuate apomorphine-induced rotation in parkinsonism rats, indicating the possible beneficial effects in attenuation of PD motor symptoms. However, it is unclear whether 4-AP exhibits neuroprotective effects against the neurodegeneration of substantia nigra (SN)-striatum system in PD. In this study, the 1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-treated mouse model was employed to evaluate the neuroprotective effects of 4-AP. Results showed that 4-AP inhibited MPTP-induced dopaminergic neuronal loss in the SN as well as dopamine depletion in the striatum. Behavior indexes of open field test and rotarod test confirmed that 4-AP attenuated MPTP-induced motor deficits. We also showed that 4-AP treatment could significantly attenuate the MPTP-induced increase in malonaldehyde (MDA) levels and decrease in superoxide dismutase (SOD) levels. Additionally, MPTP significantly reduced the Bcl-2 expression and promoted the Caspase-3 activation; 4-AP protected dopaminergic neurons against MPTP-induced neurotoxicity by reversing these changes. These results indicate that 4-AP exerts a neuroprotective effect on dopaminergic neurons against MPTP by decreasing oxidative stress and apoptosis. This provides a promising therapeutic target for the treatment of PD. [ABSTRACT FROM AUTHOR]

Herein, graphene oxide (GO) was synthesized using a standard and well-known chemical method (Hummer's). Whereas for the first time, reduced graphene oxide (rGO) was prepared using a simple greener method involving aqueous floral extract of Clitoria ternatea (CT) as a green reducer. The 4-aminopyridine (4AP) organic heterocyclic molecule was covalently grafted on the rGO layer via reaction of nucleophilic substitution. The prepared materials were analysed by Fourier transform infrared spectroscopy (FTIR), UV–visible spectroscopy, Raman spectroscopy, X-ray photoelectron spectroscopy (XPS), powder X-ray diffraction measurements (XRD), and scanning electron microscopy (SEM). A number of experimental conditions including scan rate, pH, supporting electrolytes, applied voltage and incubation time were investigated to optimize conditions for obtaining strong signal of the target analyte. The 4AP-rGO/SPCE nanocomposites offer intriguing application prospects in electrochemical lead ion sensors. The 4AP functional on rGO improves the electrochemical performance of the electrode. A 4AP-rGO/SPCE-modified screen-printed carbon electrode exhibits high sensitivity of 0.043 µA pM−1 for lead ion sensing, having a low detection limit (LOD) of 0.597 pM. These results demonstrate the capabilities of the 4AP-rGO/SPCE electrode adopted for the development of highly sensitive electrochemical lead ion sensors by employing differential pulse voltammetry (DPV). Moreover, designed electrochemical sensor was successfully employed to detect lead ions in tap water sample. [ABSTRACT FROM AUTHOR]

Silver nanoparticles (Ag NPs) were synthesised by the reduction of Ag+ to Ag0 in the presence of enol form of flavonoids present in plant extract of Tabernaemontana divaricate (T. divaricate). Prepared Ag NPs were characterised using UV–Vis, XRD, HR-TEM with EDX and XPS techniques. XPS spectra exhibited peaks at 366 eV and 373 eV, which specified spin orbits for Ag 3d3/2, and Ag 3d5/2 that confirmed the formation of Ag NPs. Ag NPs were spherical in shape with an average size of 30 nm as revealed by HR-TEM and FE-SEM techniques. EDX studies verified the high purity of Ag NPs with silver 46.96%, carbon 16.35%, oxygen 16.22%, nitrogen 20.25% and sulphur 0.21%. LC–MS analysis of plant extract confirmed the qualitative presence of alkaloids, tannins, flavonoids, phenols, and carbohydrates. Prepared Ag NPs showed good photocatalytic activity towards degradation of 4-Amniopyridine with 61% degradation efficiency at optimum conditions in 2 h of reaction time under visible light. The ten intermediates were found within the mass number of 0–450. Ag NPs synthesised using bio-extract have also shown good inactivation against Escherichia coli (E. coli) and Bacillus subtilis (B. subtilis) bacteria due to the availability of free radicals. [ABSTRACT FROM AUTHOR]

Purpose: [18F]3F4AP is a novel PET radiotracer that targets voltage-gated potassium (K+) channels and has shown promise for imaging demyelinated lesions in animal models of neurological diseases. This study aimed to evaluate the biodistribution, safety, and radiation dosimetry of [18F]3F4AP in healthy human volunteers. Methods: Four healthy volunteers (2 females) underwent a 4-h dynamic PET scan from the cranial vertex to mid-thigh using multiple bed positions after administration of 368 ± 17.9 MBq (9.94 ± 0.48 mCi) of [18F]3F4AP. Volumes of interest for relevant organs were manually drawn guided by the CT, and PET images and time-activity curves (TACs) were extracted. Radiation dosimetry was estimated from the integrated TACs using OLINDA software. Safety assessments included measuring vital signs immediately before and after the scan, monitoring for adverse events, and obtaining a comprehensive metabolic panel and electrocardiogram within 30 days before and after the scan. Results: [18F]3F4AP distributed throughout the body with the highest levels of activity in the kidneys, urinary bladder, stomach, liver, spleen, and brain and with low accumulation in muscle and fat. The tracer cleared quickly from circulation and from most organs. The clearance of the tracer was noticeably faster than previously reported in nonhuman primates (NHPs). The average effective dose (ED) across all subjects was 12.1 ± 2.2 μSv/MBq, which is lower than the estimated ED from the NHP studies (21.6 ± 0.6 μSv/MBq) as well as the ED of other fluorine-18 radiotracers such as [18F]FDG (~ 20 μSv/MBq). No differences in ED between males and females were observed. No substantial changes in safety assessments or adverse events were recorded. Conclusion: The biodistribution and radiation dosimetry of [18F]3F4AP in humans are reported for the first time. The average total ED across four subjects was lower than most 18F-labeled PET tracers. The tracer and study procedures were well tolerated, and no adverse events occurred. [ABSTRACT FROM AUTHOR]

Background: Endometrial cancer is the most common gynecological cancer in developed countries. Potassium channels, which have many types, are suggested to play a major role in cancer progression. However, their role in endometrial cancer has not been fully investigated. We aimed to demonstrate whether the ATP-sensitive potassium channel blocker glibenclamide, voltage-sensitive potassium channel blocker 4-aminopyridine, non-selective (voltage-sensitive and calcium-activated) potassium channels blocker tetraethylammonium and potassium chloride (KCl) have any effect on the proliferation and migration of HEC1-A cells. Methods and results: Proliferation and migration were evaluated by real-time cell analysis (xCELLigence system) and wound healing assays, respectively. Proliferation was reduced by glibenclamide (0.1 and 0.2 mM, P < 0.05 and P < 0.01, respectively), 4-aminopyridine (10 and 20 mM, P < 0.001) and tetraethylammonium (10 and 20 mM, P < 0.01 and P < 0.001, respectively). However, KCl did not change the proliferation. Migration was reduced by glibenclamide (0.01, 0.1 and 0.2 mM, P < 0.001, P < 0.001 and P < 0.01, respectively) and 4-aminopyridine (10 and 20 mM, P < 0.05 and P < 0.01, respectively). Tetraethylammonium did not change migration. However, KCl reduced it (10, 25 and 50 mM, P < 0.05, P < 0.01 and P < 0.01, respectively). Both proliferation and migration were reduced by glibenclamide and 4-aminopyridine. However, tetraethylammonium only reduced proliferation and KCl only reduced migration. Conclusions: Potassium channels have an important role in HEC1-A cell proliferation and migration and potassium channel blockers needs to be further investigated for their therapeutic effect in endometrial cancer. [ABSTRACT FROM AUTHOR]

