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PubMed2001

Selective cholinergic denervation inhibits expression of long-term potentiation in the adult but not infant rat hippocampus.

The present study assessed the role of the cholinergic systems on the expression of perforant path long-term potentiation (LTP) in rat hippocampal slices from the infant and adult brain. To denervate the cholinergic systems, 192 IgG--saporin was injected into the lateral ventricle of the infant (2-weeks-old) and adult (6-weeks-old) rat brain. There, choline acetyltransferase-immunoreactive fibers were barely detectable 2 weeks and 2 months after injection for both the groups. For the infant rats, perforant path LTP was not affected by selective cholinergic denervation; the probability of LTP development was 0.83 (five out of six slices) and 0.78 (seven out of nine slices) at 2 weeks and 2 months later in 192 IgG--saporin-treated slices, as compared with 0.83 at each period in control saline-treated slices. In contrast, the expression of the LTP was blocked by selective cholinergic denervation for the adult rats; the probability of LTP development was 0 (zero out of 10 slices) and 0.38 (three out of eight slices) at 2 weeks and 2 months later in 192 IgG--saporin-treated slices, as compared with 0.8 (eight out of 10 slices) and 0.83 (five out of six slices) at each period in control saline-treated slices. The results of the present study thus suggest that the cholinergic systems play a crucial role in the expression of LTP in the adult brain and that the denervated systems in the infant brain could be compensated by the sprouting of non-cholinergic fibers.

Age Factors↗
PubMed2003

Neonatal focal denervation of the rat olfactory bulb alters cell structure and survival: a Golgi, Nissl and confocal study.

Contact between sensory axons and their targets is critical for the development and maintenance of normal neural circuits. Previous work indicates that the removal of afferent contact to the olfactory bulb affects bulb organization, neurophenotypic expression, and cell survival. The studies also suggested changes to the structure of individual cell types. The current work examines the effects of denervation on the morphology of mitral/tufted, periglomerular, and granule cells. Focal denervation drastically changed mitral/tufted cell structure but had only subtle effects on periglomerular and granule cells. Denervated mitral/tufted cells lacked apical tufts and, in most cases, a primary dendrite. In addition, the denervated cells had more secondary processes whose orientation with respect to the bulb surface was altered. Our results suggest that contact between olfactory axons and the bulb is necessary for cell maintenance and may be critical for the ability of mitral/tufted cells to achieve adult morphology

Animals↗
PubMed1986

Glucose-6-phosphatase activity in normal and denervated developing chick gastrocnemii: reappraisal of glycogenolytic and glycolytic metabolism in skeletal muscle.

Biochemical changes in glycogen content and activity levels of phosphorylase (EC 2.4.1.1), glucose-6-phosphatase (EC 3.1.3.9), phosphohexose isomerase (EC 5.3.1.9) and aldolase (EC 4.1.2.13) have been studied in normal and denervated whole gastrocnemius muscle and its three fasciculi, viz., pars externus, medius and internus up to 9 weeks in chicks. Glycogen content as well as phosphorylase, phosphohexose isomerase and aldolase decrease in normal muscle with advancement of postembryonic growth whereas transiently increased glucose-6-phosphatase reveals an inverse relationship with these parameters. Denervated muscles demonstrate loss of glycogen and related enzymes owing to ablation of neural supply during the initial 4 weeks. Denervation results in a delayed stimulation of glycogenolysis and glycolysis which seems to be governed by decreasing activity of glucose-6-phosphatase. The significance of glucose-6-phosphatase in the regulation of glycogenolysis and glycolytic metabolism of normal and denervated skeletal muscle is discussed.

Animals↗
PubMed2000

Repeated administration of high dose levodopa enhances hydroxyl radical production in the rat striatum denervated with 6-hydroxydopamine.

We examined whether levodopa (L-DOPA) might increase production of hydroxyl radicals in intact and dopamine-denervated rat striatum. Salicylate trapping combined with in vivo microdialysis provided measurements of 2,3-dihydroxybenzoic acid (2,3-DHBA) as a marker of hydroxyl radical production. Acute administration of high-dose L-DOPA (200, 500 mg/kg, i.p.) did not alter 2,3-DHBA levels in intact striatum or in striatum denervated with 6-hydroxydopamine. On the other hand, L-DOPA administration (200 mg/kg, i.p.) transiently increased 2,3-DHBA in dopamine-denervated striatum of rats after repeated administration of L-DOPA (200 mg/kg, i.p., once daily for 16 days). The results indicated that repeated administration of high dose L-DOPA increased production of hydroxyl radicals in dopamine-denervated striatum.

