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PubMed1998

Long-term observation of the effect of peripheral nerve injury in neonatal and young rats.

The purpose of this study was to observe functional recovery and motoneuron death after nerve transection-and-repair in neonatal versus young animals. One hundred nine Lewis rats underwent posterior tibial nerve transection-and-repair at 6 or 22 days of age. Fifty-two and fifty-seven nerves at the 6- and 22-day times were used for endpoint analysis at 1, 3, 10, and 14 months. These assessments included serial functional walking track analysis, electrophysiologic studies, muscle mass evaluation, motoneuron counts with retrograde horseradish peroxidase tracing, and histologic and morphometric nerve analysis. Walking track analysis and nerve conduction velocity indicated significantly poorer functional regeneration in the 6-day-old group than in the 22-day-old group. Muscle mass in the 6-day-old group did not recover as well as in the 22-day-old group. Motoneuron numbers stained with horseradish peroxidase were less in the 6-day-old group than in the 22-day-old group. In contrast, morphometric analysis did not reach significance. This study suggests that the same nerve injury sustained in a neonatal rat is less likely to demonstrate functional recovery than one sustained in a young rat.

Animals↗
PubMed2001

Peripheral nerve injury: a review and approach to tissue engineered constructs.

Eleven thousand Americans each year are affected by paralysis, a devastating injury that possesses associated annual costs of $7 billion (American Paralysis Association, 1997). Currently, there is no effective treatment for damage to the central nervous system (CNS), and acute spinal cord injury has been extraordinarily resistant to treatment. Compared to spinal cord injury, damage to peripheral nerves is considerably more common. In 1995, there were in excess of 50,000 peripheral nerve repair procedures performed. (National Center for Health Statistics based on Classification of Diseases, 9th Revision, Clinical Modification for the following categories: ICD-9 CM Code: 04.3, 04.5, 04.6, 04.7). These data, however, probably underestimate the number of nerve injuries appreciated, as not all surgical or traumatic lesions can be repaired. Further, intraabodominal procedures may add to the number of neurologic injuries by damage to the autonomic system through tumor resection. For example, studies assessing the outcome of impotency following radical prostatectomy demonstrated 212 of 503 previously potent men (42%) suffered impotency when partial or complete resection of one or both cavernosal nerve(s). This impotency rate decreased to 24% when the nerves were left intact (Quinlan et al., J. Urol. 1991;145:380-383; J. Urol. 1991;145:998-1002).

Adult↗
PubMed2000

IGF-I expression is decreased in LIF-deficient mice after peripheral nerve injury.

We investigated the regulation of insulin-like growth factor 1 (IGF-1) expression after sciatic nerve crush using leukemia inhibitory factor (LIF)-deficient mice. One day post-crush, IGF-1 mRNA levels were lower in the LIF-deficient mouse nerve than in the wild type nerve. IGF-1 protein, analyzed by immunohistochemistry, was also decreased 1 day post-crush in LIF-deficient nerves relative to wild type nerves. By 3 days post-crush, IGF-1 immunoreactivity was induced in Schwann cells to equivalent levels in both types of nerve. After crush, IGF-1 expression was also found in mast cells, and these were initially decreased in the LIF-deficient mice. Thus, LIF appears to regulate IGF-1 expression in the peripheral nerve basally and early in the regeneration response in vivo.

Animals↗
PubMed1975

Experience with homologous lyophilised nerve grafts in the treatment of peripheral nerve injuries.

Report of a series of 18 late secondary nerve grafts using lyophilised (disantigenised and disenzymatised) homografts of the Braun Melsungen Company. In contrast to the publication of Kuhlendahl et al. (1972) 32% of the cases showed definitive signs of regeneration. Therefore, in spite of the fact that autografts give better results, further research into the possibilities of homografts seems desirable. Their potential usefulness obviously is restricted to cases in which from any reasons autologous nerve grafts are not available.

Adolescent↗
PubMed1990

[Surgical treatment of peripheral nerve injuries. Evaluation of a multicenter study].

