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PubMed2000

Focal denervation alters cellular phenotypes and survival in the rat olfactory bulb: a developmental analysis.

Our previous work (Couper Leo et al. [2000] J. Comp. Neurol. 417:325-336) introduced a technique for focally denervating the olfactory bulb soon after birth and described the pattern of changes incurred by this procedure by postnatal day (P) 30. The current study extends these findings with a developmental analysis of the effects of focal denervation in P10 and P20 rats. The results suggest that denervation begins to affect bulb architecture and cell survival soon after the procedure is performed, but that alterations within the bulb occur over an extended time period. For example, at P10, bulb and laminar sizes and mitral/tufted cell profile number had begun their decline, and nearly all measurements were significantly reduced by P20. Furthermore, a superficial-to-deep gradient of alterations in bulb architecture and a temporal separation of the effects on mitral/tufted cell dendrites vs. somata were observed. Immunohistochemical analyses of olfactory marker protein (OMP)-, calretinin- calbindin-, parvalbumin-, tyrosine hydroxylase-, and glutamic acid decarboxylase-stained sections indicated that: 1) denervation alters the interaction between olfactory axons and their targets in a developmentally significant manner; 2) the fine structure of denervated cells is altered; 3) cell phenotypes are differentially affected by loss of afferent contact, perhaps due to the age-dependent expression of their defining antigens; and 4) specific cell populations may be lost as a result of denervation.

Animals↗
PubMed2000

Denervation induces a rapid nuclear accumulation of MRF4 in mature myofibers.

Muscle regulatory factor 4 (MRF4) is a member of the family of myogenic transcription factors, including MyoD, myogenin, and myf-5, that are necessary for the commitment and differentiation of mesoderm to skeletal muscle. Although the function of these transcription factors during embryonic development has been demonstrated, their role in adult muscle has remained elusive. Regulation of the MRF4 gene differs from the genes encoding the other myogenic factors in that its transcripts accumulate in neonatal muscle during maturation and continue to be expressed at relatively high levels in the adult. On the basis of its mRNA expression pattern, MRF4 has been suggested to regulate genes encoding adult contractile proteins and acetylcholine receptor subunits. To test this hypothesis, a specific antiserum was developed to study MRF4 protein expression in adult innervated and denervated muscle, because MRF4 mRNA levels increase by approximately threefold 1 day after nerve resection. By using three different immunohistochemical methods that vary widely in sensitivity, we were unable to detect MRF4 immunoreactivity in adult innervated muscles. The same results were obtained with another MRF4 antiserum generated independently. In contrast, any of these three immunologic techniques readily detected MRF4 immunoreactivity in myofiber and satellite cell nuclei of muscles denervated for 24 hours. The highest proportion of immunopositive nuclei (80%) was found 2-3 days after denervation. Immunoreactivity was no longer detectable by 14 days. There was no differential accumulation of MRF4 protein in the nuclei of satellite cells nor in sole plate (synaptic) nuclei at any time after denervation. No differences were found in the temporal accumulation of MRF4 in nuclei of type I and type II denervated myofibers, consistent with the similar distribution of MRF4 mRNAs in slow- and fast-twitch muscles. Our results are consistent with the lack of phenotype observed in the adult muscles of MRF4-null mutant mice observed by others and suggest that MRF4 may have important roles in the gene programs activated after denervation and during muscle regeneration.

3T3 Cells↗
PubMed2003

Radiofrequency denervation for neck and back pain. A systematic review of randomized controlled trials.