Animals↗
PubMed2000

Aquaporin 4: lack of mRNA expression in the rat regenerating muscle fiber under denervation.

The recently identified water channel aquaporin 4 is a major component of the orthogonal arrays observed with freeze-fracture electron microscopy. We examined the expression of aquaporin 4 mRNA and protein in rat regenerating muscle under innervated and denervated conditions. We found decreased sarcolemmal immunostaining of aquaporin 4 in denervated regenerating muscle as opposed to innervated muscle. Quantitative reverse transcription-polymerase chain reaction revealed that aquaporin 4 mRNA was expressed in the innervated regenerating muscle; whereas it was not expressed in denervated muscle. Thus, lack of aquaporin 4 protein may be due to lack of aquaporin 4 mRNA in the denervated regenerating muscle. We conclude that the nerve supply influences expression of aquaporin 4 at the mRNA level in regenerating muscle.

Animals↗
PubMed2003

Total antioxidant capacity following extrinsic denervation and small intestinal transplantation in the rat.

Transplantation of small intestine in a rat model has been shown to affect expression of neurochemicals within enteric inhibitory nerves. However, the mechanism for altered expression of inhibitory neurochemicals is uncertain. Based on our previous studies, we hypothesized that small intestinal transplantation would result in altered intestinal levels of antioxidant capacity. Glutathione, total antioxidant capacity, and lipid peroxide levels were measured at 3 months following (1) transection of rat small intestine, (2) transection and extrinsic denervation of rat intestine, and (3) isotransplantation of rat ileum or (4) allotransplantation of rat ileum with cyclosporine therapy to suppress rejection. Glutathione levels were not significantly different among the four groups. There were trends toward increased lipid peroxide levels following isografting and extrinsic denervation. Total antioxidant capacity was increased following extrinsic denervation (P=0.05). Increased intestinal total antioxidant capacity in response to extrinsic denervation may represent a compensatory mechanism for protection against oxidative stress. This result enhances our understanding of the relationship between tissue antioxidant levels and alteration of enteric nerves.

Animals↗
PubMed1997

Morphological and biochemical adaptations to unilateral dopamine denervation of the neostriatum in newborn rats.

Basal ganglia of adult rats were examined for morphological and biochemical changes resulting from neonatal unilateral dopamine denervation of the striatum with increasing doses of 6-hydroxydopamine (4, 12 and 20 microg). Rotational behaviour induced by apomorphine (0.1 mg/kg) was observed in all rats injected with the high dose (20 microg) and totally absent in those injected with the low dose (4 microg). As assessed with tyrosine hydroxylase immunocytochemistry, the extent of dopamine denervation within the injected striatum was clearly related to the dose injected. In the mesencephalon, losses of tyrosine hydroxylase-immunoreactive cell bodies were proportional to the dose injected and the extent of neostriatal dopamine denervation. This retrograde cell loss predominated in the ventromedial and lateral parts of the substantia nigra pars compacta, with relative sparing of the ventral tegmental area. After the injection of the intermediate (12 microg) and the high (20 microg) doses, a network of thin tyrosine hydroxylase-immunoreactive fibres was visualized in the ventral part of the pars reticulata ipsilateral to the injected striatum, suggesting a neoinnervation of this structure by dopamine axons. After the high dose, the density of serotonin-immunoreactive fibres was enhanced in the anterior half of the lesioned striatum. Associated changes in dopamine and serotonin content and turnover were also documented on both sides, in the striatum and in two output structures of the basal ganglia, the globus pallidus and the substantia nigra. Dopamine content was decreased only on the injected side. After the low dose, equal reductions (-60%) were observed in the anterior striatum and the substantia nigra, whereas a more marked decrease was measured in the anterior striatum (-93%) than in the substantia nigra (-60% to -74%) after the intermediate and high doses. In the globus pallidus, dopamine tissue content was decreased (-51%) only after the high dose. Dopamine turnover was unchanged after the low dose in all structures examined and was increased in the striatum, on the lesioned side only, after the intermediate and high doses. Serotonin content was increased only on the injected side in the anterior striatum (+50% after the low and +92% after the high dose). Serotonin turnover was unchanged on the injected side but increased by +118% and by +81% in the contralateral anterior striatum after the low and high doses, respectively. It was also increased in both substantia nigra after the high dose. In conclusion, morphological changes similar to those described after a bilateral neonatal lesion were observed on the injected side in the model of the unilateral neonatal nigrostriatal dopamine denervation. Biochemical changes were, however, not restricted to the lesioned side. Notably, changes in serotonin turnover developed on the contralateral side. These morphological and biochemical adaptative changes need to be taken into account in considering the mechanisms implicated in the rotional behaviour measured in these animals.