In a retrospective study 674 nerve injuries of the upper limb were analysed, which were treated by operative management in 10 hospitals of the GDR. The median nerve (226 cases) and the ulnar nerve (209 cases) most were frequently concerned. 427 injured nerves were reconstructed primary or early secondary. In 46.3% epineural nerve suture was performed and in 23% interfascicular nerve grafting. Good or very good results occurred in 71% (motor recovery) and 70.7% (sensory recovery) according to the scheme of Highet. The best results occurred after primary reconstruction independent of operative technique. The results get worse with increasing age.

Adolescent↗
PubMed1993

Nitric oxide mediates ongoing discharges in dorsal root ganglion cells after peripheral nerve injury.

1. We have examined the effect of intravenously injected nitro-L-arginine methyl ester (L-NAME), inhibitor of nitric oxide (NO) synthase, on the ongoing discharges originating in dorsal root ganglia in rats. 2. Ongoing activity was recorded from dorsal rootlets that were responsive to electrical stimulation of the axotomized sciatic nerve. Resection of the nerve proximal to the neuroma did not appreciably influence the rate of ongoing activity. Intravenous L-NAME (100 and 200 mumol/kg) suppressed ongoing activity both when the neuroma was intact or acutely resected. The effect of L-NAME was reversed by L-arginine (575 and 1,150 mumol/kg). 3. L-NAME had no effect on ongoing activity recorded from dorsal rootlets in normal rats or rootlets with no sciatic input in axotomized rats. 4. No ongoing activity could be recorded from sciatic nerve filaments that had been sectioned proximally before the recording in axotomized rats, although a response could be elicited by mechanical stimulation of the neuroma. 5. Because peripheral axotomy has been shown to markedly increase the level of mRNA for NO synthase in dorsal root ganglion cells, the present results indicate that NO may be involved in the generation of spontaneous discharges in deafferentated dorsal root ganglia.

Afferent Pathways↗
PubMed2003

A nitric oxide (NO)-releasing derivative of gabapentin, NCX 8001, alleviates neuropathic pain-like behavior after spinal cord and peripheral nerve injury.

1. Nitric oxide (NO) participates, at least in part, to the establishment and maintenance of pain after nerve injury. Therefore, drugs that target the NO/cGMP signaling pathway are of interest for the treatment of human neuropathic pain. Various compounds endowed with NO-releasing properties modulate the expression and function of inducible nitric oxide synthase (iNOS), the key enzyme responsible for sustained NO production under pathological conditions including neuropathic pain. 2. With this background, we synthesized a new chemical entity, [1-(aminomethyl)cyclohexane acetic acid 3-(nitroxymethyl)phenyl ester] NCX8001, which has a NO-releasing moiety bound to gabapentin, a drug currently used for the clinical management of neuropathic pain. We examined the pharmacological profile of this drug with respect to its NO-releasing properties in vitro as well as to its efficacy in treating neuropathic pain conditions (allodynia) consequent to experimental sciatic nerve or spinal cord injuries. 3. NCX8001 (1-30 microm) released physiologically relevant concentrations of NO as it induced a concentration-dependent activation of soluble guanylyl cyclase (EC(50)=5.6 microm) and produced consistent vasorelaxant effects in noradrenaline-precontracted rabbit aortic rings (IC(50)=1.4 microm). 4. NCX8001, but not gabapentin, counteracted in a concentration-dependent fashion lipopolysaccharide-induced overexpression and function of iNOS in RAW264.7 macrophages cell line. Furthermore, NCX8001 also inhibited the release of tumor necrosis factor alpha (TNFalpha) from stimulated RAW264.7 cells. 5. NCX8001 (28-280 micromol x kg(-1), i.p.) reduced the allodynic responses of spinal cord injured rats in a dose-dependent fashion while lacking sedative or motor effects. In contrast, gabapentin (170-580 micromol x kg(-1), i.p.) resulted less effective and elicited marked side effects. 6. NCX8001 alleviated the allodynia-like responses of rats to innocuous mechanical or cold stimulation following lesion of the sciatic nerve. This effect was not shared by equimolar doses of gabapentin. 7. Potentially due to the slow releasing kinetics of NO, NCX8001 alleviated pain-like behaviors in two rat models of neuropathic pain in a fashion that is superior to its parent counterpart gabapentin. This new gabapentin derivative, whose mechanism deserves to be explored further, offers new hopes to the treatment of human neuropathic pain.

