transforming-growth-factor-beta and Peripheral-Nerve-Injuries

Topics: Animals; Cell Division; Cells, Cultured; Humans; Nerve Regeneration; Peripheral Nerve Injuries; Peripheral Nerves; Schwann Cells; Transforming Growth Factor beta; Transforming Growth Factor beta1

Spinal motor nerves are necessary for organismal locomotion and survival. In zebrafish and most vertebrates, these peripheral nervous system structures are composed of bundles of axons that naturally regenerate following injury. However, the cellular and molecular mechanisms that mediate this process are still only partially understood. Perineurial glia, which form a component of the blood-nerve barrier, are necessary for the earliest regenerative steps by establishing a glial bridge across the injury site as well as phagocytosing debris. Without perineurial glial bridging, regeneration is impaired. In addition to perineurial glia, Schwann cells, the cells that ensheath and myelinate axons within the nerve, are essential for debris clearance and axon guidance. In the absence of Schwann cells, perineurial glia exhibit perturbed bridging, demonstrating that these two cell types communicate during the injury response. While the presence and importance of perineurial glial bridging is known, the molecular mechanisms that underlie this process remain a mystery. Understanding the cellular and molecular interactions that drive perineurial glial bridging is crucial to unlocking the mechanisms underlying successful motor nerve regeneration. Using laser axotomy and in vivo imaging in zebrafish, we show that transforming growth factor-beta (TGFβ) signaling modulates perineurial glial bridging. Further, we identify connective tissue growth factor-a (ctgfa) as a downstream effector of TGF-β signaling that works in a positive feedback loop to mediate perineurial glial bridging. Together, these studies present a new signaling pathway involved in the perineurial glial injury response and further characterize the dynamics of the perineurial glial bridge.

Topics: Animals; Animals, Genetically Modified; Axons; Nerve Regeneration; Neuroglia; Peripheral Nerve Injuries; Peripheral Nerves; Signal Transduction; Transforming Growth Factor beta; Transforming Growth Factors; Zebrafish

Recovery of function after sensory nerves injury involves compensatory plasticity, which can be observed in invertebrates. The aim of the study was the evaluation of compensatory plasticity in the cockroach (Periplaneta americana) nervous system after the sensory nerve injury and assessment of the effect of electromagnetic field exposure (EMF, 50 Hz, 7 mT) and TGF-β on this process. The bioelectrical activities of nerves (pre-and post-synaptic parts of the sensory path) were recorded under wind stimulation of the cerci before and after right cercus ablation and in insects exposed to EMF and treated with TGF-β. Ablation of the right cercus caused an increase of activity of the left presynaptic part of the sensory path. Exposure to EMF and TGF-β induced an increase of activity in both parts of the sensory path. This suggests strengthening effects of EMF and TGF-β on the insect ability to recognize stimuli after one cercus ablation. Data from locomotor tests proved electrophysiological results. The takeover of the function of one cercus by the second one proves the existence of compensatory plasticity in the cockroach escape system, which makes it a good model for studying compensatory plasticity. We recommend further research on EMF as a useful factor in neurorehabilitation.

Topics: Afferent Pathways; Animals; Cell Plasticity; Electromagnetic Fields; Electrophysiological Phenomena; Peripheral Nerve Injuries; Sensory Receptor Cells; Transforming Growth Factor beta

Previously, we reported the successful regeneration of injured peripheral nerves using human dental pulp stem cells (DPSCs) or differentiated neuronal cells from DPSCs (DF-DPSCs) in a rat model. Here, we attempted to evaluate oxidative stress and supraspinal neuro-inflammation in rat brain after sciatic nerve injury (SNI). We divided our experimental animals into three SNI groups based on time. The expression of a microglial (Iba1) marker and reactive oxygen species (ROS) was lower in DPSCs and higher in DF-DPSCs. In contrast, the expression of an astroglial (GFAP) marker was higher in DPSCs and lower in DF-DPSCs at 2 weeks. However, the expression of ROS, Iba1 and GFAP gradually decreased at 8 and 12 weeks in the SNI DPSCs and DF-DPSCs groups compared to the SNI control. Furthermore, anti-inflammatory cytokine (IL-4 and TGF-β) expression was lower at 2 weeks, while it gradually increased at 8 and 12 weeks after surgery in the SNI DPSCs and DF-DPSCs groups. Similarly, SNI DPSCs had a high expression of pAMPK, SIRT1 and NFkB at the onset of SNI. However, 12 weeks after surgery, pAMPK and SIRT1 expression levels were higher and NFkB was down-regulated in both DPSCs and DF-DPSCs compared to the control group. Finally, we concluded that DPSCs responded early and more efficiently than DF-DPSCs to counterbalance peripheral nerve injury (PNI)-induced oxidative stress and supraspinal neuro-inflammation in rat brain.