3,4-Dihydroxyphenylacetic Acid↗
PubMed1998

Changes in tyrosine hydroxylase and substance P immunoreactivity in the cat carotid body following chronic hypoxia and denervation.

Long-term hypoxia elicits functional changes in the cat carotid body which are manifest as altered chemosensitivity in response to hypoxia. Previous studies have suggested that these functional adjustments may be mediated by changes in neurotransmitter levels in chemosensory type I cells. Neurotransmitter metabolism in the carotid body has also been shown to be regulated by the neural innervation to the organ. The present study using the cat carotid body demonstrates profound changes in the levels of immunoreactivity of the catecholamine-synthesizing enzyme, tyrosine hydroxylase, and the neuropeptide, substance P, in response to a two-week exposure to hypoxia (10% O2 in 90% N2). Furthermore, these changes were modulated both by sensory and sympathetic denervation of the organ. For TH, the intensity of immunostaining in type I cells was markedly increased by long-term hypoxia in both normal and chronic carotid sinus nerve-denervated carotid bodies, but this effect was blocked following chronic sympathectomy. Substance P immunoreactivity in type I cells was dramatically attenuated by hypoxia in both intact and chronic carotid sinus nerve-denervated preparations, but this effect was reduced following chronic sympathectomy. Tyrosine hydroxylase- and substance P-positive axon terminals were observed to innervate type I cells. These axons were also present in chronically sympathectomized preparations, but they disappeared following chronic carotid sinus nerve-denervation suggesting that they very likely arise from sensory neurons in the petrosal ganglion. Our data indicate that chronic chemoreceptor stimulation by hypoxia elicits multiple neurochemical adjustments in the cat carotid body. These changes suggest that catecholaminergic enzymes and neuropeptides play a significant role in the adaptive mechanisms of chemoreceptor function which occur in response to chronic physiological stimulation. Furthermore, the data suggest that neurotrophic mechanisms may influence neurotransmitter metabolism in chemosensory type I cells.

Animals↗
PubMed2002

Denervation impairs healing of the rabbit medial collateral ligament.

Little is known about the contribution of innervation to ligament healing after traumatic disruption, although there is good evidence of an important role for the peripheral nervous system in the healing of fractures and skin injuries. Tissues such as ligament, with a low resting blood supply, are dependent on substantial increases in blood flow and vascular volume during the initial stages of repair. We hypothesized that this initial healing response would be strongly promoted by neurogenic inflammation. Since the saphenous nerve (a major sensory branch of the femoral nerve) supplies the medial half of the knee joint, we elected to use femoral nerve transection as a model to determine the role of sensory and autonomic innervation in the initial outcome of repair of the injured medial collateral ligament. Twelve adult, female NZW rabbits underwent right medial collateral ligament transection. Of these, six rabbits underwent right femoral nerve transection to disrupt the somatic sensory and autonomic nerve supply to the knee joint and six were kept neurologically intact (controls). At six weeks post-injury, the animals were assessed by laser Doppler perfusion imaging (LDI) to determine the local blood flow, at both the injury site and at the uninjured contralateral ligament. The animals were then killed, the knee joints were removed and the biomechanical characteristics of the healing bone-median collateral ligament (MCL)-bone complexes assessed. In a separate cohort of 16 rabbits, vascular volumes of the injured ligaments were measured by infusion of a carmine red/gelatin solution. At six weeks post-injury, in vivo measurement of perfusion with LDI revealed that normally innervated ligaments had an almost three-fold higher average blood flow. Carmine red/gelatin infusion revealed a 50% higher density of blood vessels as compared to denervated ligaments. The force required for ultimate failure was found to be 50% higher in normally innnervated MCL's as compared to denervated MCL's: 153.14 +/- 20.71 N versus 101.29 +/- 17.88 N (p < 0.05). Static creep was increased by 66% in denervated MCL's: 2.83 +/- 0.45% versus 1.70 +/- 0.12% (p < 0.05). Total creep was increased by 45% in denervated MCL's: 5.29 +/- 0.62% compared to 3.64 +/- 0.31% in innervated MCL's (p < 0.05). We conclude that intact innervation makes a critical contribution to the early healing responses of the MCL of adult rabbits.