Background: Preparation of Ipomoea asarifolia (Desr.) (Convolvulaceae) is widely used in traditional African medicine for the treatment of different kinds of ailments such as syphilis, malaria, convulsions and rheumatism. Aim: The present study examined the median lethal dose (LD50) and possible anti-seizure potentials of Ipomoea asarifolia ethanolic leaf extract using acute seizure models. Results: The intraperitoneal LD50 of Ipomoea asarifolia ethanolic leaf extract in mice and chicks was found to be 2,150 mg/kg. The Ipomoea asarifolia ethanolic leaf extract has shown significantly (p < 0.05) delayed time for the onset of seizure against pentylenetetrazole- and strychnine-induced seizures in a non-dose dependent manner both at 300 mg/kg. The extract has also shown significant (p < 0.01, p < 0.001 and p < 0.001) delayed time for onset of seizures against 4-aminopyridine-induced seizure model in a dose-dependent manner at doses of 150, 300 and 600 mg/kg respectively. The extract has not shown appreciable activity against picrotoxin and maximum electroshock-induced seizure models. Conclusions: The present study revealed that Ipomoea asarifolia ethanolic leaf extract possesses anti-seizure properties which supports its folkloric use for the management of convulsions. [ABSTRACT FROM AUTHOR]

The aim of this study was to assess the effect of newly synthesized derivatives of 4-aminopyridine (4-AP) on cuprizone-induced model of brain demyelination in mice. 4-AP is already approved for the treatment of walking difficulties in patients with multiple sclerosis. The model of demyelination was carried out by the administration of cuprizone to the drinking water of the experimental mice. Besides cuprizone, 4-AP derivatives and 4-AP were administered to the groups in order to assess their protective effect on the demyelination. We used immunohistochemistry for visualization of changes in corpus callosum. Memory storage processes were also assessed with the passive avoidance test on the last two days of the experiment. The experimental mice treated with compounds 4b and 4c increased significantly their latency time on the second day in comparison to the control group which indicated an improved memory process. The number of mature oligodendrocytes in the groups treated with compounds 4b, 4c and 4-AP is closer to those in the control group. The results of our studies showed that the newly synthesized compounds 4b and 4c reverse the effect of cuprizone. These groups also showed increased latency time in the passive avoidance test in comparison to the control group. [ABSTRACT FROM AUTHOR]

Objective: 4-Aminopyridine (4-AP) is a potassium channel blocker that enhances nerve excitability. In this study, rat models that have facial nerve crush injury (FNCI) were grouped and treated with methylprednisolone (MP), 4-AP, and a combination of these two drugs. Electrophysiologic and histopathologic outcomes of these groups will be compared with a control group. Materials and methods: Thirty healthy male Wistar rats (mean weight of 265 g) were used in this study. The rats were randomly divided into five groups with six subjects in each: Group 1 (sham group), Group 2 (control group), Group 3 (MP group), Group 4 (4-aminopyridine group), and Group 5 (4-AP + MP group). All groups except the sham group underwent crush injury to the right facial nerve. Electrophysiologic and histologic recovery was recorded three weeks postoperatively. Results: The 4-AP group and the combined group had a more significant recovery at Nerve Excitability Thresholds (NET) at the end of three weeks. The methylprednisolone group and the control group had a minimal recovery of NET. Histologically, when compared with the control group, the combined group was the only group that had significant recovery at all three of axonal degeneration, axon diameter, and myelin thickness. Conclusion: In this experimental study, we demonstrated that a combination treatment of 4-AP and MP is more effective in the recovery of peripheric FNCI than in the no-treatment control group and in the 4-AP- or MP-alone groups. Moreover, our results suggested that 4-AP can be a potent alternative to MP in the treatment of the FNCI. Level of evidence: N/A. [ABSTRACT FROM AUTHOR]

Background: Episodic ataxia type 2 is an autosomal dominant channelopathy, caused by genetic variants in the voltage-dependent calcium channel a-1 subunit (CACNA1A), which is characterized by intermittent episodes of vertigo and ataxia. A slow progression of cerebellar signs is commonly observed in the course of the disease. Treatment with the carbonic anhydrase inhibitor acetazolamide is recommended.Methods: We report the cases of two patients with EA-2 and migraine, linked to a novel CACNA1A mutation associated with disabling ictal and interictal disease, which did not respond to acetazolamide.Results: A 30-year-old woman and a 50-year-old man, who was a ski instructor, reported disabling episodes of rotatory vertigo and progressive interictal ataxia. In both cases, the disease progressed despite treatment with acetazolamide. The concomitant use of topiramate and 4-aminopyridine significantly reduced the frequency and severity of relapses and migraine and improved the interictal cerebellar progression in both cases.Conclusions: We propose combined applications of topiramate and 4-aminopyridine in refractory cases and those with poor tolerance to acetazolamide and also in those with frequent associated migraine. The effectiveness of this combination of drugs for treating intermittent ataxic episodes and interictal signs in EA-2 has not been previously reported. [ABSTRACT FROM AUTHOR]

Cuprous oxide nanoparticles (Cu2O NPs) were synthesized using Tabernaemontana divaricate leaves extract, a reducing and stabilizing agent. Prepared Cu2O NPs were characterized by FT-IR, XPS, XRD and EDX. FT-IR analysis of Cu2O NPs showed a sharp peak at 610 cm−1 attributed to the vibration mode of Cu (I)–O. XPS spectra of Cu2O NPs exhibited peaks at 932.5 eV and 952.6 eV which indicated the presence of Cu 2p3/2 and Cu 2p1/2 and confirmed the formation of Cu2O NPs. Synthesized Cu2O NPs have a cubical and hexagonal shape with an average size length of 85 nm. EDX studies confirmed the high purity of Cu2O NPs with 81.72% copper, 11.05% oxygen and 6.05% carbon. The photocatalytic degradation of 4-aminopyridine onto Cu2O NPs in visible light showed 80% degradation efficiency, 82% chemical oxygen demand removal and 65% total organic carbon (TOC) removal after 235 min of reaction time at pH 3. Lumped kinetic model (LK) for TOC removal of 4-aminopyridine using Cu2O NPs showed a high value of regression coefficient (R2 = 0.99) which emphasized that the experimental data are best fitted to the model. Ten intermediate fragments were detected in LC–MS spectra based on mass-to-charge ratio (m/z) after 235 min of reaction time. [ABSTRACT FROM AUTHOR]