BACKGROUND: The diagnosis of cervical or lumbar zygapophyseal joint pain can only be made by using local anesthesia to block the nerves supplying the painful joint. There is a lack of effective treatment for chronic zygapophyseal joint pain or discogenic pain. Radiofrequency denervation appears to be an emerging technology, with substantial variation in its use between countries. OBJECTIVES: To assess the effectiveness of radiofrequency denervation for the treatment of musculoskeletal pain disorders. SEARCH STRATEGY: We searched MEDLINE, PsycLIT, and EMBASE from start to February 2002, plus the Cochrane Library 2002, Issue 2. The references of identified articles were checked and three experts in the field of radiofrequency treatment were consulted to identify studies we might have missed. SELECTION CRITERIA: Randomized controlled trials (RCTs) of radiofrequency denervation for musculoskeletal pain disorders, with no language or date restrictions. DATA COLLECTION AND ANALYSIS: Two reviewers selected RCTs that met predefined inclusion criteria, extracted the data, and assessed the main results and methodological quality of the selected trials, using standardized forms. Qualitative analysis was conducted to evaluate the level of scientific evidence. MAIN RESULTS: We found only nine articles, reporting on seven relevant RCTs. Six of the seven were considered to be high-quality. The selected trials included 275 randomized patients, 141 of whom received active treatment. One study examined cervical zygapophyseal joint pain, two cervicobrachial pain, three lumbar zygapophyseal joint pain, and one discogenic low-back pain. The study sample sizes were small, follow-up times short, and there were some deficiencies in patient selection, outcome assessments, and statistical analyses. The level of scientific evidence for the short-term effectiveness of radiofrequency denervation was limited for cervical zygapophyseal joint and cervicobrachial pain, and conflicting for lumbar zygapophyseal joint pain. There was limited evidence suggesting that intradiscal radiofrequency thermocoagulation was not effective for discogenic low-back pain. REVIEWER'S CONCLUSIONS: The selected trials provide limited evidence that radiofrequency denervation offers short-term relief for chronic neck pain of zygapophyseal joint origin and for chronic cervicobrachial pain; conflicting evidence on the short-term effect of radiofrequency lesioning on pain and disability in chronic low-back pain of zygapophyseal joint origin; and limited evidence that intradiscal radiofrequency thermocoagulation is not effective for chronic discogenic low-back pain. There is a need for further high-quality RCTs with larger patient samples and data on long-term effects, for which current evidence is inconclusive. Furthermore, RCTs are needed in non-spinal indications where radiofrequency denervation is currently used without any scientific evidence.

Back Pain↗
PubMed2001

Reparative myogenesis in long-term denervated skeletal muscles of adult rats results in a reduction of the satellite cell population.

This study, conducted on 25-month denervated rat hindlimb muscles, was directed toward elucidating the basis for the poor regeneration that is observed in long-term denervated muscles. Despite a approximately 97.6% loss in mean cross-sectional area of muscle fibers, the muscles retained their fascicular arrangement, with the fascicles containing approximately 1.5 times more fibers than age-matched control muscles. At least three distinct types of muscle fibers were observed: degenerating, persisting (original), and newly formed (regenerated) fibers. A majority of newly formed fibers did not appear to undergo complete maturation, and morphologically they resembled myotubes. Sites of former motor end-plates remained identifiable in persisting muscle fibers. Nuclear death was seen in all types of muscle fibers, especially in degenerating fibers. Nevertheless, the severely atrophic skeletal muscles continued to express developmentally and functionally important proteins, such as MyoD, myogenin, adult and embryonic subunits of the nicotinic acetylcholine receptor, and neural-cell adhesion molecule. Despite the prolonged period of denervation, slow and fast types of myosin were found in surviving muscle fibers. The number of satellite cells was significantly reduced in long-term denervated muscles, as compared with age-matched control muscles. In 25-month denervated muscle, satellite cells were only attached to persisting muscle fibers, but were never seen on newly formed fibers. Our data suggest that the absence of satellite cells in a population of immature newly formed muscle fibers that has arisen as a result of continuous reparative myogenesis may be a crucial, although not necessarily the only, factor underlying the poor regenerative ability of long-term denervated muscle.

Age Factors↗
PubMed1991

The effects of age on atrophy and recovery in denervated fiber types of the rat nasolabialis muscle.