Topics: Adenylate Kinase; Animals; Astrocytes; Brain; Dental Pulp; Disease Models, Animal; Female; Inflammation; Inflammation Mediators; Microglia; NF-kappa B; Oxidative Stress; Peripheral Nerve Injuries; Phosphorylation; Rats, Sprague-Dawley; Reactive Oxygen Species; RNA, Messenger; Sciatic Nerve; Sirtuin 1; Stem Cell Transplantation; Stem Cells; Transforming Growth Factor beta

Schwann cell dedifferentiation from a myelinating to a progenitor-like cell underlies the remarkable ability of peripheral nerves to regenerate following injury. However, the molecular identity of the differentiated and dedifferentiated states in vivo has been elusive. Here, we profiled Schwann cells acutely purified from intact nerves and from the wound and distal regions of severed nerves. Our analysis reveals novel facets of the dedifferentiation response, including acquisition of mesenchymal traits and a Myc module. Furthermore, wound and distal dedifferentiated Schwann cells constitute different populations, with wound cells displaying increased mesenchymal character induced by localized TGFβ signaling. TGFβ promotes invasion and crosstalks with Eph signaling via N-cadherin to drive collective migration of the Schwann cells across the wound. Consistently, Tgfbr2 deletion in Schwann cells resulted in misdirected and delayed reinnervation. Thus, the wound microenvironment is a key determinant of Schwann cell identity, and it promotes nerve repair through integration of multiple concerted signals. VIDEO ABSTRACT.

Topics: Animals; Cadherins; Cell Differentiation; Cell Movement; Cells, Cultured; Cellular Microenvironment; Female; Male; Mesenchymal Stem Cells; Mice; Mice, Transgenic; Nerve Regeneration; Peripheral Nerve Injuries; Primary Cell Culture; Rats; Rats, Transgenic; Receptors, Eph Family; Schwann Cells; Sciatic Nerve; Transforming Growth Factor beta

Previous studies have demonstrated that the red nucleus (RN) participates in the modulation of neuropathic pain and plays both a facilitated role by pro-inflammatory cytokines, such as tumor necrosis factor-alpha (TNF-α) and interleukin-1β (IL-1β), and an inhibitory role through the anti-inflammatory cytokine IL-10. In this study, we sought to investigate the expressions and roles of transforming growth factor-beta (TGF-β), a potent anti-inflammatory cytokine, as well as its type 1 receptor (TGF-β-R1) in the RN in normal and neuropathic pain rats. Immunohistochemistry showed that TGF-β and TGF-β-R1 were constitutively expressed in the RN of normal rats, and co-localized with neurons and all three glial cell types, astrocytes, microglia and oligodendrocytes. Following spared nerve injury (SNI), the expression levels of TGF-β and TGF-β-R1 were significantly down-regulated in the RN contralateral (but not ipsilateral) to the nerve injury side of rats at one week and reached the lowest level at two weeks after SNI, and both of them were co-localized with neurons and oligodendrocytes but not with astrocytes and microglia. Microinjection of different doses of anti-TGF-β antibody (250, 125, 50 ng) into the unilateral RN of normal rats dose-dependently decreased the mechanical withdrawal threshold of contralateral (but not ipsilateral) hind paw and induced significant mechanical hypersensitivity, which was similar to mechanical allodynia induced by peripheral nerve injury. In contrast, microinjection of different doses of recombinant rat TGF-β1 (500, 250, 100 ng) into the RN contralateral to the nerve injury side of SNI rats dose-dependently increased the paw withdrawal threshold and significantly alleviated mechanical allodynia induced by SNI. These results suggest that TGF-β in the RN participates in nociceptive processing and plays antinociceptive effects under normal physiological condition and in the development of neuropathic pain induced by SNI.