Two novel, amino-substituted [FeFe]-hydrogenase model compounds were synthesized and characterized using IR, NMR, mass and UV–Vis spectroscopies as well as elemental analysis. The electrochemical properties (cyclic voltammetry) and catalytic performances of compounds 1 and 2 for the hydroxylation of benzene were investigated. The reduction peaks of compounds 1 and 2 were observed at − 1.93 V, which agrees with the value of the electron density of diiron centers. Compounds 1 and 2 nearly the same electron density around the Fe–Fe bond, but the position of –NH2 group on the pyridine ring largely influenced the stability. Compound 1 demonstrated a higher phenol yield (equal to 12.8%) than compound 2 (10.2%). The biomimetic catalyst formed by the 4-aminopyridine ligand with two iron nuclei, resembling an enzyme active site, had better stability and higher catalytic activity than the 2-aminopyridine derivative. Compared the catalytic performance of complexes 1–2, despite 1 and 2 have the same electron density around the Fe–Fe bond, the 4-aminopyridine derivative 1 (12.8%) was more stable and with better catalytic activity compared to 2-aminopyridine derivative 2 (10.2%) [ABSTRACT FROM AUTHOR]

Studies have indicated that epilepsy, an important neurological disease, can generate oxidative stress and mitochondrial dysfunction, among other damages to the brain. In this context, the use of antioxidant compounds could provide neuroprotection and help to reduce the damage caused by epileptic seizures and thereby the use of anticonvulsant drugs. Rosmarinic acid (RA) is an ester of caffeic acid and 3,4-dihydroxyphenylactic acid that prevents cell damage caused by free radicals, acting as an antioxidant. It also presents anti-inflammatory, antimutagenic, and antiapoptotic properties. In this work, we used two models of acute seizure, 4-aminopyridine (4-AP) and picrotoxin (PTX)-induced seizures in mice, to investigate the anticonvulsant, antioxidant, and neuroprotective profile of RA. Diazepam and valproic acid, antiepileptic drugs already used in the treatment of epilepsy, were used as positive controls. Although RA could not prevent seizures in the models used in this study, neither enhance the latency time to first seizure at the tested doses, it exhibited an antioxidant and neuroprotective effect. RA (8 and 16 mg/kg) decreased reactive oxygen species production, superoxide dismutase activity, and DNA damage, measured in hippocampus, after seizures induced by PTX and 4-AP. Catalase activity was decreased by RA only after seizures induced by 4-AP. The activity of the mitochondrial complex II was increased by RA in hippocampus samples after both seizure models. The results obtained in this study suggest that RA is able to reduce cell damage generated by the 4-AP and PTX seizures and therefore could represent a potential candidate in reducing pathophysiological processes involved in epilepsy. [ABSTRACT FROM AUTHOR]

The reactions of 2-, 3-, 4-aminopyridines or 4-aminoquinoline with hydrolytically stable tropylium salts (perchlorate or tetrafluoroborate) have afforded N-(1′-cyclohepta-2′,4′,6′-trienyl)-2-aminopyridine, N-(1′-cyclohepta-2′,4′,6′-trienyl)-3-aminopyridine, N-(1′-cyclohepta-2′,4′, 6′-trienyl)-4-aminopyridine, and N-(1′-cyclohepta-2′,4′,6′-trienyl)-4-aminoquinoline. The effect of imidazole and the tropylium salt anion on the yield and stability of the final reaction products has been studied. [ABSTRACT FROM AUTHOR]

Abstract 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 demonstrated that 4‐AP also enhanced recovery of nerve conduction velocity, promoted remyelination, and increased axonal area post‐injury. We additionally found that 4‐AP treatment enables distinction between incomplete and complete lesions more rapidly than existing approaches, thereby potentially addressing the critical challenge of more effectively distinguishing injured individuals who may require mutually exclusive treatment approaches. Thus, 4‐AP singularly provides both a new potential therapy to promote durable recovery and remyelination in acute peripheral nerve injury and a means of identifying lesions in which this therapy would be most likely to be of value.

The age-related dynamics of the ECoG and convulsive epileptiform activity induced by intracortical microinjections of 4-aminopyridine were studied in three groups of Wistar rats at ages corresponding to childhood (P20-30), adolescence (P30-45), and adulthood (P90-P120). With aging, ECoG spectral power was found to increase during waking and "sleep spindles" and to decrease during slow-wave sleep. Rats of adolescent age also showed statistically significant differences in measures of convulsive activity - mean frequency of peak-wave complexes - and the latent period of occurrence of epileptiform activity was greater than in childhood and adulthood. In addition, the total duration of epileptiform activity in rats of adolescent age was significantly lower than that in adult rats and rats at age P20-P30. The nervous system during the adolescent period may have specific protective mechanisms decreasing the intensity of convulsive activity (the ability to generate and propagate spike-wave activity), increasing resistance to epileptogen. [ABSTRACT FROM AUTHOR]

Changes in electrical activity of the neocortex after prenatal hypoxia (day 14 of embryogenesis, E14, 7% O for 3 h) and intracortical microinjection of epileptogenic 4-aminopyridine (4-AP) were studied in adult (3-month-old) rats. The frequency-time parameters of electrocorticogram (ECoG) were analyzed during sleep and wakefulness as well as in a model of 4-AP-induced spike-wave discharge (SWD) epileptiform activity. The results showed that in rats exposed to prenatal hypoxia the theta rhythm had a lower frequency while sleep spindles displayed a lower spectral power in the low-frequency range as compared to the control group. In rats with prenatal pathology, there was revealed a delayed onset of epileptiform activity and a shifted frequency distribution of the SWD spectral power induced by 4-AP. [ABSTRACT FROM AUTHOR]

Pharmacological treatment of cerebellar ataxias and cerebellar nystagmus still remains difficult. The efficacy of most of the agents recommended in the past for symptomatic or even causative therapy could not be proven in larger state-of-the art clinical trials. Exceptions are (a) 4-aminopyridine (4-AP) for episodic ataxia type 2 (EA2): one observational and one randomized controlled trial showed a significant effect on the number of attacks of ataxia and quality of life; (b) aminopyridines in cerebellar downbeat nystagmus (DBN): two randomized controlled trials and several observational studies demonstrate a significant improvement of the intensity of DBN, visual acuity, and postural imbalance. In both diseases the sustained-release form is evidently also efficient; (c) 4-AP in cerebellar gait ataxia: evidence comes from two observational studies. (d) chlorzoxazone in DBN which, however, was so far demonstrated in only one observational study; (e) the modified amino acid acetyl-DL-leucine: evidently effective in cerebellar ataxias, shown in three observational studies, one on patients with Niemann-Pick type C; its mode of action has to be evaluated in animal models and on a cellular/electrophysiological level. There are ongoing randomized placebo-controlled trials on EA2 with 4-AP versus acetazolamide (EAT-2-TREAT), cerebellar gait ataxia with 4-AP (FACEG), and a multinational trial on cerebellar ataxia with acetyl-DL-leucine (ALCAT). [ABSTRACT FROM AUTHOR]