This study investigates the effects of advancing age on responses of nasolabialis muscle fibers to denervation and reinnervation. The nasolabialis is innervated by the facial nerve and is responsible for the whisking movement of the animal's large vibrissae. In young adult (3-month) and middle-aged (15-month) rats the muscle on one side of the head was denervated by crushing the facial nerve. At specific days postcrush, animals were sacrificed and thick sections of muscle were incubated to demonstrate cytochrome oxidase activity, a mitochondrial enzyme, which differentiated between red, white, and intermediate fiber types. The rate and extent of atrophy and recovery were evaluated using light microscope morphometric methods for which transverse fiber areas were measured and compared to fibers on the contralateral control side. There was an age-related delay in the time of functional return since older animals resumed normal whisking behavior 6 days later than the younger animals. In both age groups, white and intermediate fibers atrophied to the greatest extent and red fibers showed least atrophy. Despite the different responses of the fiber types to denervation, there was no age difference in the maximum degree of fiber atrophy within each fiber type. Age differences did occur in the rate of the denervation response since the middle-aged fibers consistently showed a more rapid significant atrophy than the young adult fibers. During recovery, older fibers may be limited in their ability to attain the size of fibers on the control side. The results indicate that through middle age, the process of advancing age increases the susceptibility of the nasolabialis muscle to denervation but does not alter the maximum extent of atrophy. The ability to recovery to normal fiber size, at least 2 months after denervation, is also age-related.

Aging↗
PubMed1994

Effects of denervation upon receptor cell survival and basal cell proliferation in tuberous electroreceptor organs of a weakly electric fish.

Weakly electric fish generate electric fields for the purposes of electrolocation and communication. These fields are detected by specialized receptor organs: the tuberous organs. In the present study we investigated the effects of denervation upon receptor cell survival and progenitor (basal) cell proliferation rate. The left, infraorbital, anterior lateral line nerve of brown ghosts (Apteronotus leptorhynchus) was sectioned, and the proximal stump was dipped in ricin to prevent regrowth. In groups of four, the animals were given two daily injections of the cell proliferation marker bromodeoxyuridine (BrdU) for 2 days at 1, 2, 3, or 4 weeks following denervation. At the completion of the BrdU injection schedule, a piece of cheek skin, rostroventral to the eye, was removed from the left (denervated) and the right (intact) sides and processed for light microscopy or immunocytochemistry. Our results show: (1) there is progressive receptor cell death and tuberous organ degeneration following denervation; (2) basal cell proliferation increases steadily with time after denervation and tuberous organ degeneration; and (3) despite denervation, some proliferating basal cells differentiate into receptor cells, but these new receptor cells eventually die. These results suggest that innervation is essential for tuberous electroreceptor cell survival and that the rate at which basal cells proliferate is regulated by receptor cell health, locally released factors, or both.

Animals↗
PubMed2006

NG2 upregulation in the denervated rat fascia dentata following unilateral entorhinal cortex lesion.

The chondroitin sulfate proteoglycan NG2 is a component of the glial scar following brain injury. Because of its growth inhibiting properties, it has been suggested to impede axonal regeneration. To study whether NG2 could also regulate axonal growth in denervated brain areas, changes in NG2 were studied in the rat fascia dentata following entorhinal deafferentation and were correlated with the post-lesional sprouting response. Laser microdissection was employed to selectively harvest the denervated molecular layer and combined with quantitative RT-PCR to measure changes in NG2 mRNA (6 h, 12 h, 2 days, 4 days, 7 days post-lesion). This revealed increases of NG2 mRNA at day 2 (2.5-fold) and day 4 (2-fold) post-lesion. Immunocytochemistry was used to detect changes in NG2 protein (1 days, 4 days, 7 days, 10 days, 14 days, 30 days, 6 months post-lesion). NG2 staining was increased in the denervated outer molecular layer at day 1 post-lesion, reached a maximum 10 days post-lesion, and returned to control levels thereafter. Electron microscopy revealed NG2 immunoprecipitate on glial surfaces and in the extracellular matrix around neuronal profiles, indicating that NG2 is secreted following denervation. Double labeling of NG2-immunopositive cells with markers for astrocytes, microglia/macrophages, and mature oligodendrocytes suggested that NG2 cells are a distinct glial subpopulation before and after entorhinal deafferentation. BrdU labeling revealed that some of the NG2-positive cells are generated post-lesion. Taken together, our data revealed a layer-specific upregulation of NG2 in the denervated fascia dentata that coincides with the sprouting response. This suggests that NG2 could regulate lesion-induced axonal growth in denervated areas of the brain.