Acetates↗
PubMed1993

Temporal and spatial expression of ciliary neurotrophic factor after peripheral nerve injury.

Schwann cells in the intact sciatic nerve express high amounts of ciliary neurotrophic factor (CNTF), but 7 days after injury to the nerve expression dramatically decreases. To determine whether this change occurs only in the region of the injury or throughout the whole nerve we examined the spatial and temporal expression of CNTF after a crush injury. One day after injury the amount of CNTF mRNA and protein decreased within the first 4 mm distal to the crush site. This decrease progressed in a centrifugal manner distally until mRNA and protein were scarcely detectable by 7 days. In nerve proximal to the crush site CNTF expression decreased slightly and was still detectable at all sample times. During regeneration CNTF expression remained very low up to 14 days after injury. By 30 days mRNA and protein were detectable and by 60 days CNTF protein was present at normal amounts. Immunohistochemical analysis of normal nerve revealed CNTF localized in outer portion of the cytoplasm of myelin-forming Schwann cells. Three days after injury CNTF coalesced with pockets of cytoplasm in the Schwann cell and by 5 days was barely detectable. Positive staining remained in proximal segments where little or no degeneration occurred. These results demonstrate that CNTF expression in Schwann cells is synchronized with their functional state. CNTF expression decreases with demyelination during Wallerian degeneration and returns to normal following remyelination during regeneration. These findings also suggest that CNTF expression requires intact axon-Schwann cell interactions.

Animals↗
PubMed1995

Peripheral nerve injury and regeneration.

The process of nerve regeneration has been studied extensively by traditional morphological methods, but it is only recently that has been possible to identify more precisely the contribution of different nerve subpopulations. By studying different models of nerve repair and regeneration, it is becoming apparent that other tissue components are contributing to the overall process. When muscle grafting is carried out to repair an injured nerve, the regenerating axons are migrating in parallel with Schwann cells to bridge the nerve gap. The presence of Schwann cells is essential for a successful nerve regeneration, most probably because their production of different neuronal trophic factors. This pattern is also repeated when fibronectin mats are used for nerve repair, indicating the possibility to use this new synthetic matrix for clinical application. If the target organ is analysed after nerve repair, the recovery of all nerve components is evident. However, the process occurs at different times in separate skin compartments, and the regeneration of the autonomic innervation appears to be preceded by that of the sensory nerves. When looking at cutaneous nerve regeneration following different type of injury, a common pattern of events becomes apparent. In skin flaps, nerve regeneration begins from the skin surrounding the wound edge, or from the pedicle, and sensory nerves are the first to penetrate into the flap. Angiogenesis precedes reinnervation of the flap, and initially regenerating fibres appear to be associated with newly formed blood vessels. This pattern is evident also in full-thickness wounds and in suction blisters, where only the more superficial cutaneous layer is disrupted. Furthermore, the presence of keratinocytes appears to exert a directional influence on both regenerating blood vessels and nerves, which follow the regenerating keratinocytes when reepidermalisation is taking place. These results would indicate that there is a close relationship between nerve fibres and blood vessels during regeneration, with a substantial contribution to the process from other tissue components and soluble factors from the surrounding environment.

Animals↗
PubMed1990

[Experimental studies on peripheral nerve injuries caused by injection needles].

