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PubMed1979

Inhibition of aminopyridine-induced contractile activity in skeletal muscle by tetrodotoxin and by magnesium.

The effects of tetrodotoxin and magnesium have been studied on aminopyridine-induced contractile activity seen in the absence of nerve stimulation. In the chick biventer cervicis muscle both tetrodotoxin and magnesium pretreatment prevented the development of fasciculations and contractures in the presence of 4-aminopyridine and 3,4-diaminopyridine. Both tetrodotoxin and magnesium abolished aminopyridine induced fasciculations and contractures. Tetrodotoxin did not reduce postjunctional sensitivity to the agonists acetylcholine and carbachol whereas magnesium produced some reduction of postjunctional sensitivity. It is concluded that conducted action potentials must be involved in the aminopyridine-induced contractile activity. In the frog sartorius muscle aminopyridines occasionally induced repetitive endplate potentials suggesting that the compounds induce repetitive nerve activity. In both tetrodotoxin and magnesium treated preparations 4-aminopyridine produced only a moderate increase in miniature endplate potential frequency. It is concluded that aminopyridines increase nerve membrane excitability resulting in the generation of repetitive action potentials in the absence of nerve stimulation.

Aminopyridines↗
PubMed1987

Analysis of unsaturated fatty acids of endoneurium and perineurium from normal and degenerating rat sciatic nerve. Morphological correlations.

The major portion of the endoneurial lipids is found in myelin. Since perineurial cells differ morphologically from endoneurial cell components, we attempted to determine whether these morphological differences also extended to a difference in fatty acid (FA) composition. Under normal circumstances, unsaturated FAs are more abundant than saturated ones (55-60% of total FAs) in endoneurium and perineurium. A characteristic biochemical difference between these two structures lies in the distribution of linoleic acid (C18:2(n-6)) which represents 20% of total FAs in perineurium and only 2% in endoneurium. Wallerian degeneration takes place after injection of pure glycerol into the endoneurium. This is followed by regeneration characterized by a proliferation of perineurial cells infiltrating the center of the nerve fascicule forming microcompartments. The changes in linoleic acid content reflect these morphological changes. A marked increase in linoleic acid is detected in the endoneurial fraction in parallel with the observed infiltration of perineurial cells into the nerve fascicule.

Animals↗
PubMed1986

Clonidine protection from soman and echothiophate toxicity in mice.

The influence of clonidine on the toxicity produced by two irreversible, organophosphate cholinesterase inhibitors, soman and echothiophate, was studied in mice. At lethal doses, soman produced whole body tremor but no muscle fasciculation; at lethal doses, echothiophate produced muscle fasciculations but no whole body tremor. Pretreatment with clonidine protected against several toxic manifestations of soman, but had little effect on echothiophate toxicity. In addition to its documented effects on acetylcholine metabolism, clonidine was found to be a weak inhibitor of acetylcholinesterase. At certain concentrations, clonidine protected the enzyme from permanent inactivation by soman. These findings indicate that the toxicity of soman and echothiophate reflect primarily central and peripheral actions, respectively, and that clonidine has a much greater protective effect versus the centrally-acting agent. Moreover, direct interactions with acetylcholinesterase may contribute to clonidine protection from cholinesterase inhibitor toxicity.

Acetylcholinesterase↗
PubMed1986

Pathophysiology of soman intoxication in primates.