Topics: Analgesics; Animals; Antibodies; Astrocytes; Disease Models, Animal; Dose-Response Relationship, Drug; Hyperalgesia; Male; Microglia; Microinjections; Neuralgia; Neurons; Oligodendroglia; Pain Threshold; Peripheral Nerve Injuries; Protein Serine-Threonine Kinases; Rats, Sprague-Dawley; Receptor, Transforming Growth Factor-beta Type I; Receptors, Transforming Growth Factor beta; Recombinant Proteins; Red Nucleus; Sciatic Nerve; Transforming Growth Factor beta

Transforming growth factor-β1 (TGF-β1) protects against neuroinflammatory events underlying neuropathic pain. TGF-β signaling enhancement is a phenotypic characteristic of mice lacking the TGF-β pseudoreceptor BAMBI (BMP and activin membrane-bound inhibitor), which leads to an increased synaptic release of opioid peptides and to a naloxone-reversible hypoalgesic/antiallodynic phenotype. Herein, we investigated the following: (1) the effects of BAMBI deficiency on opioid receptor expression, functional efficacy, and analgesic responses to endogenous and exogenous opioids; and (2) the involvement of the opioid system in the antiallodynic effect of TGF-β1. BAMBI-KO mice were subjected to neuropathic pain by sciatic nerve crash injury (SNI). Gene (PCR) and protein (Western blot) expressions of μ- and δ-opioid receptors were determined in the spinal cord. The inhibitory effects of agonists on the adenylyl cyclase pathway were investigated. Two weeks after SNI, wild-type mice developed mechanical allodynia and the functionality of μ-opioid receptors was reduced. By this time, BAMBI-KO mice were protected against allodynia and exhibited increased expression and function of opioid receptors. Four weeks after SNI, when mice of both genotypes had developed neuropathic pain, the analgesic responses induced by morphine and RB101 (an inhibitor of enkephalin-degrading enzymes, which increases the synaptic levels of enkephalins) were enhanced in BAMBI-KO mice. Similar results were obtained in the formalin-induced chemical-inflammatory pain model. Subcutaneous TGF-β1 infusion prevented pain development after SNI. The antiallodynic effect of TGF-β1 was naloxone-sensitive. In conclusion, modulation of the endogenous opioid system by TGF-β signaling improves the analgesic effectiveness of exogenous and endogenous opioids under pathological pain conditions.

Topics: Adenylyl Cyclase Inhibitors; Analgesia; Analgesics, Opioid; Animals; Disulfides; Hyperalgesia; Infusions, Subcutaneous; Membrane Proteins; Mice; Mice, Inbred C57BL; Morphine; Naloxone; Neuralgia; Peripheral Nerve Injuries; Phenylalanine; Receptors, Opioid, delta; Receptors, Opioid, mu; Sciatic Nerve; Signal Transduction; Spinal Cord; Transforming Growth Factor beta

Muscle atrophy, fatty infiltration, and fibrosis of the muscle have been described as important factors governing outcome after rotator cuff injury and repair. Muscle fibrosis is also thought to have a role in determining muscle compliance at the time of surgery. The transforming growth factor-β (TGF-β) pathways are highly conserved pathways that exert a potent level of control over muscle gene expression and are critical regulators of fibrosis in multiple organ systems. It has been shown that TGF-β can regulate important pathways of muscle atrophy, including the Akt/mammalian target of rapamycin pathway. The purpose of this study was to evaluate the expression of TGF-β and its downstream effectors of fibrosis after a massive rotator cuff tear (RCT) in a previously established rat model.. To simulate a massive RCT, infraspinatus and supraspinatus tenotomy and suprascapular nerve transection were performed on Sprague-Dawley rats with use of a validated model. Two and 6 weeks after surgery, supraspinatus muscles were harvested to study alterations in TGF-β signaling by Western blotting, quantitative polymerase chain reaction, and histologic analysis.. There was a significant increase in fibrosis in the rotator cuff muscle after RCT in our animal model. There was a concomitant increase in TGF-β gene and protein expression at both 2 and 6 weeks after RCT. Evaluation of the TGF-β signaling pathway revealed an increase in SMAD2 activation but not in SMAD3. There was an increase in profibrotic markers collagen I, collagen III, and α-smooth muscle actin.. TGF-β signaling is significantly upregulated in rat supraspinatus muscles after RCTs.

