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PubMed2003

FKBP12 mRNA expression is upregulated by intrinsic CNS neurons regenerating axons into peripheral nerve grafts in the brain.

We have examined the expression of the immunophilin FKBP12 in adult rat intrinsic CNS neurons stimulated to regenerate axons by the implantation of segments of autologous tibial nerve into the thalamus or cerebellum. After survival times of 3 days to 6 weeks, the brains were fresh-frozen. In some animals the regenerating neurons were retrogradely labelled with cholera toxin subunit B 1 day before they were killed. Sections through the thalamus or cerebellum were used for in situ hybridization with digoxygenin-labelled riboprobes for FKBP12 or immunohistochemistry to detect cholera toxin subunit B-labelled neurons. FKBP12 was constitutively expressed by many neurons, and was very strongly expressed in the hippocampus and by Purkinje cells. Regenerating neurons were found in the thalamic reticular nucleus and deep cerebellar nuclei of animals that received living grafts. Neurons in these nuclei upregulated FKBP12 mRNA; such neurons were most numerous at 3 days post grafting but were most strongly labelled at 2 weeks post grafting. Regenerating neurons identified by retrograde labelling were found to have upregulated FKBP12 mRNA. No upregulation was seen in neurons in animals that received freeze-killed grafts, which do not support axonal regeneration. We conclude that FKBP12 is a regeneration-associated gene in intrinsic CNS neurons.

Animals↗
PubMed2003

Controlled release of nerve growth factor enhances sciatic nerve regeneration.

Based on previous studies demonstrating the potential of growth factors to enhance peripheral nerve regeneration, we developed a novel growth factor delivery system to provide sustained delivery of nerve growth factor (NGF). This delivery system uses heparin to immobilize NGF and slow its diffusion from a fibrin matrix. This system has been previously shown to enhance neurite outgrowth in vitro, and in this study, we evaluated the ability of this delivery system to enhance nerve regeneration through conduits. We tested the effect of controlled NGF delivery on peripheral nerve regeneration in a 13-mm rat sciatic nerve defect. The heparin-containing delivery system was studied in combination with three doses of NGF (5, 20, or 50 ng/mL) and the results were compared with positive controls (isografts) and negative controls (fibrin alone, NGF alone, and empty conduits). Nerves were harvested at 6 weeks postoperatively for histomorphometric analysis. Axonal regeneration in the delivery system groups revealed a marked dose-dependent effect. The total number of nerve fibers at both the mid-conduit level and in the distal nerve showed no statistical difference for NGF doses at 20 and 50 ng/mL from the isograft (positive control). The results of this study demonstrate that the incorporation of a novel delivery system providing controlled release of growth factors enhances peripheral nerve regeneration and represents a significant contribution toward enhancing nerve regeneration across short nerve gaps.

Animals↗
PubMed1999

Differential expression of basolateral and canalicular organic anion transporters during regeneration of rat liver.

BACKGROUND & AIMS: Liver regeneration in response to various forms of injury or surgical resection is a complex process resulting in restoration of the original liver mass and maintenance of liver-specific functions such as bile formation. However, liver regeneration is frequently associated with cholestasis, whose molecular pathogenesis remains unknown. METHODS: To study the molecular mechanisms leading to cholestasis, expression of all major hepatic organic anion transporters contributing to bile formation was determined for up to 2 weeks in rats after 70% partial hepatectomy. RESULTS: Inversely related to serum bile acid levels, basolateral transporters including the sodium-taurocholate cotransporter (Ntcp) and the organic anion transporting polypeptides Oatp1 and Oatp2 were markedly down-regulated at both protein and steady-state mRNA levels by 50%-60% of controls (P < 0.05) during early replicative stages of regeneration (12 hours to 2 days) with a slightly delayed time course for Oatp2. Expression of all basolateral transporters returned to control values between 4 and 4 days after partial hepatectomy. In contrast, protein and mRNA expression of both the canalicular ATP-dependent bile salt export pump (Bsep) and the multiorganic anion transporter Mrp2 remained unchanged or were slightly increased during liver regeneration, but also returned to control values 7-14 days after partial hepatectomy. CONCLUSIONS: The data suggest a differential regulation of basolateral and canalicular organic anion transporters in the regenerating liver. Unaltered expression of Bsep and Mrp2 provides a potential molecular mechanism for regenerating liver cells to maintain or even increase bile secretion expressed per weight of remaining liver. However, down-regulation of basolateral organic anion transporters might protect replicating liver cells by diminishing uptake of potentially hepatotoxic bile salts, because the remaining liver initially cannot cope with the original bile acid pool size.

