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S Thesleff

Publications and source records attributed to S Thesleff.

At least 55 records · Page 3Linked to original sources
PubMed1981

Pre- and post-synaptic actions of botulinum toxin at the rat neuromuscular junction.

1. Extensor digitorum longus muscles of rats were paralysed with local, non-lethal doses of botulinum toxin Type A (BoTx). At 2 and 7 days after toxin injection, the nerve-muscle preparations were excised and end-plate currents analysed at 23 degrees C by dual-micro-electrode voltage clamp. 2. At 2 days after BoTx injection, the growth time of miniature end-plate currents (m.e.p.c.s) increased from a rather narrow range with a mean of 0.59 to a mean of 1.35 ms with a large variability between m.e.p.c.s. End-plate currents (e.p.c.s) were reduced compared to unpoisoned muscle. The decay phase of m.e.p.c.s and e.p.c.s, the growth phase of e.p.c.s and the voltage sensitivity of m.e.p.c.s were unchanged. 3. At 7 days after BoTx injection, the findings were similar to 2 days except that the time constant of the decay phase of m.e.p.c.s. and e.p.c.s. was about twice a long as normal and that the voltage sensitivity of m.e.p.c.s was increased. 4. The acetylcholine null potential (about 0 mV) was unchanged after treatment with BoTx. 5. The increase in the growth time of m.e.p.c.s compared to e.p.c.s following the injection of BoTx suggests that the poisoning, besides blocking quantal release, affects the time course of spontaneous but not that of evoked release. After BoTx poisoning the trans-synaptic diffusion of a majority of spontaneously released transmitter quanta seems to occur more slowly or from areas more distant from the highest concentration of the post-synaptic receptor than that of evoked release. 6. The increase in the decay phase of m.e.p.c.s and e.p.c.s and its increased voltage sensitivity observed in muscles poisoned for 7 days with BoTx suggest that appearance at the end-plate of a population of new receptors with a prolonged ion channel opening time similar to that previously described for extrajunctional receptors after denervation and for junctional receptors during development.

Animals↗
PubMed1981

Acetylcholine content and release in denervated or botulinum poisoned rat skeletal muscle.

1. The acetylcholine (ACh) content and spontaneous and evoked release of ACh in rat extensor digitorum longus (EDL) muscles were determined by pyrolysis-mass fragmentography. The determinations were made on muscles paralysed by local application of botulinum toxin (BoTx) type A, on unpoisoned muscles, surgically denervated or reinnervated muscles.2. The ACh content of unpoisoned control muscles was nearly uniform between animals and varied in the experimental series between 36 and 50 pmol. BoTx failed to affect the ACh content after 2 d of poisoning and caused a slight increase in content after 8 d. Surgical denervation reduced the ACh content within 24 h to less than 10% of innervated muscles and upon reinnervation the ACh content was restored. Following cholinesterase inhibition the ACh content of innervated and denervated muscles increased somewhat, about equally with time.3. Spontaneous release of ACh varied in normal innervated muscles between 40 and 100 fmol/min. In the presence of 25 mm-KCl the rate of release increased about fourfold. In BoTx poisoned muscles spontaneous release was reduced by up to 60% of control and high potassium failed to accelerate the release at 2 d after poisoning and caused only a small increase at 8 d. Denervated muscles released ACh at a rate which was less than 20% of control and it was not accelerated by high potassium.4. The results show that more than 90% of total ACh in the innervated EDL muscle is present in the nerve and its terminals. The remaining ACh is apparently formed and stored in the muscle tissue. BoTx caused a larger reduction in ACh release than can be accounted for by assuming a selective blockade of quantal release of transmitter. It suggests that BoTx has an inhibitory effect also on non-quantal ACh release.

Acetylcholine↗
PubMed1980

Alterations in membrane electrical properties during long-term denervation of rat skeletal muscles.

Some membrane electrical properties of the extensor digitorum longus muscle of the rat were examined up to 21 days after denervation. The resting potential was significantly more depolarized at 3 days after denervation than it was at later times. The rate of rise (dV/dt) of the action potential decreased throughout the time course of the study but approached a steady value between 14 and 21 days after denervation. In addition, the dV/dt of tetrodotoxin (TTX)-resistant action potentials increased up to and including 7 days after nerve section, but declined thereafter. When expressed as % of control, the dose-response to TTX was similar throughout denervation. It is suggested that the large depolarization observed early in denervation may be related to the turnover of membrane constituents occurring at this time. The results also suggest that denervation produces a reduction in the number of fast TTX-sensitive Na+ channels with the appearance of a new population of slow TTX-resistant channels. However, long term denervation results in a reduction in the density of both types of channels.

Action Potentials↗
PubMed1980

Membrane and biochemical alterations after denervation and during reinnervation of mouse skeletal muscle.

Denervation of the extensor digitorum longus (EDL) muscle of the mouse by either nerve crush or nerve section produced: a reduction of the resting membrane potential (Em), alterations in the properties of muscle fibre action potentials and the development of tetrodotoxin (TTX)-resistant action potentials. These changes in membrane electrical properties were accompanied by an increase in the endocytic activity of the muscle and an increase in the activities of the lysosomal enzymes cathepsin D and N-acetylglucosaminidase (NAGA). Reinnervation of muscle was indicated at 9 days after nerve crush by the presence of miniature end-plate potentials. The recovery of membrane electrical properties, beginning with the onset of reinnervation, were not temporally related. The Em increased in two stages: an early rapid repolarization and a later slower repolarization. The muscle fibers were sensitive to the blocking action of TTX by 12 days after nerve crush, whereas the rate of rise (dV/dt) of the action potential did not approach values of innervated muscles until 21 days. Reinnervation resulted in a decrease in endocytosis and a decrease in the activities of cathepsin D and NAGA toward innervated values by 21 days after nerve crush. The results suggest that membrane alterations after denervation and during reinnervation may occur by endo- and exocytosis of membrane constituents and that the lysosomal system may play a role in the breakdown and/or recycling of these structures.