Acetylcholinesterase↗
PubMed1992

The effect of liver denervation on hepatic hemodynamics during hypovolemic shock in swine.

This study tested the hypothesis that the denervated liver is more susceptible to hypovolemic shock than the normal liver. Fourteen swine, seven nondenervated and seven after liver denervation, were studied during hypovolemic shock to 50% of baseline blood pressure. Hepatic artery and portal vein flows were measured using transonic flow probes, and cardiac output and central venous pressure were measured using Swan-Ganz catheters. Hepatic artery flow fell equivalently in the two groups, from 132 +/- 71 to 94 +/- 17 ml/min in the nondenervated group compared with 149 +/- 56 to 91 +/- 55 ml/min in the denervated group. In contrast, portal flow in the denervated group (276 +/- 71 to 119 +/- 53 ml/min) fell significantly (p less than 0.001) more than in the nondenervated group (289 +/- 135 to 194 +/- 70 ml/min). The 58% reduction from baseline in portal flow in the denervated group compared with the 30% reduction in the nondenervated group suggests that the normal compensatory mechanism to maintain portal flow during hypovolemic shock is neurally mediated. It can be hypothesized that sensory afferent fibers might initiate a feedback to splanchnic vasodilatation in response to reduced portal flow. This study supports the hypothesis that the denervated liver is more susceptible to hypovolemic shock.

Animals↗
PubMed1983

Comparison of growth-induced resorption and denervation-induced resorption on the release of [3H]tetracycline, 45calcium, and [3H]collagen from whole bones of growing rats.

The major effect of immobilization during growth is a smaller bone mass induced by either an increased bone resorption or a decreased bone formation. Using a method of analyzing radioisotopic loss of [3H]tetracycline and [3H]collagen from bone prelabeled in vivo, we compared the amount of bone resorption due to immobilization with bone resorption induced by growth. One hind limb was denervated in growing male rats, 6 weeks of age, that had been chronically prelabeled with [3H]tetracycline, 45calcium, and [3H]proline. The total radioactivity of the whole femur and tibia/fibula from the denervated limb was compared with that from bones of the control limb at 0, 1, 2, 4, and 8 weeks after denervation. The effect of growth on bone formation was measured by net increases in bone length, volume, and mass of matrix and mineral. Experimental bones had a significantly smaller volume and mass. Bone resorption was much greater during growth modeling than during denervation. The additional bone resorption induced by denervation was a small fraction (one-fourth) of the resorption induced by growth. Denervation during growth resulted in less bone being formed due to a smaller gain in matrix and mineral mass as a result of a reduction in bone formation.

Animals↗
PubMed1986

A microsurgical method for experimental kidney denervation.

A successful microsurgical method for denervation of the kidney in the rat is presented. Unilateral kidney denervation was performed in eight animals. Ten sham-operated animals were used as controls. Under ether anaesthesia, the kidney vessels on one side were exposed. The peritoneum above the vessels was incised and the area was stained with 1% toluidine blue solution. The nerves were identified. With microsurgical technique, the nerves were carefully separated from the vessels and resected. Tissue specimens from both kidneys in all animals were removed and analysed for norepinephrine content. There was no normal difference between the kidneys in the sham-operated rats. About 1 week after denervation, the norepinephrine concentration in the denervated kidney showed a 95% reduction, indicating a complete denervation. The described microsurgical procedure was a rapid, simple, and reproducible method for kidney denervation in the rat.

Animals↗
PubMed2002

SK channels are necessary but not sufficient for denervation-induced hyperexcitability.