Adult baboons were monitored during intravenous infusion of Soman (1,2,2-trimethylpropyl ester, phosphonofluoridate). Three groups of animals were studied. Two groups were anesthetized with sodium pentobarbital (initial dose, 20 mg/kg), instrumented for measurement of systemic blood pressure (BP), pulmonary artery pressure, cardiac output (CO), ECG, ventilatory flow, translaryngeal pressure (PTL), transdiaphragmatic pressure (Pdi), transpulmonary pressure (PTP), diaphragm EMG, and efferent phrenic nerve traffic (Eph). One group received no Soman and served as controls. In the other group, Soman was infused over 10 min at doses of 13.1, 8.21, 4.92, or 3.3 micrograms/kg. The onset of intoxication occurred within 7-8 min (before the end of the 10-min infusion), manifested by muscular fasciculations, stridorous breathing, copious secretions, and atrioventricular arrhythmias. Mean BP decreased to 30 mm Hg by the combination of decreased CO and decreased vascular resistance. There was a dose-related response in the onset and duration of these effects. Apnea occurred in most animals and coincided with cessation of the Eph signal. Stimulation of the diaphragm via the phrenic nerve following apnea yielded Pdi values unchanged from baseline, indicating an intact neuromuscular apparatus. All animals required ventilatory support. Some surviving animals exhibited severe behavior changes. The third group of animals was studied without anesthesia. Instrumentation was performed 3 days before using a tether system for the measurement of BP, CO, and ECG, and an arterial line for blood withdrawal. Soman was infused over 10 min at a dose of 13.1 micrograms/kg. The onset of intoxication occurred within 2-3 min, manifested by hyperactivity, severe muscle fasciculations which simulated grand-mal convulsions, stridorous respiratory sounds, copious secretions, and cardiac arrhythmias. Apnea and severe lactic acid acidosis developed in all animals and all required ventilatory assistance. None recovered spontaneous ventilation at the end of 4 hr.

Animals↗
PubMed1985

Cardiovascular effects of brevetoxins in dogs.

In anesthetized spontaneously breathing dogs, brevetoxin caused dose-dependent periods of apnea and, at high doses, respiratory arrest. In artificially ventilated dogs, i.v. brevetoxin caused complex dose-related cardiovascular changes consisting of: (1) bradycardia; (2) triphasic blood pressure changes, sequentially characterized by depressor/pressor/depressor phases; (3) cardiac arrhythmias including ventricular fibrillation; (4) muscle fasciculations. Prevention of bradycardia by atropine, vagotomy or ganglionic blockage unmasked a tachycardic action of the toxin. Ganglionic blockade, but not atropine or vagotomy, reduced the initial depressor effect of toxin. Phentolamine prevented the toxin-induced initial hypotension and secondary hypertension. Propranolol prevented the tachycardic and late depressor effects of toxin. In reserpinized dogs, low doses of toxin caused muscle fasciculations but none of the above cardiovascular effects; large doses caused bradycardia preventable by atropine, but not by vagotomy or chlorisondamine. These results suggest that brevetoxin: elicits the Bezold-Jarisch effect, i.e. initial hypotension, bradycardia and apnea; releases catecholamines, probably adrenal epinephrine, causing tachycardic, secondary pressor and late depressor effects; in large doses, releases vagal acetylcholine; -induced catecholamine and acetylcholine release is not nicotinic; produces effects, like those reported for veratridine, attributable to a common action on excitable membranes.

Animals↗
PubMed1989

Actions of robustoxin, a neurotoxic polypeptide from the venom of the male funnel-web spider (Atrax robustus), in anaesthetized monkeys.

Robustoxin, a polypeptide consisting of a chain of 42 amino acid residues in a known sequence, has been isolated by cation exchange chromatography from the crude venom of the male funnel-web spider (Atrax robustus). Physiological activity or toxicity in the venom fractions was detected by production of fasciculation in mouse phrenic nerve-hemidiaphragm preparations and by lethality in new-born mice. In the present experiments in Macaca fascicularis monkeys anaesthetized with pentobarbitone, robustoxin (5-30 micrograms/kg infused i.v. over 5 min) produced immediate disturbances in respiration (including dyspnoea and apnoea), blood pressure and heart rate followed by severe hypotension (mean systemic blood pressure less than 50 mmHg) or death due to respiratory and circulatory failure within 196 min. Robustoxin also produced lachrymation, salivation, generalized skeletal muscle fasciculation and a parallel increase in body temperature, and increased firing in skeletal motor and autonomic nerves. These effects closely resembled those produced by i.v. infusions over 5 min of 50 micrograms/kg of crude venom from male A. robustus spiders. Crude venom from female A. robustus spiders (500 micrograms/kg i.v. over 5 min) produced some of the effects elicited by robustoxin and crude venom from male spiders, but to a much less marked extent. It was concluded that robustoxin is responsible for the neurotoxic and lethal effects of human envenomation by male A. robustus spiders.

Anesthesia↗
PubMed1989

Fasciclin III: a novel homophilic adhesion molecule in Drosophila.

