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PubMed2006

Investigation of differentially expressed proteins in rat gastrocnemius muscle during denervation-reinnervation.

To have a better insight into the molecular events involved in denervation-induced atrophy and reinnervation-induced regeneration of skeletal muscles, it is important to investigate the changes in expression levels of a great multitude of muscle proteins during the process of denervation-reinnervation. In this study, we employed an experimental model of rat sciatic nerve crush to examine the differentially expressed proteins in the rat gastrocnemius muscle at different time points (0, 1, 2, 3, 4 weeks) after sciatic nerve crush by using two-dimensional gel electrophoresis (2-DE) followed by matrix-assisted laser desorption/ionization-time-of-flight mass spectrometry (MALDI-TOF-MS), collectively referred to as the modern proteomic analysis. The results showed that 16 proteins in the rat gastrocnemius muscle exhibited two distinct types of change pattern in their relative abundance: (1) The relative expression levels of 11 proteins (including alpha actin, myosin heavy chain, etc.) were decreased either within 1 or 2 weeks post-sciatic nerve injury, followed by restoration during the ensuing days until 4 weeks. (2) The other 5 proteins (including alpha enolase, beta enolase, signal peptide peptidase-like 3, etc.) displayed an up-regulation in their relative expression levels within 1 week following sciatic nerve injury, and a subsequent gradual decrease in their relative expression levels until 4 weeks. Moreover, the significance of the changes in expression levels of the 16 proteins during denervation-reinnervation has been selectively discussed.

Animals↗
PubMed1975

Electrophysiologic studies in the denervated transplanted human heart. II. Response to norepinephrine, isoproterenol and propranolol.

Five patients who had received a transplanted human heart 1 to 3 years previously were studied to determine the effects of norepinephrine, isoproterenol and propranolol on the atrioventricular (A-V) conduction system. Using the His bundle technique, atrial, His bundle and ventricular electrograms were recorded, and central aortic pressure was monitored during the administration of these drugs. Norepinephrine was given by continuous infusion to four patients in doses ranging from 4 to 8 mug/min, with the systolic arterial pressure increasing by an average of 72 mm Hg. Concomitantly, there was an average increase in the rate of the donor atrium of 32 beats/min, and a reflex slowing of the recipient atrium of 23 beats/min. The A-H interval shortened by an average of 27 msec. Isoproterenol dose-response curves were performed in three patients, with the maximal dose being 5.2 mug by intravenous bolus infusion. The rate of the donor atrium increased by an average of 40 beats/min, and that of the recipient atrium by 18 beats/min. The A-H time shortened by an average of 25 msec, with a drop in systolic blood pressure averaging 23 mm Hg. Propranolol (7 mg intravenously) was given to three patients and the peak doses of norepinephrine and isoproterenol were again infused. Beta adrenergic blockade was achieved at this dose of propranolol since there was only a minimal increase in the donor atrial rate after infusion of the drug. The A-H interval was not altered by catecholamine infusion after achievement of beta blockade. However, the levels of systolic hypertension noted after infusion of norepinephrine was not altered by propranolol. The denervated transplanted human heart appears to respond normally to norepinephrine and isoproterenol, and the electrophysiologic effects of these agents are blocked by propranolol. Extensive investigative work in the denervated canine model has demonstrated the presence of the alpha and beta cardiovascular receptors. Although the automonic nervous system is important in cardiac performance, this work is the first validation in man that (1) the functional integrity of the beta receptor is maintained even when the autonomic nerves are absent, and (2) the intrinsic properties of the sinus and atrioventricular nodes are the keystone in stabilizing cardiac electrophysiology after denervation.

Atrioventricular Node↗
PubMed1976

The centrineurogenic etiology of the respiratory distress syndrome: induction by isolated cerebral hypoxemia and prevention by unilateral pulmonary denervation.