GABA receptor-mediated inhibition-which is due to Cl and HCO currents controlled by KCC2 and carbonic anhydrase activity, respectively-contributes to short- and long-lasting interictal events recorded from the CA3 region of hippocampus during application of 4-aminopyridine (4AP, 50 μM). Here, we employed field potential recordings in an in vitro brain slice preparation to establish the effects induced by the KCC2 blockers VU0240551 (10 μM) or bumetanide (50 μM) and by the carbonic anhydrase inhibitor acetazolamide (10 μM) on the two types of interictal events. We found that blocking KCC2 activity decreased the amplitude of the short-lasting events. In addition, this pharmacological procedure increased the interval of occurrence of the long-lasting events and reduced their amplitude. Blocking carbonic anhydrase activity with acetazolamide reduced the interval of occurrence and the duration of the short-lasting events while increasing their amplitude; acetazolamide also reduced the duration and amplitude of the long-lasting events. Finally, blocking either KCC2 or carbonic anhydrase activity increased the interval of occurrence of pharmacologically isolated synchronous GABAergic events and decreased their duration and amplitude. These data substantiate further the role of GABA receptor-mediated signaling in driving neuronal populations toward hypersynchronous states presumably by increasing extracellular [K]. [ABSTRACT FROM AUTHOR]

Sustained-release fampridine (fampridine-SR) improves gait velocity and self-perceived capacities in people with multiple sclerosis (MS). However, little is known about the treatment's effect on temporospatial gait parameters, walking endurance, general fatigue, hand function and quality of life (QoL). We therefore sought to evaluate these parameters in a real-world setting: 120 consecutive, eligible patients with MS were evaluated at baseline (D0) and after two weeks (D14) of fampridine-SR. Lastly, D14 responders were again evaluated after three months (M3). Response to treatment was defined as a 15 % improvement in at least one of the following tests: the Timed 25-Foot-Walk (T25FW), the 2-min walk test (2MWT) and the Multiple Sclerosis Walking Scale (MSWS-12). Eighty-three patients (74 %) were found to be responders. The response rate was lower when assessed as a 20 % improvement in the T25FW (50.9 %), and this difference was particularly marked for fast-walking subjects (i.e. T25FW <8 s at baseline). Responders displayed mean improvements (at D14 and M3, respectively) of 34.5 and 35.5 % in the T25FW, 39 and 36.7 % in the 2MWT and 19 and 11.6 % in the MSWS-12. The increase in gait velocity was due to both a higher cadence and a greater step length. Responders showed also significant, lasting reductions in fatigue (visual analogue scale and the Fatigue Severity Scale; p < 10 at D14 and <0.01 at M3) and significant, lasting improvements in hand function (9 Hole Peg Test; p < 0.05) and QoL (SF-12; p < 0.01). In conclusion, several MS-induced symptoms other than gait velocity may be improved by fampridine-SR, even if this remains to be more specifically evaluated in future studies. [ABSTRACT FROM AUTHOR]

Entorhinal cortex is a highly epilepsy-prone brain region. Effects of repetitive seizures on ionotropic glutamate receptors (iGluRs) were investigated in rat entorhinal cortex slices. Seizures were induced by daily administration of 4-aminopyridine (4-AP). Electrophysiological, pharmacological and histological investigations were carried out to determine changes in synaptic efficacy and in sensitivity of iGluRs due to recurring seizures. Repeated 4-AP-induced seizures increased the amplitude of evoked synaptic field responses in rat entorhinal cortical slices. While vulnerability to inhibition of AMPA receptors by the specific antagonist GYKI 52466 was slightly reduced, responsiveness to NMDA receptor antagonist APV remained unaffected. Testing of bivalent cation permeability of iGluRs revealed reduced Ca-influx through non-NMDA receptors. According to the semi-quantitative histoblot analysis GluA1-4, GluA1, GluA2, GluK5, GluN1 and GluN2A subunit protein expression differently altered. While there was a marked decrease in the level of GluA1-4, GluA2 and GluK5 receptor subunits, GluA1 and GluN2A protein levels moderately increased. The results indicate that brief convulsions, repeated daily for 10 days can increase overall entorhinal cortex excitability despite a reduction in AMPA/kainate receptor activity, probably through the alteration of local network susceptibility. [ABSTRACT FROM AUTHOR]

A series of N-benzylidenepyridin-4-amines ( 1a-1j) were synthesized by refluxing 4-aminopyridine with various substituted aromatic aldehydes in toluene. The structures of the synthesized compounds were confirmed on the basis of IR, H NMR, C NMR, and mass spectroscopy data. The synthesized compounds were screened for anthelmintic activity on earth worms. Tested compounds showed paralysis time from 0.44 to 2.46 min and death time from 1.03 to 3.50 min, whereas the standard drugs albendazole and piperazine citrate showed paralysis time of 0.54 and 0.58 min and death time of 2.16 and 2.47 min, respectively, at the same concentration of 1 % m/V. Three compounds, including N-(2-hydroxybenzylidene)pyridin-4-amine ( 1e), N-(4-nitrobenzylidene)pyridin-4-amine ( 1h), and N-(4-methoxybenzylidene)pyridin-4-amine ( 1j), showed significant anthelmintic activity compared to the standard drugs. [ABSTRACT FROM AUTHOR]

Excitotoxicity due to excessive glutamatergic neurotransmission is a well-studied phenomenon that has been related to the mechanisms of neuronal death occurring in some disorders of the CNS. We have previously shown that the intrahippocampal perfusion by microdialysis of 4-aminopyridine (4-AP) in rats stimulates endogenous glutamate release from nerve endings and this results in excitotoxic effects such as immediate seizures and delayed neuronal death, due to the overactivation of N-methyl- d-aspartate (NMDA) receptors. To study whether mitochondrial energy dysfunction and oxidative stress could be involved in this 4-AP-induced excitotoxicity, we evaluated in awake rats the protective effect of several energy substrates and antioxidant compounds, using microdialysis, electroencephalographic (EEG) recording and histological analysis. The 4-AP-induced behavioral and EEG seizures, which progressed to status epilepticus in about 30 min, were prevented by the NMDA receptor antagonist MK-801, whereas acetoacetate, dl- and l-β-hydroxybutyrate did not protect against seizures but increased the latency to the onset of status epilepticus; pyruvate, α-ketoglutarate and glutathione ethyl ester did not show any protective effect. 4-AP also produced nearly complete loss of pyramidal neurons in CA1 and CA3 regions of the ipsilateral hippocampus 24 h after the experiment. MK-801 totally prevented this neuronal death and the energy substrates tested protected by about 50 %, whereas the antioxidants showed only a weak protection. We conclude that ketone bodies possess weak anticonvulsant effects and that energy metabolism impairment plays a more important role than oxidative stress in the delayed hippocampal neurodegeneration resulting from the excitotoxic action of 4-AP mediated by endogenous glutamate. [ABSTRACT FROM AUTHOR]

It is known that the mitochondrial ATP-sensitive potassium channel (mitoK) plays a key role in protecting myocardium during ischemia. We have suggested that the mechanism of this protection is associated with the potassium cycle in mitochondria. In this paper, for the first time, a direct proof was obtained of the existence of a cycle of potassium ions in rat liver mitochondria that are associated with the functioning of mitoK. Activation of the cycle was recorded by optical density changes of mitochondrial suspension in the form of two or three swelling-contraction waves of the organelles. Using activators and inhibitors of mitoK we showed that a significant role in the potassium cycle belongs to the channel. It was found that in vitro sildenafil has a direct effect on mitoK, being its activator. The results obtained indicate that the cardioprotective effect of sildenafil observed previously is associated with the activation of mitoK. In order to study the structure and volume changes of mitochondria in various stages of the cycle in the presence of potassium channel modulators, the electron microscopy studies of mitochondria preparations were carried out. A correlation between the optical density decrease of mitochondrial suspension and the swelling of mitochondria was revealed. The data obtained in this study suggest participation of mitoK in the protection of tissues from hypoxic damage. [ABSTRACT FROM AUTHOR]