Differences in neural damage due to different injection needles were investigated in vitro on sciatic nerve specimens of adult rabbits. METHODS. Three types of 22-gauge needles were tested: one typical, long-bevelled venous puncture needle; a short bevelled, typical nerve block needle; and a tapered, atraumatic spinal needle. Both sciatic nerves of 50 adult rabbits weighing from 2.5 to 3.0 kg were used for electrophysiological investigations on one side and fluorescence microscopy on the other. ELECTROPHYSIOLOGY. The nerve specimens were placed in an experimental chamber on silver-silver chloride electrodes that were aligned at a distance of 10 mm. Two electrodes at the distal ends of the nerve were used for stimulation by rectangular waves (6-10 v) of 0.01 ms duration. The compound action potential (CAP), its amplitude, and its latency were measured by monopolar recording from four additional electrodes (R1 to R4). Ten nerves were apportioned to each of five groups and the needles were perpendicularly pierced three times in the middle of the nerve trunk at the midpoint between recording sites R2 and R3. THE GROUPS. 1. Long-bevelled needle, the face of the bevel inserted rectangular to the nerve fibers; 2. long-bevelled needle, the face of the bevel parallel to the nerve fibers; 3. short-bevelled needle, the face of the bevel inserted rectangular to the nerve fibers; 4. short-bevelled needle, the face of the bevel parallel to the nerve fibers; 5. tapered, pencil-point needle pierced perpendicularly through the nerve trunk. The amplitude of the CAP was recorded before and after nerve injury from R1 to R4. FLUORESCENCE MICROSCOPY. According to the method described by Steinwall and Olsson, the other five groups of injured nerves were immersed in Evans blue albumin (EBA) and, after washing in saline solution, fixed in 5% formalin. The extent of nerve damage was evaluated by fluorescence microscopy of the glycerol-imbedded frozen sections (longitudinal and transverse). RESULTS. Electrophysiology. After injuring the area between R2 and R3 there was almost no change in the amplitude of the CAP at sites R1 and R2. The amplitude at R3 and R4 was reduced in comparison with the controls. This reduction was most marked in group 1 and very slight in group 5. The percentages of amplitude at R3 after injury compared with control values (mean +/- SD) were 42.2% +/- 22.0% in group 1; 60.9% +/- 18.2% in group 2; 51.0% +/- 22.3% in group 3; 71.0% +/- 18.0% in group 4; and 90.1% +/- 10.9% in group 5. Statistically significant differences were obtained between the tapered, atraumatic needle group and the other four groups (Fig. 3). Fluorescence microscopy. With the tapered injection needle there was the least leakage of EBA, which suggests the least damage to the perineurium, and almost no rupture or tearing of the nerve fibers was observed. In the short- and long-bevelled needles, the damage was reduced when the face of the bevel was inserted parallel to the fibers.

Action Potentials↗
PubMedDate not supplied

The quest for better recovery from peripheral nerve injury: current status of nerve regeneration research.

The author reviews relevant nerve regeneration research in the past half-century to give the reader familiarity with the background of current research efforts. Recent research has been aided by newer knowledge of the biology of nerve regeneration. Early efforts to improve nerve regeneration centered on improvements in technical or surgical repairs, with only modest gains. Although current technical improvements with lasers or fibrin glue to repair nerves may show promise, the approach of deMedinaceli et al. combines several new ideas with some improvement experimentally. With the discovery of nerve growth factors and a host of newer nerve growth promoting factors, the biochemical arena has explored. Special tubes to repair nerves enable easy manipulation of the environment to study the effects of various factors on nerve regeneration. Silastic and bioresorbable tubes show the most promise to enhance nerve regeneration by tubulization. Because of the explosion of knowledge and high levels of activity of research, it is apparent that further improvements of nerve regeneration are on the horizon.

Axons↗
PubMed1989

Painful dysaesthesias following peripheral nerve injury: a clinical and electrophysiological study.