Drosophila fasciclin III is an integral membrane glycoprotein that is expressed on a subset of neurons and fasciculating axons in the developing CNS, as well as in several other tissues during development. Here we report on the isolation of a full-length cDNA encoding an 80 kd form of fasciclin III. We have used this cDNA, under heat shock control, to transfect the relatively nonadhesive Drosophila S2 cell line. Examination of these transfected cells indicates that fasciclin III is capable of mediating adhesion in a homophilic, Ca2+-independent manner. Sequence analysis reveals that fasciclin III encodes a transmembrane protein with no significant homology to any known protein, including the previously characterized families of vertebrate cell adhesion molecules. The distribution of this adhesion molecule on subsets of fasciculating axons and growth cones during Drosophila development suggests that fasciclin III plays a role in growth cone guidance.

Amino Acid Sequence↗
PubMed1985

Survival, morphology and adhesion properties of cerebellar interneurones cultured in chemically defined and serum-supplemented medium.

Cultures obtained from early postnatal rat cerebellum, grown in either chemically defined or in serum-supplemented medium containing 25 mM K+, contained predominantly (greater than 90%) small interneurones, mostly granule cells, with good and comparable viability (assessed by the retention of preloaded 51Cr). Neuronal survival was prolonged in the chemically defined medium, nerve cells living up to two weeks longer than in serum-supplemented medium, although the proportion of non-neuronal cells was not greatly increased. In the serum-supplemented medium neurones became organised into clumps connected by thick, fasciculated bundles of neurites by about one week in vitro. In comparison, in the chemically defined medium aggregation of neurones and fasciculation of neurites was markedly reduced even after 4 weeks in culture. The possible relationship between the organisation of neurones and the nature of the substratum, chemical factors in the medium as well as the surface properties of the cells is discussed.

Animals↗
PubMed1990

Migration and aggregation of embryonic chicken neurons in vitro: possible functional implication of polysialogangliosides.

The presented study reports a primary culture system of embryonic chicken optic lobe neurons, which turned out to be a suitable model for cell migration and aggregation: Freshly dissociated neurons developed short processes, contacted one another and formed fasciculated bundles, on which neurons migrated as long-shaped cells, similar to migrating neurons in vivo. We used this system to study the possible involvement of c-pathway polysialogangliosides for neuronal migration and aggregation. These highly negative charged glycosphingolipids are the predominant gangliosides of migrating and outgrowing neurons in vivo. Addition of a purified ganglioside mixture (50 microM), extracted from brains of the corresponding embryonic stage, strongly enhanced neuronal migration and aggregation, while incubation of the cells with monoclonal antibody Q211, specifically binding c-polysialogangliosides, reduced aggregate formation in a dose-dependent manner. Cultures treated with 10 micrograms/ml Q211, instead, displayed a more divergent growth, leading to the formation of a fine network of single neuronal processes. These results suggest a functional implication of c-polysialogangliosides in neuronal fasciculation, migration and aggregation.

Animals↗
PubMed1990

Neuron-glia cell adhesion molecule (Ng-CAM) expression in the chick embryo spinal cord: observations on the earliest developing intersegmental interneurons.

The pattern of expression of the neuron-glia cell adhesion molecule (Ng-CAM) among the presumptive intersegmental interneurons in the early chick embryo spinal cord (stage 14-19) was examined using whole-mount and cryostat preparations double-stained with anti-Ng-CAM antibody and a neuron-specific anti-beta-tubulin antibody. In brachial segments, primitive longitudinal cells (PL-cells), located in the ventrolateral region of the spinal cord, express Ng-CAM both on their cell bodies and longitudinally growing axons, beginning at Hamburger-Hamilton stage 15 (embryonic day (E) 2.5). Shortly thereafter, at stage 16, circumferential cells (C-cells), composed of associational and commissural interneurons in the dorsolateral and lateral region of the spinal cord begin to express Ng-CAM both on their cell bodies and their axons which project ventrally along the lateral surface of the spinal cord. In the following stages. PL-cells express Ng-CAM strongly and begin to fasciculate to form a longitudinal fascicle in the ventrolateral marginal region of the spinal cord. C-Cells either extend their Ng-CAM-positive axons ventrally without fasciculation to join the Ng-CAM positive ipsilateral longitudinal fascicle at stage 17 (which has already been formed by PL-cell axons), or they cross the midline to join the Ng-CAM positive contralateral longitudinal fascicle after growing through the floor plate at stage 19. By stage 19, cell bodies and proximal segments of the C-cell axons exhibit decreased Ng-CAM expression, whereas the distal segment of these axons, including growth cones, strongly express Ng-CAM. Many contacts were observed between Ng-CAM-positive growth cones and axons in the ventral region of the spinal cord, both within the longitudinal fascicle and the floor plate region, suggesting the involvement of Ng-CAM in neurite-neurite interactions.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1988

Prevention of diisopropylphosphorofluoridate (DFP)-induced skeletal muscle fiber lesions in rat.