The present study was to investigate the anticonvulsant and antiepileptogenic potential of thymol. Anticonvulsant activity of thymol (5-100 mg/kg i.p.) was studied using maximal electroshock, pentylenetetrazole (PTZ), strychnine and 4-aminopyridine (4-AP) models. Thymol at the selected dose was also studied for its effect on locomotion. Antiepileptogenic property of thymol (5-25 mg/kg) was evaluated using PTZ-induced kindling model along with its effect on malondialdehyde and glutathione levels. Thymol (50 and 100 mg/kg, i.p.) showed anticonvulsant activity against maximal electroshock and pentylenetetrazole (66.66 and 83.33 % protection at 50 and 100 mg/kg, respectively) model but not against strychnine and 4-aminopyridine models. Thymol exhibited decreased locomotor activity in dose-dependent manner at the same dose range. Thymol at the dose of (25 mg/kg, i.p.) significantly decreased the seizure score, increased glutathione levels and decreased malondialdehyde levels in pentylenetetrazole-induced kindling model. Thymol exhibited significant anticonvulsant and antiepileptogenic property. [ABSTRACT FROM AUTHOR]

Two homometal-organic coordination polymers, [Ba(CHNO)(HO)Ba(HO)]·(2HO) and [[Cu(CHNO)(CHN)]Cu(CHN)(HO)]·(6HO), have been synthesized and characterized by X-ray single-crystal diffraction. In the barium compound (the first example of chelidamic acid introduced into the alkaline earth metal organic framework), two independent barium ions are coordinated by water and chelidamic acid molecules in monocapped and bicapped square anti-prismatic geometries. The two independent chelidamic acid molecules bridge several alkaline earth metal ions assembling a layered metal organic structure. In the copper compound, chelidamic acid shows its versatility as a ligand since it bridges three copper ions, with the carboxylate O atoms, the hydroxyl O atom, and the pyridine N atom coordinating the 3D metal ions. 4-Aminopyridine and water as ligands complete the coordinating sphere of the two independent Cu ions in distorted octahedral geometries. The equilibrium constants for the chelidamic acid-4-aminopyridine proton transfer system and the stoichiometry and stability of complexation of this system with Cu(II) and Ba(II) ions in aqueous solution were investigated by potentiometric pH titration method. The stoichiometry of some complex species in solution was found to be similar to the cited crystalline metal ion complexes. Graphical Abstract: [Figure not available: see fulltext.] [ABSTRACT FROM AUTHOR]

4-Aminopyridine (4AP) potentiates acetylcholine (ACh) release by blocking potassium channel in axon terminal and can be used in the treatment of Alzheimer's type of dementia and cognitive disorder. It is reported that ACh is well related with memory and learning. On the basis of these fact, we decided to synthesis and evaluate some new Schiff bases of 4AP (SBAPs) for their putative cognition enhancing, antiamnesic, and anticholinesterase activity. The synthesized and purified SBAPs were characterized by elemental analysis, UV, FTIR, H-, and C-NMR. SBAPs facilitated the learning on elevated plus maze model and they also significantly reversed the scopolamine-induced amnesia on the same model. The effect of SBAPs on learning and memory was qualitatively similar to standard nootropic drug piracetam used. The SBAPs were found to inhibit acetylcholinesterase enzyme significantly in specific brain regions prefrontal cortex, hippocampus, and hypothalamus. Thus, SBAPs derivatives showed cognitive and antiamnesic activities in the model tested and these effects may probably be due to their anticholinesterase activity. [ABSTRACT FROM AUTHOR]

Introduction: 4-Aminopyridine (4-AP) selectively blocks voltage-gated potassium channels, prolongs the action potential, increases calcium influx, and subsequently, enhances interneuronal and neuromuscular synaptic transmission. This medication has been studied and used in many disease processes hallmarked by poor neuronal transmission in both the central and peripheral nervous systems including: multiple sclerosis (MS), spinal cord injuries (SCI), botulism, Lambert-Eaton syndrome, and myasthenia gravis. It has also been postulated as a potential treatment of verapamil toxicity and reversal agent for anesthesia-induced neuromuscular blockade. To date, there have been limited reports of either intentional or accidental 4-AP toxicity in humans. Both a case of a patient with 4-AP toxicity and review of the literature are discussed, highlighting commonalities observed in overdose. Case Report: A 37-year-old man with progressive MS presented with diaphoresis, delirium, agitation, and choreathetoid movements after a presumed 4-AP overdose. 4-AP concentration at 6 h was 140 ng/mL. With aggressive benzodiazepine administration and intubation, he recovered uneventfully. Discussion: The commonalities associated with 4-AP toxicity conforms to what is known about its mechanism of action combining cholinergic features including diaphoresis, altered mental status, and seizures with dopamine-related movement abnormalities including tremor, choreoathetosis, and dystonia. Management of patients poisoned by 4-AP centers around good supportive care with definitive airway management and controlling CNS hyperexcitability aggressively with gamma-aminobutyric acid agonist agents. Adjunctive use of dopamine antagonists for extrapyramidal effects after sedation is a treatment possibility. As 4-aminopyridine recently received Federal Drug Administration approval for the treatment of ambulation in patients with MS, physicians should be keenly aware of its presentation, mechanism of action, and management in overdose. [ABSTRACT FROM AUTHOR]

Protein kinase C blocker chelerythrine prevented the increase in quantal content of single and rhythmic evoked end-plate potentials after disinhibition of L-type Ca-channels with paxillin. Phorbol ester increased quantal content of single end-plate potentials and changed rhythmic activity of mouse motor synapses. The effects of phorbol ester were to a great extent neutralized by L-type Ca-channel blocker nitrendipine and were completely abolished by К-channel blocker 4-aminopyridine. Thus, we discovered different facilitations of transmission after protein kinase C activation with calcium current through L-type channels and with phorbol ester. [ABSTRACT FROM AUTHOR]

Excitatory and inhibitory neurotransmission in the central nervous system can be modulated by neurosteroids. We previously found that in rat hippocampal slices allopregnanolone (3α-hydroxy-5α-pregnan-20-one), a positive GABA receptor modulator, suppresses the epileptic discharges induced by 4-aminopyridine (4-AP), a convulsant K channel blocker that stimulates glutamate release. Here, we tested the action of allopregnanolone on the epileptogenic and excitotoxic effects of the intrahippocampal administration of 4-AP in vivo. Drugs were perfused by a microdialysis cannula-electrode in the dorsal hippocampus and the EEG was recorded. Extracellular levels of aspartate, glutamate and GABA were analyzed by HPLC in the microdialysis fractions, and 24 h after the experiment the hippocampus was studied histologically. 4-AP induced intense epileptic discharges, increased the extracellular levels of aspartate, glutamate, and GABA by 383, 420, and 245%, respectively, and produced a notable neurodegeneration in CA1 and CA3 areas. Allopregnanolone administration alone did not affect the electrical activity, amino acids levels or cellular morphology, but when co-infused with 4-AP incremented 55-77% the duration of the epileptic discharges, and potentiated 32-49% the release of glutamate in comparison with 4-AP alone. The 4-AP-induced neurodegeneration was not modified by allopregnanolone. The NMDA receptor antagonist MK-801 protected against the epilepsy and neurodegeneration produced by 4-AP, and allopregnanolone did not affect this protection. We conclude that, differently from the observations in vitro, allopregnanolone potentiated the stimulatory effect of 4-AP on glutamate release and that this may explain the potentiation of the epileptogenic effect of 4-AP in vivo. [ABSTRACT FROM AUTHOR]