Animals↗
PubMed1996

Inhibition of gastric mucosal regeneration by tyrphostin: evaluation of the role of epidermal growth factor receptor tyrosine kinase.

Although induction of mucosal cell proliferation is a crucial event in gastric mucosal regeneration after injury, intracellular regulatory processes have not been fully elucidated. We hypothesize that tyrosine kinases (Tyr-k)--specifically the enzyme associated with epidermal growth factor receptor (EGF-R)--play an important role in mucosal regeneration. Utilizing tyrphostin--a Tyr-k inhibitor with a greater specificity for EGF-R Tyr-k than for other Tyr-ks--we have examined the role of EGF-R Tyr-k in gastric mucosal regeneration after injury. Gastric mucosal injury in 3-to 4-month-old rats was induced by orogastric administration of 2 mol/L NaCl, whereas the control animals received an equivalent volume of water. The animals were killed 24 hours later. During this 24-hour experimental period (reparative phase), one of the groups was also injected (IP) with tyrphostin-51 (0.65 mg/kg in 30% dimethyl sulfoxide), whereas the control group received the vehicle. In the absence of tyrphostin, the gastric mucosa showed signs of extensive regeneration, whereas in its presence the degree of regeneration was greatly attenuated. These changes were accompanied by parallel alterations in the number of proliferating cell nuclear antigen-immunoreactive cells and the Tyr-k activity of EGF-R. In water-fed control animals, tyrphostin also caused a significant 30% reduction in proliferating cell nuclear antigen-immunoreactive cells. In these animals, the Tyr-k activity of EGF-R was also decreased by 30%. At 24 hours after injury, EGF-R mRNA levels were increased 36-fold over the water-fed controls, and this increase was not significantly affected by tyrphostin. Our current data suggest that activation of EGF-R is an important event in mucosal regeneration.

Animals↗
PubMed2003

Intravital analysis of microcirculation in the regenerating mouse liver.

BACKGROUND: Liver tissue remodeling after surgery includes development of new hepatic microvasculature. Although various endothelial growth factors have been shown to play a role in liver tissue repair, the functional consequences of rapid endothelial cell proliferation are unknown. To determine the influence of endothelial cell proliferation on vessel functionality, we have analyzed the in vivo morphology of microvasculature in the regenerating liver. MATERIALS AND METHODS: Mice were subjected to 70% partial hepatectomy (PH) and at 24, 48, 96 h, 7 and 14 days post PH underwent intravital microscopy of the exposed liver remnant. Intrahepatic microvessels were visualized with fluoresceine-labeled dextran. Recorded parameters were: functional vessel length (VL), functional vessel diameter (VD), hepatic cell plate width (PW), and functional vessel surface area (FVSA). RESULTS: VL showed a transient decrease (17-31%) after PH. PW was significantly increased in the regenerating liver. VD significantly increased on days 1 and 2 post PH. On days 4, 7, and 14, VD returned to normal. In contrast, FVSA remained within normal range until day 14 post PH. CONCLUSIONS: Despite changes in vessel length and hepatic cell plate width in the early regenerating liver, functional vessel surface area remains normal until day 14 post PH. These changes may indicate compensatory vascular growth mechanisms to ensure adequate hepatocyte perfusion during liver regeneration. Better understanding of functional variations during physiological liver regeneration may be of use in liver conditions characterized by defective regeneration, e.g., cirrhosis.

Animals↗
PubMed1992

The evolution of regeneration: adaptive or inherent?

If regeneration were adaptive, it would have arisen autonomously by natural selection from non-regenerative antecedents. Unless each episode coincidentally reinvented the same method of regeneration independently, one would expect the various lineages to differ basically from each other, which they do not. On the other hand, if regeneration were inherent to metazoan life, a derivative of embryogenesis, its various expressions should be as much like each other as they resemble the development of embryonic appendage buds, which they do. It follows that the uneven distribution of regeneration must have been due to its extinction here and there, not as a negative adaptation by natural selection but as a pleiotropic epiphenomenon linked to more useful adaptations with which it was incompatible. In vertebrate evolution, these adaptations have included the transition from aquatic to terrestrial habitats and the modification of poikilothermic to homeothermic metabolism. The former advance rendered the regeneration of weight-bearing limbs impractical; the latter favored rapid wound healing and scar formation which effectively precluded blastema formation. If the latent capacity for regeneration persists in non-regenerative appendages, as would seem to be the case, then the restoration of its overt expression should be possible if the mechanisms of its inhibition could be discovered and eventually rendered ineffectual.