Twenty-eight anemic control dogs were subjected to isolated cerebral hypoxemic (PO2,35+/-5 mm Hg) perfusion for 2 hours. All were found to have functional pulmonary impairment. Two hours later, twenty were sacrificed and found to have the bilateral anatomic complex of the respiratory distress syndrome (RDS). All those not sacrificed expired within 20 hours with progressive respiratory distress and at autopsy had the bilateral anatomic complex. Twenty-three beagles with chronic denervation (autotransplantation) of the left lung also were subjected to the 2 hour isolated cerebral arterial hypoxemic perfusion. Minimal pulmonary functional impairment was measurable in all. Ten of sixteen were long-term survivors. The six that succumbed did not appear to suffer respiratory deaths. These six, as well as seven sacrificed 2 hours after perfusion, had the anatomic complex of RDS in the normally innervated right lungs. However, the denervated left lungs were anatomically normal. These findings are offered as additional evidence that RDS has a centrineurogenic etiology. We postulate the following sequence: "shock" causes cerebral (probably hypothalamic) cellular oxygen deprivation and dysfunction; there is autonomically mediated, increased resistance of the pulmonary venules ("postcapillary sphincters"); this leads to capillary hypertension, congestion, hemorrhage, edema, surfactant inactivation, and atelectasis. Pulmonary denervation blocks this sequence and protects the lung.

Animals↗
PubMed1994

Motor activity and transit in the autonomically denervated jejunum.

The role of extrinsic (autonomic) innervation in postprandial contractile activity of the small intestine is unknown. Using a canine model, we investigated the effects of complete extrinsic denervation on the parameters of fasting and postprandial jejunal contractions and their relationship to intestinal transit. Individual contractions were recorded using strain gauge transducers. Spatial and temporal parameters of contractions were analyzed by computer methods. Bolus injection of 14C-polyethylene glycol was used to calculate intestinal transit rates. Statistical comparisons of control and denervated animals were made by nonparametric tests. Extrinsic denervation did not abolish fasting or fed motor activity, but the following effects were observed: (1) the frequency of migrating motor complexes (MMCs) increased; (2) the onset of fed motor activity was delayed, and the duration of fed activity was shortened; (3) frequency, mean amplitude, and mean area of postprandial contractions were decreased; (4) fewer contractions propagated distally, and mean propagation distance was shortened; and (5) intestinal transit was slower for solids, but not for liquids. In the small intestine, extrinsic nerves modulate motor activity, which is under primary control of the intrinsic (enteric) nervous system.

Animals↗
PubMed1986

Electrical stimulation of sciatic nerve of rats after partial denervation of soleus muscle.

The purpose of this study was to determine the effect of electrical stimulation of the sciatic nerve on the recovery of the weight and tension of partially denervated rat soleus muscle. Electrodes were implanted unilaterally adjacent to the sciatic nerve in 30 adult female Wistar rats. Fifteen rats underwent bilateral partial nerve section (PNS) of the sciatic nerve to stimulate the plantar flexors. Both the normal and partially nerve sectioned animals were stimulated unilaterally with 4 ms, 2-4 mA current given at 10 pulses per second. Groups of five normal and five partially denervated animals were stimulated for two, four or eight hours per day, five days per week for six weeks. The soleus muscles were evaluated for muscle weight (MW), twitch (Pt) and tetanic (Po) tension, contraction time (CT) and fiber areas of the type 1 and type 2 fibers. The MW, Pt, Po, CT and area of the type 1 and 2 muscle fibers of the normal soleus muscles were 114 +/- 15 mg, 21 +/- 4 mg, 95 +/- 20 mg, 95 +/- 21 ms, 1532 +/- 84 microns m2 and 1267 +/- 136 microns m2 respectively. The electrical stimulation had no effect on the normal soleus muscles. The MW, Pt, Po, CT and area of type 1 and 2 muscles fibers of the partially denervated control soleus muscles were 59 +/- 12 mg, 9 +/- 4 mg, 22 +/- 14 mg, 104 +/- 32 ms, 1028 +/- 514 microns m2, and 849 +/- 292 microns m2 respectively. Two hours of electrical stimulation significantly increased the MW (87 +/- 17 g), Pt (17 +/- 6g), and Po (49 +/- 23 g) but not the type 1 and 2 fiber areas.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1979

Denervation supersensitivity to serotonin in rat forebrain: single cell studies.