Acetylglucosaminidase↗
PubMed1979

T-tubule endocytosis in dystrophic chicken muscle and its relation to muscle fiber degeneration.

Pectoralis muscles from normal and dystrophic chickens were investigated 2 h after an i.v. injection of horseradish peroxidase, by cytochemical and biochemical techniques to demonstrate peroxidase activity. Light microscopic examination of dystrophic muscles showed that peroxidase activity could be detected inside a population of fibers, in deliminated bodies often restricted to segments of the muscle fiber. Such bodies containing peroxidase were not observed in normal muscle fibers. Electron microscopy of dystrophic muscle fibers revealed that numerous vesicles containing peroxidase were frequently present in fiber regions with signs of cytoplasmic degradation. These vesicles, which occasionally were found to be coated, were 50--100 nm in size and appeared to be derived from t-tubules. Larger (up to 1.7 micrometers) inclusions containing peroxidase and delimited by a single membrane were also present at degenerating areas of dystrophic muscle fibers. These bodies seemed to be formed by fusion between several primary t-tubule vesicles and probably also lysosomes. Vacuoles containing the peroxidase were frequently encountered. Biochemical determination of horseradish peroxidase activity, performed after extensive washing of the muscle tissue, showed that dystrophic muscles contained about twice as much peroxidase as normal control muscles. It is suggested that endocytosis from t-tubules is an early and essential pathological phenomenon in dystrophic muscle fibers, which may be related to lysosomal function and muscle fiber degeneration

Animals↗
PubMed1978

4-Aminopyridine and evoked transmitter release from motor nerve endings.

1 In the presence of tetrodotoxin, electrotonic depolarization of frog motor nerve terminals causes the appearance of stimulus-graded endplate potentials. When 4-aminopyridine is added, the graded endplate potential is converted into a triggered all-or-none response resulting in giant endplate potentials of about 70 mV amplitude and 50 ms duration. The triggered endplate potentials are abolished in Ca(2+)-free saline and are blocked by Mn(2+) ions. Sr(2+) but not Ba(2+) can replace Ca(2+) in supporting transmitter release. Mg(2+) fails, even in concentrations as high as 32 mM, to affect the amplitude and the shape of the endplate potential but abolishes it when the Ca(2+) concentration is reduced to 0.2 mM.2 Despite the large amplitude of the triggered endplate potential in the presence of 4-aminopyridine and tetrodotoxin, repetitive stimulation up to 10 Hz causes only a small decline in amplitude of successive endplate potentials. However, in the presence of (+)-tubocurarine or gallamine, repetitive nerve stimulation produces a marked decline in successive endplate potential amplitude. The fall is counteracted when evoked transmitter release is reduced in the presence of 0.2 mM Ca(2+). The results suggest that in the presence of 4-aminopyridine such large amounts of transmitter are released that even during repetitive stimulation (5 to 10 Hz) endplate potentials are of maximal amplitude.3 4-Aminopyridine causes a prallel shift to the right of the dose-response curve to Mg(2+) for blockade of nerve impulse-evoked transmitter release (in the absence of tetrodotoxin). A similar parallel shift occurs in the presence of tetraethylammonium and guanidine.4 It is concluded that 4-aminopyridine increases transmitter release by enhancing the transport efficacy for Ca(2+) across the nerve terminal membrane during nerve terminal depolarization.

Aminopyridines↗
PubMed1978

Studies on neurotrophic regulation of murine skeletal muscle.

1. A quantitative comparison was made of the effects of the paralysis caused by botulinum toxin (BoTx) type A with those of surgical denervation on the development of tetrodotoxin (TTX) resistant action potentials and of extrajunctional acetylcholine (ACh) receptors in rat and mouse skeletal muscle.2. After surgical denervation, TTX resistant action potentials were present in all fibres on the third day and their rate of rise and amount of overshoot reached peak values at the fifth day. BoTx poisoning failed, despite causing complete paralysis, to induce TTX resistant action potentials in all fibres and their average rate of rise was at all times (4-12 days) only about half that in denervated fibres. Similarly BoTx poisoning induced a smaller increase than surgical denervation in the number of extrajunctional ACh receptors, measured as (3)H-labelled Naja naja siamensis alpha-neurotoxin binding sites.3. Surgical denervation of BoTx poisoned muscles induced TTX resistant action potentials in all fibres and their rate of rise and amount of overshoot were 2-3 times those in BoTx poisoned muscles only. Denervation also significantly increased the binding of labelled alpha-neurotoxin. These effects of denervation were prevented by the administration of actinomycin D, a blocker of protein synthesis.4. Administration of the alpha-neurotoxin to BoTx poisoned animals resulted in the appearance of TTX resistant action potentials in all fibres and in a significant increase in their rate of rise and overshoot.5. The results show that, despite causing complete paralysis, BoTx is less effective than surgical denervation in inducing denervatory changes in skeletal muscle. This suggests that the BoTx poisoned nerve has an influence which suppresses the appearance of denervation signs. Since the alpha-neurotoxin blocked this influence remaining release of ACh, quantal or non-quantal, may be responsible for this neurotrophic action.

Action Potentials↗