The objective of the present investigation was to assess the comparative efficacy of prophylactic treatment with d-tubocurarine (d-TC) (0.075 mg/kg), atropine sulfate (16 mg/kg), and atropine methylnitrate (16 mg/kg), employed singly or in combination against the diisopropylphosphorofluoridate (DFP)-induced myopathy in rat. DFP (1.5 mg/kg, s.c.) produced signs of cholinergic toxicity with predominantly peripheral involvement manifest as severe muscle fasciculations beginning within 5-7 min and persisting in excess of 4-6 h. Maximal muscle fiber necrosis was observed within 24 h. Rats were protected against the apparent behavioural and morphological changes as well as electrophysiological signs of neuromuscular toxicity by all pretreatment agents. Combined pretreatment with d-TC (0.075 mg/kg, s.c.) and atropine methylnitrate (16 mg/kg, s.c.) was found to be most effective in attenuating DFP-induced muscle fiber necrosis as evidenced by complete absence of lesions and the prevention of DFP-induced hyperactivity in nerve and muscle. Significant protection was afforded by all pretreatment agents when given alone. It is suggested that the pretreatment agents act presynaptically by preventing drug-induced backfiring and muscle fasciculations possibly by reducing the release of acetylcholine (ACh). The protective drugs in the concentrations used had no significant effect on the normal characteristics of conduction and transmission.

Action Potentials↗
PubMed1983

Growing corticospinal axons by-pass lesions of neonatal rat spinal cord.

The anterograde transport of horseradish peroxidase was used to label newly growing corticospinal axons after they had entered lesioned regions of the neonatal rat spinal cord. Two types of lesions were made at thoracic and lumbar levels before the arrival of the first corticospinal axons. (1) Thermal lesions were produced by the brief application of a heated rod to the vertebral column and could destroy the normal growth path over several spinal segments. Corticospinal axons, when successful in growing distal to thermal lesions, did so at the same rate as in normal controls and retaining their normal relative positions and morphology, especially fasciculation. (2) Surgical lesions were produced by cutting the spinal cord and were limited to one segment but could result in a barrier in the normal growth path composed of a cyst or glial scar. Corticospinal axons that succeeded in growing distal to a surgical lesion did so by being deflected to unusual positions, became defasciculated, and sometimes their normal growth rate was slowed. That corticospinal axons could in many instances grow past the two types lf lesion suggests that a morphologically stereotyped glial scaffolding is not necessary for axon growth. The role of fasciculation in normal axon growth is highlighted by the disparate effects of the two types of lesion.

Animals↗
PubMed1990

Organization of radial glia and related cells in the developing murine CNS. An analysis based upon a new monoclonal antibody marker.

A monoclonal antibody, RC1, has been generated which provides a selective and sensitive immunohistochemical marker of radial glial cells and related cell forms during development of the mouse CNS. Beginning on embryonic day E10, immunocytochemistry performed on cryostat sections stains throughout the CNS a subpopulation of cells in the ventricular zone with radial processes that terminate with endfeet at the pial surface. These processes become fasciculated and attain maximal densities by E12-14 in the spinal cord and lower brainstem and by E14-16 in the midbrain, cerebellum and forebrain. Fasciculation is especially prominent for a subclass of these cells at the midline of the brainstem and spinal cord. As nuclear and cortical structures develop, the trajectories of the radial fiber fascicles undergo systematic and region-specific distortions in their initially simple linear configuration, in the process maintaining a consistent spatial registration of germinal ventricular zones with distal sites of assembly of post-migratory neurons. In the late fetal period, radial glial progressively disappear and scattered immature astrocytes bearing multiple fine processes appear in most regions of the CNS. In the spinal cord, a transitional unipolar radial form is identified in the emerging ventral and lateral funiculi between E13 and E17. In the cerebellum, precursors to the unipolar Bergmann glial cell are identified by E15, and in the retina, precursors of the bipolar Müller cell are identified by E16. Postnatally, RC1-stained radial glia become sparse, and after one week, immunoreactive cells include only ependymal cells, hypothalamic tanycytes, Bergmann glia, Müller cells, a unipolar radial form in the dentate gyrus, and a subpopulation of white matter astrocytes. These results suggest that radial cells of astroglial lineage comprise a diverse set of cell classes which subserve multiple functions in the developing and adult brain.