Multiple sclerosis (MS) is a demyelinating disease of the central nervous system characterized by episodic decline in various neurologic functions. Gait dysfunction in MS is distinguished by decreased gait speed, walking endurance, step length, cadence and joint motion, as well as increased metabolic cost of walking and increased variability of gait. Standardized clinical, timed, and patient-based measures can identify MS patients with gait dysfunction, and observational gait analysis, instrumented walkways, or three-dimensional gait analysis can help determine which problem underlies their gait dysfunction to help direct effective treatment. Exercise may ameliorate all types of gait dysfunction. In addition, gait dysfunction due to weakness may be alleviated by orthoses or functional electrical stimulation; gait dysfunction due to spasticity may be relieved by oral, intrathecal, or intramuscular medications. Assistive devices and balance training may reduce gait dysfunction from imbalance, and dalfampridine may accelerate gait in people with MS who walk slowly. [ABSTRACT FROM AUTHOR]

Transient A-type K currents (I) are known to influence the firing pattern of a number of thalamic cell types, but have not been investigated in intralaminar thalamocortical (TC) relay neurons yet. We therefore combined whole-cell patch-clamp techniques, PCR analysis, and immunohistochemistry to investigate the voltage-dependent and pharmacological properties of I and to determine its molecular basis in TC neurons from the centrolateral, paracentral, and centromedial thalamic nuclei. I revealed half-maximal ( V) activation and inactivation at about −17 and −67 mV, respectively. At a concentration of 5-10 mM 4-aminopyridine (4-AP) completely blocked I. Furthermore, I was nearly unaffected by two sea anemone toxins (blood depressing substances 1 and 2, BDS1 and BDS2; 6-8% block at a concentration of 1 μM) but strongly sensitive to the K4 channel blocker Heteropoda venatoria toxin 2 (HpTx2; about 45% block at a concentration of 5 μM). PCR screening revealed the expression of K4.1-4.3, with strongest expression for K4.2 and weak expression for K4.1. Accordingly K4.1 was not detected in immunohistochemical staining. Furthermore, K4.2 and K4.3 revealed mainly dendritic and somatic staining, respectively. Together with current clamp recordings, these findings point to a scenario where the fast transient I in intralaminar TC neurons has a depolarized threshold at potentials negative to −50 mV, is substantially generated by K4.2 and K4.3 channels, allows prominent burst firing at hyperpolarized potentials, prevents the generation of high-threshold potentials, generates a delayed onset of firing at more depolarized potentials, and allows fast tonic firing. [ABSTRACT FROM AUTHOR]

Single crystal X-ray diffraction is used to investigate two synthesized β-diketonate complexes of copper(II) with aminopyridine: Cu(4-NHPy)(aa) ( I) and Cu(4-NHPy)(hfa) ( II). The crystals of I and II have a monoclinic system; the unit cell parameters of I are: P2/ n space group, a = 8.2921(3) Å, b = 14.7243(5) Å, c = 13.4970(4) Å, β = 102.426(1)°, V = 1609.32(9) Å, Z = 4; for II: C2/ c space group, a = 23.5704(5) Å, b = 11.4977(2) Å, c = 16.0285(3) Å, β = 109.265(1)°, V = 4100.6(1) Å, Z = 8. The structures of I and II are molecular; they are composed of isolated molecules. The coordination polyhedron of the copper atom is formed by the O atoms of two acetylacetonate ligands (Cu-O 1.940(2)-2.171(2) I and the O atoms of two hexafluoroacetylacetonate ligands (Cu-O 1.940(2)-2.215(3) Å) in II. The molecules of 4-NHPy are bonded to the copper atom via the nitrogen atom of the aromatic ring (Cu-N 2.008(2) Å in I and Cu-N 1.978(3) Å in II). Noncoordinated amino groups join the molecules of the complexes together by means of N-H...O hydrogen bonds. [ABSTRACT FROM AUTHOR]

Copyright of Der Ophthalmologe is the property of Springer Nature and its content may not be copied or emailed to multiple sites or posted to a listserv without the copyright holder's express written permission. However, users may print, download, or email articles for individual use. This abstract may be abridged. No warranty is given about the accuracy of the copy. Users should refer to the original published version of the material for the full abstract. (Copyright applies to all Abstracts.)

Copyright of Neuroscience Bulletin is the property of Springer Nature and its content may not be copied or emailed to multiple sites or posted to a listserv without the copyright holder's express written permission. However, users may print, download, or email articles for individual use. This abstract may be abridged. No warranty is given about the accuracy of the copy. Users should refer to the original published version of the material for the full abstract. (Copyright applies to all Abstracts.)

Aminopyridines, widely used as a K+ channel blocker, are membrane-permeable weak bases and have the ability to form vacuoles in the cytoplasm. The vacuoles originate from acidic organelles such as lysosomes. Here, we investigated the effects of 4-aminopyridine (4-AP) on organelle movement in neurites of cultured mouse dorsal root ganglion (DRG) neurons by using video-enhanced microscopy. Some experiments were carried out using fluorescent dyes for lysosomes and mitochondria and confocal microscopy. Treatment of DRG neurons with 4 mM 4-AP caused Brownian movement of some lysosomes within 5 min. The Brownian movement gradually became rapid and vacuoles were formed around individual lysosomes 10–20 min after the start of treatment. Axonal transport of organelles was inhibited by 4-AP. Lysosomes showing Brownian movement were not transported in longitudinal direction of the neurite and the transport of mitochondria was interrupted by vacuoles. The 4-AP-induced Brownian movement of lysosomes with vacuole formation and inhibition of axonal transport were prevented by the simultaneous treatment with vacuolar H+ ATPase inhibitor bafilomycin A1 or in Cl−-free SO medium. These results indicate that changes in organelle movement by 4-AP are related to vacuole formation and the vacuolar H+ ATPase and Cl− are required for the effects of 4-AP. [ABSTRACT FROM AUTHOR]