To investigate the development of denervation supersensitivity to serotonin (5-hydroxytryptamine, 5-HT) in the amygdala (AMYG) and the ventral lateral geniculate nucleus (vLGN), single cell recordings, microiontophoretic, histochemical and biochemical techniques were used in the present study. 5-HT projections to the vLGN and the AMYG were destroyed by 5,7-dihydroxytryptamine (5,7-DHT, a relatively selective toxin for 5-HT neurons) injected directly into the lateral ventricle or the ascending 5-HT pathway in the ventromedial tegmentum area. Enhanced responsiveness of cells to the inhibitory effect of microiontophoretically applied 5-HT (ionto-5-HT) began to develop within 24 h and approached a maximum 7 days after 5,7-DHT pretreatment. In general, the time courses for the reduction in both the density of 5-HT fluorescent varicosities and synaptosomal 5-HT uptake activity paralleled the time course for the development of denervation supersensitivity to 5-HT. During the first 2 days after 5,7-DHT, the enhanced sensitivity was selective for 5-HT; responses to D-lysergic acid diethylamide (LSD), norepinephrine (NE) and gamma-aminobutyric acid (GABA) were unchanged. Seven or more days after 5,7-DHT there was a marked increase of the responsiveness of neurons in the vLGN and the AMYG to both 5-HT and LSD (a 5-HT agonist which is not a substrate for the high affinity 5-HT uptake system). At these later times, the responsiveness of cells in the AMYG to NE and to a lesser extent GABA was also increased. In contrast to the marked supersensitivity seen after 5,7-DHT induced denervation, chronic administration of parachlorophenylalanine, a 5-HT synthesis inhibitor, failed to induce 5-HT supersensitivity.

5,7-Dihydroxytryptamine↗
PubMed1980

Monoaminergic denervation of the rat hippocampus: microiontophoretic studies on pre- and postsynaptic supersensitivity to norepinephrine and serotonin.

The responsiveness of hippocampal CA3 pyramidal neurons to microiontophoretic applications of serotonin (5-HT), norepinephrine (NE), gamma-aminobutyric acid (GABA) and isoproterenol (ISO) was assessed in rats following 5,7-dihydroxy-tryptamine (5,7-DHT) and 6-hydroxydopamine (6-OHDA) pretreatments and bilateral locus coeruleus lesions. The intraventricular administration of 200 micrograms (free base) of 5,7-DHT and of 6-OHDA produced 89% and 93% decreases of 5-HT and NE respectively. None of these pretreatments modified the inital responsiveness to, or recovery from iontophoretic application of 5-HT. In 6-OHDA pretreated and locus-lesioned rats, the initial effectiveness of NE was not altered but its effect was markedly prolonged. However, there was no such prolongation of the effect of ISO which is not a substrate for the high affinity NE reuptake. The effect of GABA was not affected by these pretreatments. Acute pharmacological blockade of the NE reuptake with desipramine (5 mg/kg, i.p.) similarly induced a prolongation of the effect of iontophoretically applied NE, while fluoxetine (10 mg/kg, i.p.) a 5-HT reuptake blocker, failed to alter the recovery of pyramidal cells from iontophoretic application of 5-HT. It is concluded that 5-HT denervation induces neither pre- nor postsynaptic types of supersensitivity in hippocampal pyramidal cells, contrasting with the previously shown supersensitivity of ventral lateral geniculate and amygdaloid neurons following 5-HT denervation. NE denervation fails to induce a postsynaptic type of supersensitivity but leads to a marked prolongation of the response to NE indicative of a presynaptic mechanism. These results underscore the necessity for regional studies of neurotransmitters and drug action.

Animals↗
PubMed1980

Denervation-induced decreases in enzyme activity of rat superior cervical ganglia differ in vivo and in vitro.

The decrease in tyrosine hydroxylase activity following denervation in vivo and subsequent culture in vitro was examined to determine the role of the preganglionic nerve in this decrease. Ganglia denervated in vivo prior to culture showed a greater decrease than ganglia maintained for the same total period in vitro, and hence denervated for the same time, suggesting factors in addition to the loss of the preganglionic nerve are involved in vivo.