Skeletal muscle hyperexcitability is characteristically associated with denervation. Expression of SK3, a small conductance Ca(2+)-activated K(+) channel (SK channel) in skeletal muscle is induced by denervation, and direct application of apamin, a peptide blocker of SK channels, dramatically reduces hyperexcitability. To investigate the role of SK3 channels in denervation- induced hyperexcitability, SK3 expression was manipulated using a transgenic mouse that harbors a tetracycline-regulated SK3 gene. Electromyographic (EMG) recordings from anterior tibial (AT) muscle showed that denervated muscle from transgenic or wild-type animals had equivalent hyperexcitability that was blocked by apamin. In contrast, denervated skeletal muscle from SK3tTA mice lacking SK3 channels showed little or no hyperexcitability, similar to results from wild-type innervated skeletal muscle. However, innervated skeletal muscle from SK3tTA mice containing SK3 channels did not show hyperexcitability. The results demonstrate that SK3 channels are necessary but not sufficient for denervation-induced skeletal muscle hyperexcitability.

Action Potentials↗
PubMed2005

Successful intramuscular neurotization is dependent on the denervation period. A histomorphological study of the gracilis muscle in rats.

To characterize the extent to which reinnervation potential depends on the duration of denervation, intramuscular neurotization of the gracilis muscle was performed either immediately or 2, 4, 6, and 8 weeks after transection of the obturator nerve. For neurotization, the sciatic nerve was split into three fascicle groups and fixed intramuscularly. Muscle morphology after 6 weeks of regeneration was identified with anti-myosin immunohistochemistry and NADH staining. Newly formed motor endplates were characterized using acetylcholinesterase staining and electron microscopy. Wet muscle weight ratio indicated the functional state of synapses. Depending on the denervation period, three levels of regenerative outcome were evident. Best results were seen after immediate neurotization or after 2 weeks of denervation. Regeneration, although at a significantly lower level, also occurred after denervation periods of 4 and 6 weeks. Regeneration following neurotization after 8 weeks of denervation was negligible. Quantity and quality of motor endplate formation depended on the denervation period. Thus, in special clinical situations intramuscular neurotization within a distinct time window provides a good reconstructive option.

Animals↗
PubMed1986

Sodium channel kinetics in normal and denervated rabbit muscle membrane.

The effects of chronic denervation on sodium (Na) channels in rabbit muscle membrane were determined using intracellular microelectrodes and Vaseline gap voltage clamp techniques. The Hodgkin-Huxley model was used to describe the kinetic and steady-state parameters of channel activation and fast inactivation. Chronic (7-10 days) denervation was found to cause a decreased resting potential, lowered action potential peak, and fibrillation potentials in rabbit extensor digitorum longus (EDL) muscles. Under voltage clamp conditions, no differences were observed between denervated and normal fibers in the voltage dependence of the steady-state Na channel activation and fast inactivation curves, or in the time course of development of fast inactivation. However, in denervated fibers, the time course of recovery from fast inactivation was approximately half that measured in normal fibers. Also, whereas depolarizing holding potentials induced a long-term inactivation to varying degrees in normal EDL fibers, denervated EDL fibers and normal soleus fibers were uniformly resistant to prolonged depolarization. These results suggest that the denervation-induced development of spontaneous activity may be due in part to changes in the mechanisms that control the refractoriness of Na channels.

Animals↗
PubMed1986

Electrophysiologic denervation changes of human muscle fibers in motoneuron diseases.

Muscle denervation and reinnervation by sprouting of the surviving motoneurons characterizes motoneuron diseases (MND). In mammalian muscles, experimental denervation induces the appearance of extrajunctional acetylcholine (ACh) receptors and tetrodotoxin (TTX) resistant action potentials (AP). These denervation changes have been investigated in muscle biopsies from 10 MND patients and in 2 traumatically denervated normal human muscles. Extrajunctional ACh sensitivity was present in 113 of the 140 (73%) fibers from MND muscles studied. In 50 of 84 (70%) ACh-sensitive fibers, no TTX-resistant AP were present. The remaining fibers (30%) showed small regenerative responses. In contrast, all the traumatically denervated muscle fibers showed extrajunctional ACh sensitivity and TTX-resistant AP. Histochemical analysis of the biopsies showed no direct correlation between the frequency of ACh-sensitive fibers and that of the atrophic or normal-appearing fibers. The absence of TTX-resistant AP in ACh-sensitive fibers and its lack of correlation with the histochemical criteria of denervation suggest the presence of a state of innervation in MMD, where the motoneuron is not able to maintain its fully trophic influence on the muscle fiber membrane.