4-aminopyridine (4-AP) is commonly used to block the transient outward potassium current, Ito, in cardiac and noncardiac tissues. In the present work, we found that 4-AP inhibited the rapid component of the delayed rectifier potassium current, IKr, in rabbit-isolated sinoatrial node myocytes by 25% (1 mM) and 51% (5 mM) and inhibited the slow component of the delayed rectifier potassium current, IKs, in cat- isolated sinoatrial node myocytes by 39% (1 mM) and 62% (5 mM). In cat- and rabbit-isolated sinoatrial node myocytes, 4-AP activated muscarinic receptors in a voltage-dependent manner to increase the acetylcholine-activated potassium current, IKACh. In multicellular preparations of the central region of the sinoatrial node from nonreserpinized rabbits, 4-AP produced an increase in action potential overshoot, frequency, and rate of diastolic depolarization. In the presence of the β-adrenergic antagonist propranolol, 4-AP produced a marked increase in duration and a marked decrease in maximum diastolic potential and eventually, cessation of the spontaneous activity in preparations from the sinoatrial central region. In multicellular preparations from reserpinized rabbits, 4-AP produced similar effects to those observed in the presence of propranolol. We conclude that 4-AP inhibits multiple cardiac K+ currents, including Ito, IKr, and IKs, and that these activities mask IKACh activation. In addition, in multicellular preparations, 4-AP produces neurotransmitter release from the autonomic nerve terminals. These multiple effects need to be considered when using 4-AP as a “specific” Ito blocker. [ABSTRACT FROM AUTHOR]

Mobility limitation is a frequent clinical symptom of multiple sclerosis (MS) that poses a therapeutic challenge. For years results of animal experiments and clinical experience have indicated that the potassium channel blocker 4-aminopyridine improves axonal excitatory circuits and thus muscular strength in demyelinating diseases. A recently conducted randomized, placebo-controlled, multi-center phase 3 clinical trial in MS patients was able to show that an oral sustained-release formulation of 4-aminopyridine (Fampridine-SR) represents a suitable agent for treatment of walking disability in MS patients. This overview presents the study data and discusses the value of 4-aminopyridine for the symptomatic treatment of MS as a neurofunctional modifier of this disabling disease. [ABSTRACT FROM AUTHOR]

HIV-1-associated neurocognitive disorders (HAND) remains a significant source of morbidity in the era of wide spread use of highly active antiretroviral therapy. Disease is precipitated by low levels of viral growth and glial immune activation within the central nervous system. Blood borne macrophage and microglia affect a proinflammatory response and release viral proteins that affects neuronal viability and leads to death of nerve cells. Increasing evidence supports the notion that HAND is functional channelopathy, but proof of this concept remains incomplete. Based on their role in learning and memory processes, we now posit that voltage-gated potassium (Kv) channels could be a functional substrate for disease. This was tested in the severe combined immunodeficient (SCID) mouse model of HIV-1 encephalitis (HIVE) by examining whether the Kv channel blocker, 4-aminopyridine (4-AP), could affect behavioral, electrophysiological, and morphological measures of learning and memory. HIVE SCID mice showed impaired spatial memory in radial arm water maze tests. Electrophysiology studies revealed a reduction of long-term potentiation (LTP) in the CA1 region of the hippocampus. Importantly, systemic administration of 4-AP blocked HIV-1-associated reduction of LTP and improved animal performance in the radial arm water maze. These results support the importance of Kv channel dysfunction in disease but, more importantly, provide a potential target for adjunctive therapies for HAND. [ABSTRACT FROM AUTHOR]

The mechanism underlying the voltage-dependent action of 4-aminopyridine (4-AP) is investigated in experiments on amphibian myelinated nerve fibres ( Rana ridibunda Pallas) by way of extracellular recording of electrical activity and using activators of potassium current (potassium-free solution and nitric oxide NO) and inhibitors of sodium current (tetrodotoxin). Measurement of action potential (AP) areas was used to evaluate the extent of general membrane depolarization during the activity of nerve fibres. Tetrodotoxin-induced decrease in general membrane depolarization (when the action potential amplitude was reduced by less than 20%) leads to an increase in the duration of depolarizing after-potential (DAP). This supports the dependence of time course of DAP in the presence of 4-AP on ratio of fast and slow potassium channels. In the absence of 4-AP, potassium-free solution and NO increase the potassium current through fast potassium channels (decreasing AP duration, reducing DAP and sometimes producing fast hyperpolarizing after-potential (HAP) after shortened AP), and in the presence of 4-AP these activators increase potassium current through unblocked slow potassium channels (making the development of slow HAP induced by 4-AP more rapid). The increase of slow HAP induced by 4-AP under the influence of potassium-free solution with NO supports the idea that slow HAP is due to activation of slow potassium channels and argues against the notion of removal of block of fast potassium channels. All analyzed phenomena of voltage-dependent action of 4-AP in amphibian myelinated nerve fibers can be accounted for by the activation of slow potassium current produced by membrane depolarization and a decrease of the amount of fast potassium channels involved in the membrane repolarization. [ABSTRACT FROM AUTHOR]

Study design:Double-blind, randomized, placebo-controlled, parallel-group clinical trial.Objective:Assess safety and efficacy of sustained-release fampridine in subjects with chronic spinal cord injury.Setting:A total of 11 academic rehabilitation research centers in the United States.Methods:A total of 91 subjects with motor-incomplete spinal cord injury (SCI), randomized to three arms: fampridine, sustained release, 25 mg b.i.d. (Group I), 40 mg b.i.d. (Group II), and placebo (Group III) for 8 weeks. Outcome measures: Patient diary questionnaire, Ashworth score, American Spinal Cord Injury Association International Standards, International Index of Erectile Function, bladder and bowel management questionnaires, and Clinician and Subject Global Impressions (Clinician Global Impression of change, Subject Global Impression (SGI)). Safety was evaluated from adverse events, physical examinations, vital signs, electrocardiograms, and laboratory tests.Results:In total, 78% of the subjects completed the study. More (13/30) discontinued from Group II than Group I (4/30) and Group III (3/31). The most frequent adverse events across groups were hypertonia, generalized spasm, insomnia, dizziness, asthenia, pain, constipation, and headache. One subject in Group II experienced a seizure. SGI changed significantly in favor of Group I (P=0.02). Subgroup analysis of subjects with baseline Ashworth scores >1 showed significant improvement in spasticity in Group I versus III (P=0.02).Conclusions:Group I showed significant improvement in SGI, and potential benefit on spasticity. The drug was well tolerated. Group II showed more adverse events and discontinuations.Sponsorship:The study was sponsored by Acorda Therapeutics, Inc.Spinal Cord (2007) 45, 158–168. doi:10.1038/sj.sc.3101947; published online 13 June 2006 [ABSTRACT FROM AUTHOR]

Reactions of 3-[( N-aryl- N-chloroacetyl)amino]-2-formylindoles with substituted anilines gave 1,4-diaryl-2-oxo-1,2,3,6-tetrahydro[1,4]diazepino[6,5- b]indol-4-ium chlorides and those with 4-aminopyridine yielded 4-amino-1-(1-aryl-2-oxo-2,5-dihydro-1 H-pyrido[3,2- b]indol-3-yl)pyridinium chlorides. Reduction of 1,2,3,6-tetrahydrodiazepinoindol-4-ium chlorides afforded the corresponding hexahydro derivatives. An alternative synthesis of 1-(4-nitrophenyl)-3-oxo-4-phenyl-1,2,3,4,5,6-hexahydro[1,4]diazepino[6,5- b]indole from 3-[ N-(4-nitrophenyl)amino]-2-[(phenylimino)methyl]indole was developed. The method involves the following sequence of transformations: reduction, chloroacetylation, and intramolecular alkylation. [ABSTRACT FROM AUTHOR]