Topics: Animals; Disease Models, Animal; Female; Fibrosis; Peripheral Nerve Injuries; Rats; Rats, Sprague-Dawley; RNA, Messenger; Rotator Cuff; Rotator Cuff Injuries; Tendon Injuries; Transforming Growth Factor beta; Up-Regulation

Topics: Bone and Bones; Bone Development; Bone Morphogenetic Proteins; Humans; Nerve Growth Factor; Peripheral Nerve Injuries; Peripheral Nerves; Transforming Growth Factor beta; Wound Healing

Neurogenic erectile dysfunction remains a serious complication in the postprostatectomy population. Effective protective and regenerative neuromodulatory strategies are needed.. To determine the effect of growth differentiation factor-5 (GDF-5) on erectile function and its mechanism in a rat model of cavernous nerve (CN) injury.. Erectile function was assessed by CN electrostimulation at 4 weeks. Penile tissues were examined by real-time polymerase chain reaction (PCR) and immunohistochemical analyses.. Forty-eight male Sprague-Dawley rats were randomly divided into six equal groups: one group underwent sham operation (uninjured controls), while five groups underwent bilateral CN crush. Crush-injury groups were treated at the time of injury with intracavernous injection of a slow-release suspension of liquid microparticles containing no GDF-5 (vehicle), 0.4 microg (low concentration), 2 microg (intermediate concentration), or 10 microg GDF-5 (high concentration). One untreated group served as injured controls.. GDF-5 enhanced erectile recovery and significantly increased intracavernous pressure in the low and intermediate-concentration groups vs. injured controls. Low-concentration GDF-5 demonstrated the best functional preservation, as the intracavernous pressure increase in this group did not differ significantly from uninjured controls. A dose-response relationship was confirmed for the effects of GDF-5 in penile tissue. Low-concentration GDF-5 showed better preservation of the penile dorsal nerves and antiapoptotic effects in the corpus cavernosum (P < 0.05 vs. injured controls). Although high concentration GDF-5 did not confer meaningful erectile recovery, this dose was more effective at decreasing transforming growth factor-beta than low-concentration GDF-5.. Intracavernous injection of low (0.4 microg) or intermediate-concentration GDF-5 (2 microg) was effective in preserving erectile function in a rat model of neurogenic erectile dysfunction. The underlying mechanism appears to involve neuron preservation and antiapoptosis.

Topics: Animals; Apoptosis; Blood Pressure; Disease Models, Animal; Dose-Response Relationship, Drug; Erectile Dysfunction; Gene Expression; Growth Differentiation Factor 5; In Situ Nick-End Labeling; Injections; Male; Nerve Crush; Nitric Oxide Synthase; Penile Erection; Penis; Peripheral Nerve Injuries; Rats; Rats, Sprague-Dawley; RNA, Messenger; Transforming Growth Factor beta

We have used adult rat peripheral nerve avulsion models to evaluate the effects of neuroprotective molecules on motoneuron degeneration. The right facial nerves of adult Fischer 344 male rats were avulsed and adenoviral vectors encoding glial cell line-derived neurotrophic factor (GDNF), brain-derived neurotrophic factor (BDNF), transforming growth factor-beta2 (TGFbeta2), and growth inhibitory factor (GIF) were injected into the facial canal. The treatment with the vectors significantly prevented the loss of lesioned facial motoneurons, improved choline acetyltransferase (ChAT) immunoreactivity and suppressed the induction of nitric oxide synthase activity in these neurons. In separate experiments, animals were orally administered a solution of a neuroprotective compound T-588 after avulsion. Both free oral administration and oral tube administration of T-588 improved the survival of injured motoneurons and ameliorated their ChAT immunoreactivity. These results indicate that the gene transfer of GDNF, BDNF, TGFbeta2, and GIF and oral administration of T-588 may prevent the degeneration of motoneurons in adult humans with motoneuron injury and motor neuron diseases.