Animals↗
PubMed2002

Selective joint denervation promotes knee osteoarthritis in the aging rat.

Osteoarthritis is the most common joint disorder with aging, but its cause is unknown. Mice lose joint afferents with aging, and this loss precedes development of osteoarthritis. We hypothesized a loss of joint afferents is involved in the pathogenesis of osteoarthritis. To test this hypothesis, we denervated knee joints of 16 rats at age 2 months, by intra-articular injection of an immunotoxin. The immunotoxin killed neurons after retrograde axonal transport to the cell body. At 16 or 24 months follow-up, each joint was histologically assessed and assigned an osteoarthritis score. At follow-up, the number of joint afferents had spontaneously decreased by 42% in control knees and 69% in denervated knees. We found that control knees developed osteoarthritic changes with aging. However, denervated knees had far more severe changes, as evidenced by a 54% higher average osteoarthritis score than control knees (P = 0.0016, both groups 16 knees). These results suggest a loss of afferents predisposes a joint to osteoarthritis. We propose the spontaneous loss of neurons with aging may be a normal developmental process. To explain the mechanism causing osteoarthritis, we suggest denervation permits aberrant joint loading, either by disturbing neuromuscular joint control, or by inducing joint laxity after neurogenic loss of tissue homeostasis.

Aging↗
PubMed2003

Selective peripheral denervation of the levator scapulae muscle for laterocollic cervical dystonia.

Laterocollis, as a symptom of idiopathic cervical dystonia may be due to abnormal contraction of the levator scapulae muscle (LSM). The purpose of this study is to define the effects of selective peripheral denervation of LSM in patients with laterocollic cervical dystonia.The clinical records of 10 patients who underwent LSM denervation for laterocollic torticollis were reviewed. Preoperatively, all patients showed sustained lateral tilt of the head and elevation of the shoulder. Abnormal contraction of LSM was observed and the muscle was denervated surgically in the posterior cervical triangle. The mean age at operation was 38.4 years (range, 20-58 years) and the mean duration of the symptom ranged from 14 to 80 months (mean, 41months). The postoperative follow up ranged from 6 to 72 months (mean, 29.4months). The cervical dystonia rating score of Tsui was 10.8 on average before the operation, and the postoperative follow up score was 1.3. According to the changes of the rating score, success rates, including excellent and good results, were 40% and 60%, respectively. Five patients (50%) postoperatively showed transient dysaesthesia in the neck. There was no disturbance of shoulder elevation or arm raising. When abnormal contraction of LSM is responsible for laterocollis in patients with cervical dystonia, selective peripheral denervation of this muscle is a safe and effective procedure for alleviation of the symptom.

Adult↗
PubMed2003

Denervation and repeated L-DOPA induce a coordinate expression of the transcription factor NGFI-B in striatal projection pathways in hemi-parkinsonian rats.