Aging↗
PubMed1982

Altered neuronal responsiveness to biogenic amines in rat cerebral cortex after serotonin denervation or depletion.

To further investigate monoaminergic mechanisms in cerebral cortex, responsiveness of cortical neurons to microiontophoretic applications of serotonin (5-HT), dopamine (DA) or noradrenaline (NA) was examined in the frontoparietal region of control, 5,7-dihydroxytryptamine (5,7-DHT)- and p-chlorophenylalanine (PCPA)-treated rats anesthetized with urethane. As a rule, 100 nA applications of either one of these biogenic amines induced marked slowing or total interruption of 'spontaneous' firing overlasting the 30 s period of ejection. Given the large amounts of monoamines ejected, it could be inferred that such microiontophoretic applications produced a maximal activation of receptors. In control rats, the responses to 5-HT, DA and NA were of approximately equal duration (approximately equal to 5 min). Two to 4 weeks after denervation with 5,7-DHT, most neurons (75%) exhibited greatly prolonged responses to 5-HT (approximately equal to 14 min), and marked depressions of firing could be induced by small ejection currents (approximately equal to 2 nA) having little or no effect in the controls. In addition, 85% of the units supersensitive to 5-HT showed considerably shortened responses to DA and NA (approximately equal to 1 min). After 2-14 days of depletion with PCPA, there was no change in the responsiveness to 5-HT in spite of a 91% lowering of cortical 5-HT content equivalent to that measured after denervation. Nevertheless, responsiveness to DA and NA was again diminished in a majority (80%) of the units tested. In control or PCPA-treated rats, acute administration of the 5-HT re-uptake blocker fluoxetine increased the duration of depressions induced by 100 nA applications of 5-HT but did not enhance responsiveness to low ejection currents. This suggested that, after 5-HT denervation, the suppression of re-uptake was mainly responsible for the prolongation of 5-HT responses ('presynaptic' component of supersensitivity), whereas a modification of 5-HT receptors accounted for the greater efficacy of small doses of 5-HT ('postsynaptic' component). Responsiveness to the microiontophoretic application of phenylephrine (PHE), a noradrenergic a-agonist, was comparable with that to NA in PCPA- and 5,7-DHT-treated as well as in control rats. Therefore, the hyposensitivity to DA and NA appeared indicative of a desensitization of catecholamine receptors caused by the absence of 5-HT. Such a desensitization may be viewed as an adaptive change resulting from an increased release of endogenous DA and NA. This interpretation would in turn imply that, normally, 5-HT regulates catecholamine release in the neocortex.

Afferent Pathways↗
PubMed1983

Alpha 1-adrenoceptor denervation supersensitivity in brain: physiological and receptor binding studies.

Electrophysiological and radioligand binding methods were used to characterize noradrenergic denervation supersensitivity at alpha 1-adrenoceptors in rat thalamus. Denervation was accomplished either by intraventricular or intracerebral injection of the catecholamine neurotoxin 6-hydroxydopamine (6-OHDA). In the physiological studies, the sensitivity of single lateral geniculate neurons to norepinephrine, carbachol, and serotonin was compared in sham and lesioned animals various times after 6-OHDA. Conducted in parallel were radioligand binding studies in which the density and affinity of thalamic alpha 1-adrenoceptors were measured with the specific antagonist [3H]prazosin. The results indicate that denervation produces a selective increase in the sensitivity of geniculate neurons to alpha 1-adrenergic stimulation and a concomitant increase in alpha 1-adrenoceptor density and agonist affinity.

Animals↗
PubMed1984

Muscles of adult rats and mice express the Thy-1 glycoprotein on denervation.