Adaptation, Physiological↗
PubMed2001

Differences in DNA synthesis in vitro using isolated nuclei from regenerating livers of young and aged rats.

To detect changes in DNA synthesis during ageing, we compare DNA synthesis in the livers of young and aged rats. As an intermediate between an in vivo system using intact cells and an in vitro system using purified DNA polymerases, isolated nuclei were prepared and used as the machinery for DNA synthesis. The DNA synthesizing capacity of nuclei from regenerating liver was higher than that of nuclei from normal liver and these capacities from liver and regenerating liver were lower in nuclear preparations from aged rats. DNA synthesis using isolated nuclei was stimulated by ATP and the cytoplasmic preparation. The cytoplasmic preparation from regenerating rat liver was found to stimulate DNA synthesis more than the preparation from normal liver. The activity in regenerating liver from young rats was also greater than in that from aged rats. It is well known that DNA replication is inhibited by aphidicolin and DNA repair by ddTTP. We examined the effects of aphidicolin and ddTTP on DNA synthesis using the nuclear system. Surprisingly, the inhibition by aphidicolin was 30% of total DNA synthesis using the nuclear system from young rats. On the other hand, the inhibition by ddTTP was approximately 80%. We measured the sizes of the DNA synthesized in the presence of both inhibitors. DNA synthesis was allowed to proceed for 10 min using isolated nuclei from regenerating liver of young rats and the size of the DNA was determined by sucrose density gradient centrifugation analysis. DNA products appeared in two fractions. Following a chase of 50 min in the presence or absence of aphidicolin, the short DNA product grew larger in both cases, although the amount of DNA in the presence of aphidicolin was approximately 90% that in its absence. In the same experiment using nuclei from aged rats, the amount in the presence of aphidicolin was approximately 60% that in its absence. These results suggest that DNA polymerase beta is closely related to abnormal replication when DNA polymerases alpha and delta are inhibited and that the effect of cytosol on DNA synthesis, as well as the DNA synthetic capacity of isolated nuclei, becomes lower in regenerating rat liver during ageing.

Aging↗
PubMed1998

Gene expression during amphibian limb regeneration.

Limb regeneration in adult urodeles is an important phenomenon that poses fundamental questions both in biology and in medicine. In this review, we focus on recent advances in the characterization of the regeneration blastema at cellular and molecular levels and on the current understanding of the molecular basis of limb regeneration and its relationship to development. In particular, we discuss (i) the spatiotemporal distribution of genes and gene products in the mesenchyme and wound epidermis of the regenerating limb, (ii) how growth is controlled in the regeneration blastema, and (iii) molecules that are likely to be involved in patterning the regenerating limb such as homeobox genes and retinoids.

Animals↗
PubMed2001

The geometric design of micromachined silicon sieve electrodes influences functional nerve regeneration.

A neural interface could be used to control a limb prosthesis. Such an interface can be created by facilitating axonal regeneration through a sieve electrode and then register nerve signals intended to control the prosthesis. A key question is how to design the electrodes to ensure the best possible regeneration. Our previous studies have indicated that regeneration can be achieved using electrodes with square-shaped, 100 x 100 microm, via holes (holes that axons will regenerate through). Other reports have indicated a suitable range of these holes between 40 and 65 microm. In the present study we used silicon sieve electrodes with via holes of either 30 or 90 microm. The transparency, i.e. the percentage of the total via hole area, of these electrodes was either 20 or 30%. The electrodes were inserted into a silicone chamber which was used to bridge a gap in a rat sciatic nerve. After 12 weeks of nerve regeneration electrodes with a hole size of 30 microm and a 30% transparency had the most favourable result as judged by the regained gastrocnemius muscle force and the formation of reactive tissue inside the chamber. The sieve electrode transparency is crucial for ensuring regeneration.

Animals↗
PubMed1997

Rat sciatic nerve regeneration through a micromachined silicon chip.