Animals↗
PubMed1988

Factors influencing neuronal growth in primary cultures derived from 3-day-old chick embryos.

We compared neuronal growth patterns in primary cultures prepared by dissociating 3-day-old chick embryos, either whole embryo (E3WE) or head only (E3H) and plating the dispersed cells onto Petri dishes coated with either poly-L-lysine, collagen or laminin. The culture medium was Dulbecco's Modified Eagle's Medium (DMEM), supplemented with either 5 or 10% fetal bovine calf serum (FCS). As we have previously described, in E3WE cultures on poly-L-lysine the neuronal primary growth patterns were aggregation with neuritic fasciculation, presence of growth cones with microspikes and very few flat cells. In contrast with cultures grown on poly-L-lysine, in cultures grown on collagen or laminin the distinct growth pattern was extensive networks of isolated and differentiated neurons lying on acquired monolayers of flat cells. When 5% FCS was used, as compared to 10% FCS, neuronal aggregates were fewer and smaller on poly-L-lysine; on collagen or laminin a tendency to aggregate was observed. Several differences were observed in the E3H cultures when compared to E3WE: (a) aggregates were less numerous with the prevailing pattern being a web-like, self-contained aggregate; (b) aggregates connected with other aggregates or flat cells were rare and the aggregate adhesivity was minimized; (c) neurons on collagen or laminin formed networks with the exception of a few, small aggregates displaying no fasciculation; (d) flat cells did not form a monolayer but islets which hosted the neuronal meshy networks. We attribute these differences in the growth patterns between the various types of cultures to be the combined result of a variety of environmental signals, derived from the provided substrata, the serum and the nonneuronal cell factors and cell surface, all primarily regulating neuronal adhesivity.

Animals↗
PubMed1995

Ethanol neurotoxicity on neuroblast-enriched cultures from three-day-old chick embryo is attenuated by the neuronotrophic action of GABA.

In the present study, using neuroblast-enriched cultures derived from three-day-old chick embryos (E3WE), we examined the morphological effects of ethanol and/or GABA, as well as the developmental profile of the cholinergic and GABAergic neuronal phenotypes, as assessed by the activities of choline acetyltranferase (ChAT) and glutamate decarboxylase (GAD). Cultures exposed to ethanol (50 mM) exhibited smaller and fewer aggregates than controls with a neuritic network that lacked fasciculation. In cultures treated with GABA (10(-5) M) alone or ethanol+GABA the size and number of the neuronal aggregates was increased and also neuritic arborization and fasciculation was enhanced. Thus, addition of GABA restored the normal growth pattern in the ethanol-treated cultures. As previously shown, E3WE culture treated with ethanol alone showed a decrease in both ChAT and GAD activities compared to controls. Both cholinergic and GABAergic neuronal phenotypes were enhanced in cultures treated with GABA as assessed by increases in ChAT and GAD activities, respectively, compared to controls. Moreover, in cultures treated concomitantly with ethanol and GABA both ChAT and GAD activities were higher than in ethanol-alone-treated cultures. Thus, the presence of GABA in the ethanol-treated cultures counteracted the decline in ChAT and GAD activities observed in the ethanol-alone-treated cultures. We conclude that GABA through its neuronotrophic actions can rescue neuroblasts from ethanol insult and restore neuronal phenotypes.

Animals↗
PubMed1994

Polysialic acid regulates growth cone behavior during sorting of motor axons in the plexus region.