Thirty-three patients with complete median, ulnar or digital nerve transections were studied 4 months to 13 years subsequent to suture or nerve grafting. In all cases, sensory disturbances, in terms of paraesthesia or hypaesthesia, were encountered. Painful or unpleasant symptoms, allodynia or hyperpathia, were observed most frequently in patients with poor recovery. The clinical findings and the patients' subjective complaints were correlated to microneurographic single fibre recordings of regenerated cutaneous mechanoreceptors. In more than 80% of the recordings, discharge properties of regenerated receptors, thresholds and a variety of other electrophysiological data were similar or equal to normal controls. Less than 20% of the receptors exhibited atypical properties suggesting defective steady-state regeneration. The ratio of rapidly adapting (RA-units) to slowly adapting mechanoreceptors (SA-units) was inverse in relation to normals. The density of regenerated RA-receptors was higher in the proximal than in the distal part of the reinnervated area. This paralleled the clinical finding of reduced sensory discrimination in these cases and suggests that SA-units may regenerate preferentially. In painful conditions no single fibres could be recorded, reflecting the relative paucity of fibres and probably the atrophy of the nerve. The results of the microstimulation experiments, although less reliable, revealed some evidence that the central processing of regenerated units is abnormal. Clinical and electrophysiological data supported this concept of central changes underlying some of the phenomena observed during peripheral nerve regeneration.

Adolescent↗
PubMed2001

Somatotopic reorganization in the brainstem and thalamus following peripheral nerve injury in adult primates.

Injury-induced reorganization of central somatotopic maps is a phenomenon that has proven to be useful for elucidating the mechanisms and time course of neural plasticity. To date, the overwhelming majority of this line of research has focused on such plastic events in cortical areas, at the expense of subcortical structures. In this study, we used multi-unit electrophysiological recording techniques to assess the somatotopic organization of brainstem and thalamic areas following chronic survival from paired median and ulnar nerve section in adult squirrel monkeys. We report that the extent of cutaneously-driven reorganization in both the cuneate nucleus of the brainstem and the ventroposterior lateral nucleus of the thalamus is comparable to that previously documented for area 3b of cortex. These observations are consistent with those previously reported in thalamus, and are unique for brainstem.

Action Potentials↗
PubMed1979

Two modes of cutaneous reinnervation following peripheral nerve injury.

The return of sensation to the foot following sciatic nerve crush injury was analyzed behaviorally and electrophysiologically in the rat. Functional recovery begins within four days. Its early phase is accounted for by expansion of the functional distribution of intact neighboring fibers of the saphenous n. It occurs even if the sciatic n. is ligated, and it disappears with section of the saphenous n. Accompanying this functional expansion we began to encounter in electrophysiological recordings from the saphenous n., fibers with unusually large receptive fields (RF's) extending onto the plantar surface of the foot, well beyond their limits in intact rats. All of the expanded RF's were high threshold mechanoreceptors. On about the twentieth day after crushing, the regenerating sciatic n. began to make a functional contribution. This was seen by return of sensation to zones not invaded by the saphenous n. and by the onset of sensation in rats in which the saphenous n. had previously been ligated. With return of the sciatic n. the expanded distribution of the saphenous n. went back to its original boundaries. Correspondingly, we could no longer find expanded saphenous n. RF's. We conclude that cutaneous reinnervation begins with the collateral expansion of high threshold afferents from intact neighboring nerves. This alien innervation is later replaced upon regeneration of the original nerve.

Animals↗
PubMed2002

Replicate high-density rat genome oligonucleotide microarrays reveal hundreds of regulated genes in the dorsal root ganglion after peripheral nerve injury.