Repeated intermittent administration of L-DOPA in rats with a unilateral 6-hydroxydopamine (6-OHDA) lesion of the nigrostriatal pathway results in a progressive increase of contraversive circling behavior. In this study, we have investigated the effects of denervation and repeated L-DOPA administration on the expression of the nuclear receptor nerve growth factor inducible-B (NGFI-B) in striatal output pathways of unilaterally 6-OHDA-lesioned rats. The denervation process induced an increase of NGFI-B and enkephalin (ENK) mRNA levels and the increase of NGFI-B took place predominantly in ENK-containing cells. The percentage of cells colocalizing NGFI-B and dynorphin (DYN) was significantly reduced. Repeated L-DOPA treatment increased the striatal level of DYN mRNA but it further reduced the percentage of NGFI-B/DYN double-labeled cells. On the intact side, repeated L-DOPA treatment increased NGFI-B expression in both striatal subpopulations. Additional acute studies were performed in normal rats to determine the role of the denervation process in the coordinate expression of NGFI-B in striatal subpopulations. A combination of selective D(1) and D(2) agonists induced an important increase of striatal NGFI-B expression selectively in DYN-containing neurons. These results demonstrate that the denervation process causes a differential regulation of NGFI-B in the two striatal output pathways which is further exacerbated by L-DOPA treatment. These molecular changes in response to dopamine depletion and dopamine replacement therapy may contribute to the long-term effects of L-DOPA and to the development of behavioral sensitization.

Animals↗
PubMed2003

Nogo (Reticulon 4) expression in innervated and denervated mouse skeletal muscle.

The nogo gene encodes at least three different proteins, which share a high C-terminal homology with other members of the Reticulon family. Nogo (Reticulon 4) expression has been studied in innervated and denervated mouse hind-limb and hemidiaphragm muscles. A common Nogo A, B, and C probe hybridized to three transcripts, in accordance with human and rat data. Denervation caused decreased Nogo C and increased Nogo A mRNA expression, while Nogo B was not substantially altered. Western blots and immunohistochemistry confirmed the presence of Nogo A-like and Nogo B-like immunoreactivity in muscle. Nogo A-like immunoreactivity increased after denervation and was also present in intramuscular nerves in both innervated and denervated muscle. Nogo B-like immunoreactivity was observed in connective tissue surrounding muscle fibres and nerves. The different Nogo transcripts are produced by both alternative splicing (A and B) and alternative promoter usage (C); both mechanisms seem to be under neural control in skeletal muscle.

Animals↗
PubMedDate not supplied

Neuronal adrenergic and muscular cholinergic contractile hypersensitivity in canine jejunum after extrinsic denervation.

Extrinsic denervation may be responsible for motor dysfunction after small bowel transplantation. The aim of this study was to examine the role of extrinsic innervation of canine jejunum on contractile activity. An in vitro dose response of cholinergic and adrenergic agonists was evaluated in canine jejunal strips of circular muscle at 0, 2, and 8 weeks in a control group and after jejunoileal extrinsic denervation (EX DEN). Neurons in circular muscle were quantitated by means of immunohistochemical techniques. Adrenergic and cholinergic responses did not differ at any time in the control group. However, at 2 and 8 weeks, extrinsic denervation caused an increased sensitivity to the procontractile effects of the cholinergic agonist bethanechol at the level of the smooth muscle cells, and increased sensitivity to the inhibitory effects of the adrenergic agent norepinephrine mediated at the level of the enteric nervous system. Immunohistochemical analysis showed a reduction in all neurons and a complete lack of adrenergic fibers in the EX DEN group after 2 and 8 weeks. Extrinsic denervation induces enteric neuronal cholinergic and adrenergic smooth muscle hypersensitivity in canine jejunal circular muscle.

Acetylcholine↗
PubMedDate not supplied

Small bowel extrinsic denervation does not alter water and electrolyte absorption from the colon in the fasting or early postprandial state.

Small bowel transplantation (SBT) causes watery diarrhea. The decreases shown previously in absorption of water, electrolytes, and bile salts in the jejunum and ileum, although present, are not dramatic and seem not to be great enough to explain the diarrhea. Our aim was to determine changes in water and electrolyte absorption in the colon during fasting and postprandially in a canine preparation of jejunoileal extrinsic denervation, which serves as a model of jejunoileal autotransplantation. We hypothesized that colonic absorption of water and electrolytes decreases transiently in the colon after SBT. Six dogs had cannulas implanted in the colon to study absorption of an ileal-like basal electrolyte solution with or without 10 mmol/L glucose. Absorption during fasting and postprandially was measured before and 2 and 12 weeks after a validated preparation of jejunoileal extrinsic denervation. All dogs developed diarrhea after SBT. Net colonic absorptive fluxes of water and electrolytes in the colon did not change from baseline values at 2 or 12 weeks after extrinsic denervation, either during fasting or postprandially; glucose in the infusate did not alter absorptive fluxes during fasting or postprandially. Extrinsic denervation of the small intestine does not appear to alter colonic absorption of water or electrolytes during fasting or postprandially. These observations suggest that the neurally intact colon has a minimal role in the diarrhea after SBT.