Removal of polysialic acid (PSA) from N-CAM during the time when chick motoneuron axons are segregating into target-specific fascicles at the base of the limb was previously shown to result in motoneuron projection errors. Here, it is established that these errors are associated with altered growth cone behavior in the plexus. In contrast to control embryos, in which individual axons were observed to exhibit dramatic changes in direction and extensive divergence, axonal trajectories following the removal of PSA were relatively straight. To determine whether enhanced axon-axon fasciculation following PSA removal had prevented growth cones from responding appropriately to guidance cues at the base of the limb, we also examined the role of L1, a major mediator of axon-axon fasciculation in this system. Anti-L1 reversed the effects of PSA removal on both growth cone trajectories and projection errors. These results indicate that PSA plays a permissive role, attenuating axon-axon interactions in the plexus and thereby allowing the axonal reorganization that is essential for the formation of specific motoneuron projections.

Animals↗
PubMed1996

Propofol permits tracheal intubation but does not affect postoperative myalgias.

STUDY OBJECTIVE: To determine the effect of propofol without succinylcholine on intubating conditions and postoperative myalgias in ambulatory surgical patients undergoing general anesthesia. DESIGN: Prospective, double-blind, randomized study. SETTING: Ambulatory surgery adult patients. PATIENTS: 56 ASA physical status I and II adult patients undergoing general endotracheal anesthesia. INTERVENTIONS: Group 1 patients received thiamylal plus succinylcholine, Group 2 patients received propofol plus succinylcholine; and Group 3 patients received propofol plus saline. All patients received fentanyl, lidocaine, and nitrous oxide plus isoflurane in oxygen. MEASUREMENTS AND MAIN RESULTS: Incidence and severity of fasciculations, tracheal intubating conditions, and myalgias on the first and third postoperative days were measured. Propofol did not affect the incidence or severity of fasciculations following succinylcholine, or the incidence of myalgias. Of patients who received propofol without succinylcholine, intubation was successful in 85%. CONCLUSIONS: Propofol did not affect the incidence or severity of postoperative myalgias following succinylcholine.

Adult↗
PubMed2004

Comparison of the effect of TAK-147 (zanapezil) and E-2020 (donepezil) on extracellular acetylcholine level and blood flow in the ventral hippocampus of freely moving rats.

The effects of zanapezil (TAK-147) and donepezil (E2020) on extracellular acetylcholine (ACh) levels were investigated by HPLC-microdialysis of ventral hippocampus (VH) in freely moving intact rats. The results showed that the basal ACh release rate in the VH is 116.7 +/- 12.4 to 158.4 +/- 22.86 fmol/20 microl. At 2, 5 and 10 mg/kg, single p.o., each drug increased ACh level by 9.4%, 106.5%, 50.8% (TAK-147) and 14.8%, 76.1%, 120.94% (E2020), respectively. The ED50 values were 4.52 mg/kg (1.43 - 14.29; R=0.52) and 4.07 mg/kg (1.77 - 9.37; R=0.985) for TAK-147 and E2020, respectively. Analysis of data revealed that the relative TAK-147/E2020 potency ratio is 0.773, but the effect of E2020 was accompanied by more prominent skeletal muscle fasciculation, gnawing, increased defecation and to lesser extent salivation. Moreover, the significant effect of TAK-147 was observed earlier (20 min) than E2020 (60 min). In this study, we also investigated the effect of both drugs at dose of 5 mg/kg p.o. on blood flow in the VH using Laser Doppler Flowmetry. The results showed that the average blood flow rate in the VH is 6.5 +/- 0.9 ml/min/100 g. TAK-147 did not change blood flow, but E2020 increased blood flow in a biphasic manner. The first increment was obtained between 5 and 40 min (11.5 +/- 2.2 to 12.7 +/- 2.2 ml/min/100 g), and the second one 80-105 min (10.7 +/- 1.6 to 13.4 +/- 3.6 ml/min/100 g). In conclusion, the present results indicate that both TAK-147 and E2020 increase ACh level in the VH. E2020 showed greater potency than TAK-147, but it induced more fasciculation and other side effects than TAK-147. Moreover, the blood flow increasing properties of E2020 could be beneficial in some patients with Alzheimer' disease especially those with chronic vascular dementia, but at the same time, it could also indicate less specific ACh increasing activity than TAK-147 and higher risk of cerebral hemorrhage. On the other hand, the fast and specific effect of TAK-147 may be useful for cure of early stages of Alzheimer's disease (AD).

Acetylcholine↗