Topics: Adenoviridae; Animals; Brain-Derived Neurotrophic Factor; Diethylamines; Disease Models, Animal; Facial Nerve Injuries; Gene Transfer Techniques; Genetic Vectors; Glial Cell Line-Derived Neurotrophic Factor; Male; Metallothionein 3; Motor Neuron Disease; Motor Neurons; Nerve Degeneration; Nerve Tissue Proteins; Neuroprotective Agents; Peripheral Nerve Injuries; Peripheral Nerves; Rats; Thiophenes; Transforming Growth Factor beta

The capacity of Schwann cells (SCs) in the peripheral nervous system to support axonal regeneration, in contrast to the oligodendrocytes in the central nervous system, has led to the misconception that peripheral nerve regeneration always restores function. Here, we consider how prolonged periods of time that injured neurons remain without targets during axonal regeneration (chronic axotomy) and that SCs in the distal nerve stumps remain chronically denervated (chronic denervation) progressively reduce the number of motoneurons that regenerate their axons. We demonstrate the effectiveness of low-dose, brain-derived neurotrophic and glial-derived neurotrophic factors to counteract the effects of chronic axotomy in promoting axonal regeneration. High-dose brain-derived neurotrophic factor (BDNF) on the other hand, acting through the p75 receptor, inhibits axonal regeneration and may be a factor in stopping regenerating axons from forming neuromuscular connections in skeletal muscle. The immunophilin, FK506, is also effective in promoting axonal regeneration after chronic axotomy. Chronic denervation of SCs (>1 month) severely deters axonal regeneration, although the few motor axons that do regenerate to reinnervate muscles become myelinated and form enlarged motor units in the reinnervated muscles. We found that in vitro incubation of chronically denervated SCs with transforming growth factor-beta re-established their growth-supportive phenotype in vivo, consistent with the idea that the interaction between invading macrophages and denervated SCs during Wallerian degeneration is essential to sustain axonal regeneration by promoting the growth-supportive SC phenotype. Finally, we consider the effectiveness of a brief period of 20 Hz electrical stimulation in promoting the regeneration of axons across the surgical gap after nerve repair.

Topics: Animals; Autonomic Denervation; Axons; Axotomy; Brain-Derived Neurotrophic Factor; Cell Count; Colforsin; Dextrans; Disease Models, Animal; Dose-Response Relationship, Drug; Drug Interactions; Electric Stimulation; Evoked Potentials, Motor; Humans; In Vitro Techniques; Mice; Mice, Knockout; Motor Neurons; Muscle Contraction; Nerve Degeneration; Nerve Growth Factors; Nerve Regeneration; Peripheral Nerve Injuries; Peripheral Nerves; Rats; Receptor, Nerve Growth Factor; Receptor, trkB; Receptors, Nerve Growth Factor; Recovery of Function; Rhodamines; Schwann Cells; Tacrolimus; Time Factors; Transforming Growth Factor beta

Transforming growth factor-beta (TGF-beta) plays a central role in the regulation of Schwann cell (SC) proliferation and differentiation and is essential for the neurotrophic effects of several neurotrophic factors (reviewed by Unsicker and Krieglstein, 2000; Unsicker and Strelau, 2000). However, its role in peripheral nerve regeneration in vivo is not yet understood. Our studies were carried out to characterize (1) the effects of duration of regeneration, and chronic SC denervation on the number of tibial (TIB) motor neurons that regenerated axons over a fixed distance (25 mm into distal common peroneal [CP] nerve stumps), and (2) the effect of in vitro incubation of 6-month chronically denervated sciatic nerve explants with TGF-beta and forskolin on their capacity to support axonal regeneration in vivo. TIB--CP cross-suture in Silastic tubing was used, and regeneration into 0-24-week chronically denervated CP stumps was allowed for either 1.5 or 3 months. Chronically denervated rat sciatic nerve explants (3 x 3 mm(2)) were incubated in vitro with either DMEM and 15% fetal calf serum (D-15) plus TGF-beta/forskolin or D-15 alone for 48 h and placed into a 10-mm Silastic tube that bridged the proximal and distal nerve stumps of a freshly cut TIB nerve. The number of tibial motor neurons that regenerated axons through the explants and 25 mm into the distal nerve stump after 6 months, and TIB regeneration into the CP nerve stumps, were assessed using retrograde tracers, fluorogold, or fluororuby. We found that all tibial motor neurons regenerate their axons 25 mm into 0-4-week denervated CP nerve stumps after a regeneration period of 3 months. Reducing regeneration time to 1.5 months and chronic denervation, reduced the number of motor neurons that regenerated axons over 25 mm. Exposure of 6-month denervated nerve explants to TGF-beta/forskolin increased the number of motor neurons that regenerated through them from 258 +/-13; mean +/- SE to 442 +/- 22. Hence, acute treatment of atrophic SC with TGF-beta can reactivate the growth-permissive SC phenotype to support axonal regeneration.