BACKGROUND: Rat oligonucleotide microarrays were used to detect changes in gene expression in the dorsal root ganglion (DRG) 3 days following sciatic nerve transection (axotomy). Two comparisons were made using two sets of triplicate microarrays, naïve versus naïve and naïve versus axotomy. RESULTS: Microarray variability was assessed using the naïve versus naïve comparison. These results support use of a P < 0.05 significance threshold for detecting regulated genes, despite the large number of hypothesis tests required. For the naïve versus axotomy comparison, a 2-fold cut off alone led to an estimated error rate of 16%; combining a >1.5-fold expression change and P < 0.05 significance reduced the estimated error to 5%. The 2-fold cut off identified 178 genes while the combined >1.5-fold and P < 0.05 criteria generated 240 putatively regulated genes, which we have listed. Many of these have not been described as regulated in the DRG by axotomy. Northern blot, quantitative slot blots and in situ hybridization verified the expression of 24 transcripts. These data showed an 83% concordance rate with the arrays; most mismatches represent genes with low expression levels reflecting limits of array sensitivity. A significant correlation was found between actual mRNA differences and relative changes between microarrays (r2 = 0.8567). Temporal patterns of individual genes regulation varied. CONCLUSIONS: We identify parameters for microarray analysis which reduce error while identifying many putatively regulated genes. Functional classification of these genes suggest reorganization of cell structural components, activation of genes expressed by immune and inflammatory cells and down-regulation of genes involved in neurotransmission.

Animals↗
PubMed1996

Self-reinnervated cat medial gastrocnemius muscles. I. comparisons of the capacity for regenerating nerves to form enlarged motor units after extensive peripheral nerve injuries.

1. The aims of this study are to determine 1) whether regenerating motor axons have the capacity to form enlarged motor units (MUs) in muscles reinnervated by few motoneurons and 2) whether the type of nerve injury, repair, and/or growth environment affects this capacity. 2. MU innervation ratio (IR) was estimated by measuring isometric unit tetanic force in reinnervated cat medial gastrocnemius muscles 3-16 mo after denervation by either 1) crushing its nerve, 2) transecting the nerve and suturing the proximal end to the distal stump (N-N suture), or 3) transecting the nerve and suturing the proximal end directly to the muscle fascia (N-M suture). In addition, the number of regenerating axons was experimentally reduced by cutting one of two contributing ventral roots. 3. Muscles were reinnervated by 2-88% of their normal complement of MUs. Mean unit tetanic force increased as the number of reinnervated MUs decreased in reinnervated muscles after nerve crush or N-N suture, but not after N-M suture, even when few axons made functional connections. When the number of MUs was < 20% of normal, mean unit force was significantly higher in reinnervated muscles after nerve crush compared with muscle reinnervated after N-N suture. 4. The cross-sectional areas (CSAs) of all muscle fiber types were similar to normal in reinnervated muscles after nerve crush, but the CSAs of type IIa and IIb fibers were significantly smaller in muscles reinnervated after complete nerve transections (i.e., N-N or N-M sutures). 5. When MU force was normalized to mean muscle fiber CSA, cut motor axons displayed the same capacity to form enlarged MUs as crushed motor axons. The force of the MUs increased by as much as 5-8 times that of normal, provided the axons grew along the distal nerve stump (N-N suture). 6. Tetanic force increased in the normal order slow < fast-fatigue resistant < fast-fatigue intermediate = fast-fatigable. However, the increase in tetanic force of the slow (S) units was significantly larger than the corresponding increase of the more forceful fast (F) units. The disproportional increase in S and not F unit force, was primarily due to a significant decline in CSA of the type IIa and IIb muscle fibers. 7. The technique of glycogen depletion was used to count MU fibers to estimate the IR of MUs in 5 normal and 11 reinnervated muscles (7 N-N sutures, 4 N-M sutures). Unit tetanic force covaried with IR in both normal and reinnervated muscles. 8. These results show that regenerating axons have the same capacity as intact axons in partially denervated muscles to form enlarged MUs to compensate for a reduced number of functioning MUs. Only when axons regenerate in the absence of the distal nerve sheath is this capacity compromised.

Animals↗
PubMed2004

Pathophysiology of peripheral nerve injury: a brief review.

Clinicians caring for patients with brachial plexus and other nerve injuries must possess a clear understanding of the peripheral nervous system's response to trauma. In this article, the authors briefly review peripheral nerve injury (PNI) types, discuss the common injury classification schemes, and describe the dynamic processes of degeneration and reinnervation that characterize the PNI response.

Axons↗