The interaction of the Co( iso-Bu2PS2)2 chelate with 4-NH2Py afforded a paramagnetic complex [Co(4-NH2Py)( iso-Bu2PS2)2] (µeff = 4.53 BM). Single crystals of [Ni(4-NH2Py)2( iso-Bu2PS2)2] ( I) and [Co(4-NH2Py)( iso-Bu2PS2)2] ( II) were grown and used for X-ray diffraction investigation (X8 APEX diffractometer, Mo K α radiation). Crystals I are monoclinic with unit cell parameters a = 12.5336(5) Å, b = 9.4356(4) Å, c = 16.4095(6) Å; β = 111.351(1)°; V = 1807.4(1) Å3; Z = 2, ρ = 1.223 g/cm3, space group P21/ n. Crystals II are triclinic with unit cell parameters a = 8.7572(4) Å, b = 9.6934(6) Å, c = 18.665(1) Å; α = 79.374(2)°, β = 87.049(2)°, γ = 75.640(2)°; V = 1508.6(1) Å3; Z = 2, ρ = 1.259 g/cm3; space group $$P\bar 1$$ . The structures of I and II are formed by isolated mononuclear molecules. The coordination unit is NiN2S4 (octahedron) in I and CoNS4 (tetragonal pyramid) in II. The 4-NH2Py molecule is coordinated through the N atom of the heterocycle. Electronic spectroscopy data for II agree with the symmetry of the NS4 polyhedron found by X-ray diffraction (XRD) analysis. The noncoordinated amine groups link the complex molecules via N-H...S hydrogen bonds. [ABSTRACT FROM AUTHOR]

The interaction of the Co( iso-Bu2PS2)2 chelate with 4-NH2Py afforded a paramagnetic complex [Co(4-NH2Py)( iso-Bu2PS2)2] (µeff = 4.53 BM). Single crystals of [Ni(4-NH2Py)2( iso-Bu2PS2)2] ( I) and [Co(4-NH2Py)( iso-Bu2PS2)2] ( II) were grown and used for X-ray diffraction investigation (X8 APEX diffractometer, Mo K α radiation). Crystals I are monoclinic with unit cell parameters a = 12.5336(5) Å, b = 9.4356(4) Å, c = 16.4095(6) Å; β = 111.351(1)°; V = 1807.4(1) Å3; Z = 2, ρ = 1.223 g/cm3, space group P21/ n. Crystals II are triclinic with unit cell parameters a = 8.7572(4) Å, b = 9.6934(6) Å, c = 18.665(1) Å; α = 79.374(2)°, β = 87.049(2)°, γ = 75.640(2)°; V = 1508.6(1) Å3; Z = 2, ρ = 1.259 g/cm3; space group $$P\bar 1$$ . The structures of I and II are formed by isolated mononuclear molecules. The coordination unit is NiN2S4 (octahedron) in I and CoNS4 (tetragonal pyramid) in II. The 4-NH2Py molecule is coordinated through the N atom of the heterocycle. Electronic spectroscopy data for II agree with the symmetry of the NS4 polyhedron found by X-ray diffraction (XRD) analysis. The noncoordinated amine groups link the complex molecules via N-H...S hydrogen bonds. [ABSTRACT FROM AUTHOR]

Animal and human research have shown that the drug 4-aminopyridine (4-AP) may improve gait in spinal cord lesions by enhancing nerve transmission to affected muscles.STUDY DESIGN::Prospective, randomized, double-blind, placebo-controlled, crossover trial. OBJECTIVES::To determine the efficacy of 4-AP in improving lower limb muscle strength and biomechanical gait patterns of chronic spinal cord injuries (SCI). SETTING::The Rehabilitation Centre (Ottawa, Canada). METHODS::In all, 15 chronic, ambulatory SCI persons were randomized to an initial 2 weeks of 40?mg/day, oral medication of either placebo or immediate-release, 4-AP and subsequently crossed over to the alternate medication for the following 2 weeks. Evaluations were conducted at baseline (before starting 4-AP or placebo medication), 2 weeks, and 4 weeks. Measures included dynamometer lower limb isometric muscle force and biomechanical gait measures including temporal-spatial parameters, electromyographic activation patterns, joint kinematics and kinetics. Subjective impressions of the drug by the participants were obtained from an exit survey. RESULTS::Despite some positive comments from subjects, statistical and clinical analyses showed no within-subject differences between placebo and 4-AP measures of lower limb muscle force and objective gait analyses (ANOVA statistic P>0.05). CONCLUSION::Results demonstrated the importance of placebo-controlled trials and quantitative outcome measures for the evaluation of 4-AP aimed to enhance gait for chronic, ambulatory SCI persons. Energy expenditure measures and mood may relate more to subjective comments and is suggested for future investigations. SPONSORSHIP::American Paraplegia Society and the former American Paralysis Association.Spinal Cord (2004) 42, 674-685. doi:10.1038/sj.sc.3101653; Published online 7 September 2004 [ABSTRACT FROM AUTHOR]

In order to find out the role of sodium bicarbonate (NaHCO3) on the initiation of sperm motility in the Japanese eelAnguilla japonica, interactions were investigated between NaHCO3 and various reagents (K+ channel blocker 4-aminopyridine[4-AP], ammonium chloride[NH4Cl], sodium acetate and calcium chloride[CaCl2]) that could regulate internal factors (intracellular K+, intracellular pH[[pH]i] and intracellular Ca2+) in sperm motility. Contradictory effects of NaHCO3 were observed (i.e. an inhibitory effect when 4-AP was absent and a promoting effect when 4-AP was present). Sodium bicarbonate inhibited the initiation of sperm motility in the Japanese eel. However, NaHCO3 restored the motility of immotile sperm that 4-AP inhibited. The inhibitory effect of NaHCO3 disappeared with the addition of NH4Cl, which raised[pH]i, but the promoting effect was not affected by[pH]i. Although NaHCO3 recovered motility in the presence of 4-AP, this recovery was also observed with the addition of CaCl2 instead of NaHCO3. In the initiation of sperm motility in the Japanese eel, two roles for NaHCO3 are suggested: an inhibitory role relating to the regulation of[pH]i and a promoting role relating to the uptake of another initiation factor, which could be Ca2+. [ABSTRACT FROM AUTHOR]

Mixed-ligand complexes [Ni(4-NH2Py) ( i-Bu2PS2)2] (I) and Ni(4-NH2Py)2( i-Bu2PS2)2 (II) have been synthesized. Single crystals were grown and X-ray diffraction data (CAD-4 diffractometer, MoK α radiation, 1477 F hkl, R = 0.0320) were used to determine the structure of I. The crystals are orthorhombic: a = 10.675(1) Å; b = 21.681(2) Å; c = 26.302(4) Å, V = 6087.5(12) Å3, Z = 8, ρ(calc) = 1.247 g/cm3, space group Pbca. Complex I possesses a mononuclear molecular structure. The coordination polyhedron of the Ni atom is a tetragonal pyramid NS4 whose base is formed by four S atoms of two cyclic bidentate ligands i-Bu2PS and the axial position is occupied by the N atom of the 4-NH2Py cycle. According to electron spectroscopy data, complex II has an octahedral N2S4 environment of the Ni atom. [ABSTRACT FROM AUTHOR]