Topics: Animals; Axons; Colforsin; Denervation; Disease Models, Animal; Female; Motor Neurons; Nerve Regeneration; Neurosurgical Procedures; Organ Culture Techniques; Peripheral Nerve Injuries; Peripheral Nerves; Prostheses and Implants; Rats; Rats, Sprague-Dawley; Recovery of Function; Schwann Cells; Time Factors; Tissue Transplantation; Transforming Growth Factor beta; Treatment Outcome; Wallerian Degeneration

The poor ability of injured central nervous system (CNS) axons to regenerate has been correlated, at least partially, with a limited and suppressed postinjury inflammatory response. A key cell type in the inflammatory process is the macrophage, which can respond in various ways, depending on the conditions of stimulation. The aim of this study is to compare the activities of macrophages or microglia when encountering CNS and peripheral nervous systems (PNS), on the assumption that nerve-related differences in the inflammatory response may have implications for tissue repair and thus for nerve regeneration. Phagocytic activity of macrophages or of isolated brain-derived microglia was enhanced upon their exposure to sciatic (PNS) nerve segments, but inhibited by exposure to optic (CNS) nerve segments. Similarly, nitric oxide production by macrophages or microglia was induced by sciatic nerve segments but not by optic nerve segments. The previously demonstrated presence of a resident inhibitory activity in CNS nerve, could account, at least in part, for the inhibited phagocytic activity of blood-borne macrophages in CNS nerve as well as of microglia resident in the brain. It seems that the CNS microglia are reversibly immunosuppressed by the CNS environment, at least with respect to the activities examined here. It also appears from this study that the weak induction of early healing-related activities of macrophages/microglia in the environment of CNS might explain the subsequent failure of this environment to acquire growth-supportive properties in temporal and spatial synchrony with the needs of regrowing axons.

Topics: Animals; Cells, Cultured; Central Nervous System; Coculture Techniques; Culture Media, Conditioned; Inflammation; Macrophage Activation; Macrophages; Male; Microglia; Nerve Regeneration; Nitric Oxide; Optic Nerve; Optic Nerve Injuries; Organ Culture Techniques; Organ Specificity; Peripheral Nerve Injuries; Peripheral Nerves; Phagocytosis; Rats; Rats, Wistar; Sciatic Nerve; Transforming Growth Factor beta

In contrast to the central nervous system (CNS), the peripheral nervous system (PNS) displays an important regenerative ability which is dependent, at least in part, on Schwann cell properties. The mechanisms which stimulate Schwann cells to adapt their behavior after a lesion to generate adequate conditions for PNS regeneration remain unknown. In this work, we report that adult rat dorsal root ganglion (DRG) neurons are able, after a lesion performed in vivo or when they are dissociated and cultured in vitro, to synthesize transforming growth factor beta (TGF beta), a pleiotropic growth factor implicated in wound healing processes and in carcinogenesis. This TGF beta is tentatively identified as the beta-1 isoform. Adult rat DRG neurons release a biologically active form of TGF beta which is able to elicit multiple Schwann cell responses including a stimulation to proliferate. Moreover, purified TGF beta-1 produces a Schwann cell morphology alteration and decreases the secretion of tissue-type plasminogen activator (tPA) and enhances the secretion of plasminogen activator inhibitor (PAI) by Schwann cells. This generates conditions which are thought to favor a successful neuritic regrowth. Furthermore, purified TGF beta-1 stimulates type IV collagen mRNA expression in Schwann cells. This subtype of collagen is associated with the process of myelinization. Finally, TGF beta-1 decreases nerve growth factor (NGF) mRNA expression by Schwann cells, an effect which could participate in the maintenance of a distoproximal NGF gradient during nerve regeneration. We propose that neuronal TGF beta plays an essential role as a neuronoglial signal that modulates the response of Schwann cells to injury and participates in the successful regeneration processes observed in the PNS.

Topics: Animals; Cell Division; Cells, Cultured; Culture Media; Extracellular Matrix Proteins; Ganglia, Spinal; Immunohistochemistry; Nerve Growth Factors; Neuroglia; Neurons; Peripheral Nerve Injuries; Peripheral Nerves; Plasminogen Activators; Plasminogen Inactivators; Rats; RNA, Messenger; Schwann Cells; Signal Transduction; Transforming Growth Factor beta