Adult-skeletal muscles when denervated undergo extensive changes in biochemical and physiological properties. Many of these changes, for example the appearance of acetylcholine receptors along the length of the fibres, are characterized by a reacquisition of features normally found in developing muscles. This generalization can now be extended to the surface glycoprotein, Thy-1, which is expressed in myoblasts and transiently in newly fused myotubes in culture, for we have found that denervation leads to extensive production of Thy-1 in hindlimb muscles of adult rats and mice where its expression is normally very low. In addition, there is a slight transient rise in Thy-1 in muscles contralateral to the denervation.

Animals↗
PubMed1985

Myotrophic effects on denervation atrophy of hindlimb muscles of mice with systemic administration of nerve extract.

Atrophy was assessed in denervated hindlimb muscles of adult mice which either were not otherwise treated or received daily intraperitoneal injections of extract of rats' sciatic nerves. After 7 days, the denervated muscles of injected animals exhibited significantly smaller decreases in wet weight, total protein and cross-sectional areas of muscle fibers relative to innervated contralateral control muscles. The effects of denervation and nerve extract on different muscles varied.

Animals↗
PubMed1986

Simultaneous measurement of dopamine release and rotational behaviour in 6-hydroxydopamine denervated rats using intracerebral dialysis.

Amphetamine- and L-DOPA-induced changes in extracellular levels of striatal dopamine (DA) were monitored during rotational behaviour in rats with a unilateral 6-hydroxydopamine (6-OHDA) lesion of the nigrostriatal DA pathway. In vivo DA release measurements were obtained using intracerebral dialysis combined with high-performance liquid chromatography with electrochemical detection (HPLC-ED). In unilaterally denervated rats no DA was detected in dialysates collected from the striatum ipsilateral to the lesion while the contralateral side showed a compensatory increase in basal DA levels when compared to non-lesioned controls. Amphetamine (0.5-5.0 mg/kg s.c.) caused a dose-dependent release of DA in the striatum of normal rats and in the intact striatum of DA denervated rats but did not significantly release DA in the lesioned striatum. In response to amphetamine (0.5-5.0 mg/kg s.c.) lesioned animals showed dose-related ipsilateral rotational behaviour which in general correlated well with the time-course change in, and the total amount of, DA release in striatum contralateral to the lesion. In contrast to amphetamine, in lesioned rats, the DA precursor L-DOPA (20 mg/kg s.c.) induced readily detectable amounts of DA in dialysates collected from the DA denervated striatum. The L-DOPA-induced appearance of DA, which approached basal DA levels seen on the intact side, was concomitant with contralateral rotational behaviour. However, the time-course change in DA levels did not closely correlate with the apparently two-peak pattern of contralateral rotation induced by L-DOPA.

Amphetamine↗
PubMed1987

Musculotrophic effects of insulin receptors before and after denervation.

Insulin binding and metabolic effects have been used to assess properties of the insulin receptor of rodent skeletal muscles before and after denervation. It has been found that the amount of insulin-displaceable insulin binding on both type I (soleus) and type II (extensor digitorum longus) muscles rises slowly for up to 3 weeks after denervation, following a brief period of reduced binding. As estimated from weight loss and unstimulated deoxyglucose uptake, the extra binding sites are not functional. Stimulation in vitro with shocks or excess potassium can temporarily cause a relative increase in sugar uptake in both types of muscle, but an excess of insulin rapidly loses its effect in the soleus muscle. The effects of stimulation are taken to mean either conformational changes in the receptor or enhancement of some postbinding step, or both. It is suggested that the slow increase of binding sites for insulin after denervation may reflect loss of a neural substance normally effective in activating receptor degradation.

Animals↗
PubMed1989

Cholesterol conservation in skeletal muscle associated with age- and denervation-related atrophy.