Acetylcholine↗
PubMed1988

Effects of denervation on spectrin concentration in avian skeletal muscle.

The effect of denervation on avian muscle alpha-spectrin was examined in fast and slow muscles. Using immunofluorescence, the surgically denervated fast-twitch posterior latissimus dorsi (PLD) exhibited a significant increase in spectrin antigen associated with the sarcolemma and within the sarcoplasm compared with the contralateral innervated control muscle. Using gel electrophoresis followed by immunoblotting, we found a two- to three-fold increase in the levels of spectrin in the denervated PLD over that found in the innervated PLD. These levels were comparable to those found previously in slow and dystrophic muscle. The intrafiber distribution of spectrin is similar between the denervated PLD and the slow-tonic anterior latissimus dorsi (ALD). When spectrin was examined in dystrophic PLD muscle, denervation was found to have no effect. These results support our hypothesis that the concentration of spectrin within muscle fibers reflects the physiological state of those fibers. Changes in spectrin concentration may be a useful probe to study the various alterations in physical parameters found among fast, slow, dystrophic, and denervated fibers.

Animals↗
PubMed1989

Fibrillatory activity and other membrane changes in partially denervated muscles.

Rat soleus muscles were partially or totally denervated by sectioning the radicular nerve L5 or the radicular nerves L3 through L6, respectively. Three days after these procedures, fibrillation potentials were not observed in the case of partial denervation, whereas they were clearly detectable after total denervation. At later times, spontaneous spike activity also developed in the partially denervated muscles. The difference in time of onset of fibrillation between partially and totally denervated muscles was confirmed by a more gradual increase in the number of acetylcholine receptors and a greater sensitivity to tetrodotoxin of the former muscles. These differences between partially and totally denervated muscles are interpreted on the basis of the different amounts of nerve breakdown products generated in the two situations.

Acetylcholine↗
PubMed1990

Phosphorylase kinase isozymes and phosphorylase in denervated skeletal muscles.

The effects of motor denervation on levels of phosphorylase kinase isozymes and phosphorylase were investigated in rat epitrochlearis, hemidiaphragm, and soleus muscles. Amounts of the proteins were measured after quantitative immunoprecipitation and found to be decreased by as much as 70% 2 weeks after denervation. Unexpectedly, denervation had little, if any, effect on the relative proportions of the two phosphorylase kinase isozymes. Phosphorylase and phosphorylase kinase were decreased by essentially the same extent after denervation, and the effects of denervation were comparable in all three muscles. The decreases in these enzymes explain, at least in part, the marked alterations in glycogen metabolism that occur after motor denervation.

Animals↗
PubMed1990

Growth and denervation response of skeletal muscle fibers of newborn rats.

The cross-sectional area of the fibers of hindlimb muscles of rats increased 10-40 times during the first 6 weeks after birth. Denervation at birth stopped the growth of the muscle fibers. The number of satellite cells decreased, and eventually all fibers vanished. Reinnervation, if any, was poor. Partial denervation did not induce collateral reinnervation. Some denervated gastrocnemius muscles were reinnervated and after 8-12 months contained hypertrophic fibers and signs of necrosis and regeneration. When soleus muscles were completely denervated and cross-reinnervated after 4 weeks by the peroneal nerve, only half as many fibers became reinnervated after neonatal denervation as compared to muscles denervated at the age of 4 weeks. The experiments suggest that immature muscle fibers are less apt to become reinnervated than mature fibers. The few reinnervated fibers may be overloaded and therefore hypertrophy and eventually necrotize. Regeneration is abortive because satellite cells are scarce. These results may be relevant for the understanding of neuromuscular disorders with early (fetal) onset.

Animals↗