Animals↗
PubMed2003

An implantable device for stimulation of denervated muscles in rats.

The purposes of the present study were (1) to develop an implantable device capable of being pre-programmed to generate a protocol of chronic contractions in denervated hind-limb muscles of rats, and (2) to verify the design by implanting the stimulators for five weeks in rats to identify a protocol of stimulation that maintains muscle mass and maximum force in stimulated-denervated extensor digitorum longus (EDL) muscles. This implantable stimulator system did not hinder animal movement or hygiene, and enabled the animals to be housed in regular animal facilities, since neither external equipment nor an externally generated magnetic field was required. The pre-programmable microcontroller allows detailed basic research into the cellular and tissue response to different stimulation protocols. The micropower design of the battery powered device enabled chronic stimulation of denervated EDL muscles for the five weeks of this initial study. Stimulation protocols of 9-11 V pulse amplitude, 0.4 ms bipolar pulse width, 100 Hz, 20 pulses per contraction, and 100 or 300 contractions generated per day maintained muscle mass and maximum force in denervated EDL muscles of rats at values near control values for innervated muscles.

Animals↗
PubMed1979

The effects of partial chronic denervation on forearm metabolism.

Effects of chronic denervation upon in vivo forearm metabolism were studied in six patients and six controls. The diagnosis was amyotrophic lateral sclerosis in four patients, the neuronal form of Charcot-Marie Tooth disease in one patient, and an unclassified chronic disease of the lower motor neurons in one patient. In all cases the forearm muscles showed clinical weakness and electrical evidence of denervation, while muscle biopsy from a proximal muscle of the upper limb showed typical denervation atrophy. At rest there was increased oxygen utilization and lactate output as well as a tendency for increased uptake of glucose and long chain fatty acids from arterial blood per 100 ml of forearm tissue. During exercise the abnormally high lactate output increased further. An increased arterial lactate concentration was present during rest and exercise. Oxidation of fatty acids was not impaired. It is suggested that these abnormalities are consistent with an augmented utilization of blood borne fuels at rest by denervated muscles. A concurrent regional ischemia of muscles during rest and exercise, possibly due to defective autoregulation of skeletal muscle blood flow, may explain the abnormally high lactate generation.

Adult↗
PubMed1976

Cholinergic sites in skeletal muscle. I. Denervation effects.

Cholinergic interactions in systems derived from rat skeletal mixed muscle are detailed. The isotherms of the binding of [125I]diiodo-alpha-bungarotoxin over the range of 10(-10)-10(-5) M toxin have been separated into a "nonspecific" component exclusive to the toxin and a "specific" component that binds both the toxin and d-tubocurarine. The "specific" component appears to reflect two independent sets of binding sites. One of the sets has an affinity constant on the order of 10(9) M-1. Following denervation, the number of sites in this high-affinity set begins to increase after 3 days, reaches a peak (28-fold higher than normal) on the 8th day, and begins to decline. Similar results are obtained when sensitivity of this set to an antibody derived from patients with myasthenia gravis is examined. This sensitivity is reflected by the inhibition of the alpha-bungarotoxin binding by the myasthenic IgG fraction. Following denervation, sensitivity first appears on day 3 progresses coincidentally with the increase in new sites in the set. The charcteristics of this set suggest that it represents the acetylcholine receptor and that the new sites appearing during the course of denervation are extrajunctional receptor sites. The interaction with the myasthenic IgG indicates an antigenic difference between junctional and extrajunctional receptors. The second set of specific binding sites has an affinity constant on the order of 10(5) M-1. The number of sites in this set increases only fivefold as a result of denervation. The increase also begins between days 2 and 3. The definition of this low affinity set of sites is not presently clear.

Animals↗