The lipid composition of muscles with age- and denervation-atrophy was assayed in whole muscle and isolated sarcolemma of rats aged 10 and 25 months. Although muscle mass decreased at least 17% during aging, muscle cholesterol concentration rose 15-20%. However, phospholipid concentrations were maintained; therefore, the cholesterol-to-phospholipid ratio increased during aging. Plasma cholesterol levels also rose 35%, but this could account for only about 10% of the age-related difference in muscle cholesterol. Likewise, following denervation (7 days) muscle mass decreased by at least 30%, but muscle cholesterol-to-phospholipid ratio increased; the magnitude of the denervation-induced response was unaffected by aging. To localize the source of cholesterol deposition during aging, these assays were repeated on isolated sarcolemma, sarcoplasmic reticulum, and mitochondria membrane fractions. Neither cholesterol nor phospholipid levels changed significantly with age in any of these major membrane systems. Furthermore, sarcolemmal fluidity, which depends on cholesterol content, did not vary significantly with age. At this level of resolution, it thus appears that skeletal muscle membrane phospholipid composition and fluidity do not change appreciably with age. Elevated cholesterol-to-phospholipid ratios detected in whole muscle may be due to cholesterol deposition in non-myofiber locations.

Aging↗
PubMed1991

Nerve sprouting and endplate growth induced in normal muscle by contralateral partial denervation of rat plantaris.

The incidence of motor nerve and terminal sprouting was quantitatively analyzed in normal unoperated muscles, in homologous muscles contralateral to muscles which have been partially denervated, in partially denervated muscles, and in sham-operated muscles. Muscles were studied by light microscopy after staining motor endplates by a combined silver-cholinesterase stain. In addition, the incidence of endplates containing terminal sprouts, the number of terminal branch points per endplate, and endplate, and endplate size were also assessed in the various groups examined. We observed that following section of the L4 spinal nerve, the incidence of sprouting (preterminal and intranodal) in the contralateral muscle exhibited a 2-fold increase over sham-operated controls. We also found a correlation between nerve terminal sprouting, terminal branch point number and endplate size. All of these parameters were significantly increased in the contralateral muscles as compared to the sham-operated control muscles. These findings suggest that normal muscles undergo sprouting which can be enhanced by contralateral partial denervation. The possible underlying mechanism may be the transneuronal induction of sprouting.

Animals↗
PubMed1995

Denervation induced abnormal phosphorylation in hippocampal neurons.

This study demonstrates that combined dopaminergic and cholinergic denervation of the hippocampus results in the appearance of morphologically altered, Tau reactive, apical dendrites of granule cells in the rat dentate gyrus. The denervated granule cells and their apical dendrites also display immunoreactivity to a mitogen-activated protein kinase, ERK-1, and also evidence of abnormal phosphorylation of these dendrites as revealed by SMI-31 immunoreactivity. Dopaminergic denervation alone also causes mitogen activated protein kinase reactivity without the Tau-reactive apical dendrities. These results suggest an analogy to synaptophysin loss and the appearance of dendritic threads described in Alzheimer's disease (AD), as an early stage in the formation of neurofibrillary tangles (NFT). This is the first animal model in which abnormal phosphorylation of Tau has been shown to be produced experimentally in vivo.

Alzheimer Disease↗
PubMed1995

Hippocampal sympathetic ingrowth and cholinergic denervation uniquely alter muscarinic receptor subtypes in the hippocampus.

Following cholinergic denervation of the hippocampus by medial septal lesions, and unusual neuronal reorganization occurs, in which peripheral sympathetic fibers, originating from the superior cervical ganglia, grow into the hippocampus. Previously, we have found that both hippocampal sympathetic ingrowth (HSI) and cholinergic denervation (CD), alone, altered the total number and affinity of muscarinic cholinergic receptors (mAChR). In this study, we utilized the muscarinic antagonist [3H]Pirenzepine, in combination with membrane radioligand binding techniques, to determine the effects of HSI and CD on hippocampal M1 and M1 + M3 mAChR subtypes, 4 weeks after MS lesions. In both the dorsal and ventral hippocampus, HSI was found to markedly diminish the number of M1 AChRs, while CD was found to increase the number of M1 AChRs. Neither treatment affected the affinity of the M1 AChR. However, when M1 + M3 binding was assessed, CD was found to decrease the affinity in both hippocampal regions, without altering the number of receptors. Neither affinity nor number of M1 + M3 receptors was altered by HSI. The results of this study suggest that both cholinergic denervation and hippocampal sympathetic ingrowth uniquely affect hippocampal muscarinic receptors.

Acetylcholine↗