The capacity of regenerating nerve fibres to grow through a perforated silicon chip was tested using the silicone chamber model for nerve regeneration. The chips were fabricated as circular membranes, 4 mm in diameter, thickness 60 microns, with a perforated area, 2 mm in diameter, in the centre. Three types of chips were fabricated utilizing anisotropic etching. The chips were glued with silicone adhesive between two halves of silicone rubber tubing (total length 8 mm, inner diameter 1.8 mm, outer diameter 3.0 mm) which was used to bridge a 4 mm gap between the proximal and distal nerve stumps of a transected rat sciatic nerve. The capacity of regenerating nerve fibres to grow through the holes of the chip was analysed by light and scanning electron microscopy after 4 or 16 weeks of regeneration. Furthermore, the muscle contractility force of the gastrocnemius muscle was measured after 16 weeks of regeneration and compared as a percentage of the contralateral uninjured side. Nerves generated through chips with hole diameters of 10 or 50 microns were morphological and functional failures. The nerve structures distal to chips with hole diameters of 100 microns contained many myelinated nerve fibres in a minifascicular pattern after both 4 and 16 weeks of regeneration. The muscle contractility force was 56% of that of contralateral control muscles.

Animals↗
PubMed1999

Highly permeable polylactide-caprolactone nerve guides enhance peripheral nerve regeneration through long gaps.

We compared regeneration and functional reinnervation after sciatic nerve resection and tubulization repair with bioresorbable guides of poly(L-lactide-co-epsilon-caprolactone) (PLC) and permanent guides of polysulfone (POS) with different degrees of permeability, leaving a 6 mm gap in different groups of mice. Functional reinnervation was assessed to determine recovery of motor, sensory and sweating functions in the hindpaw during four months postoperation. Highly permeable PLC guides allowed for faster and higher levels of reinnervation for the four functions tested than impermeable or low-permeable PLC guides, while semipermeable 30 and 100 kDa POS tubes yielded very low levels of reinnervation. The regeneration success rate was higher with PLC than with POS tubes. Morphometrical analysis of cross-sectional nerves under light microscopy showed the highest number of regenerated myelinated fibers at mid tube and distal nerve in high-permeable PLC guides. Impermeable PLC guides allowed slightly worse levels of regeneration, while low-permeable PLC guides promoted neuroma and limited distal regeneration. The lowest number of regenerated fibers were found in POS tubes. In summary, highly permeable bioresorbable PLC guides offer a suitable alternative for repairing long gaps in injured nerves, approaching the success of autologous nerve grafts.

Absorbable Implants↗
PubMed2003

The appearance and maturation of excitatory and inhibitory neurotransmitter sensitivity during retinal regeneration of the adult newt.

Using living slice preparations from newt retinas at different stages of regeneration, we examined the time course of appearance and maturation of neurotransmitter-induced currents with whole-cell patch-clamp methods. Neurons from which currents were recorded were identified by Lucifer Yellow fills. All progenitor cells examined at the regenerating retinas did not express any voltage-gated Na+ currents and responsiveness to excitatory amino acid analogues (AMPA and NMDA) and inhibitory amino acids (GABA and glycine). Voltage-gated Na+ currents were first detected in premature ganglion cells with round cell body located at the most proximal level of the 'intermediate-II' regenerating retina. AMPA- GABA- and glycine-induced currents were simultaneously observed in many premature ganglion cells expressing Na+ channels, but not all, suggesting that the onset of the Na+ channels is slightly earlier than that of excitatory and inhibitory amino acid receptors in regeneration. NMDA-evoked currents were first observed in the 'intermediate-III' regenerating retina just before the synaptogenesis. Pharmacological properties and reversal potential values of the excitatory and inhibitory amino acid responses did not change substantially between regenerating ganglion cells and mature ganglion cells, while rectification properties of current-voltage relations for AMPA and NMDA responses were somewhat different between them.

Action Potentials↗
PubMed2000

Bone regeneration by transforming growth factor beta1 released from a biodegradable hydrogel.

This paper describes the sustained release of transforming growth factor beta1 (TGF-beta1) from a biodegradable hydrogel based on polyion complexation for the enhancement of bone regeneration activity. Basic TGF-beta1 was adsorbed onto the biodegradable hydrogel of acidic gelatin with an isoelectric point of 5.0 by an electrostatic interaction. The TGF-beta1 could not be adsorbed onto basic gelatin. When acidic gelatin hydrogels incorporating 125I-labeled TGF-beta1 were implanted into the back subcutis of mice, the radioactivity decreased with time and the in vivo retention of TGF-beta1 was prolonged with a decrease in the water content of hydrogels. The higher the water content of hydrogels, the faster their biodegradation. The in vivo retention of TGF-beta1 correlated well with that of gelatin hydrogels, indicating that TGF-beta1 was released from the gelatin hydrogel as a result of hydrogel biodegradation. The ability of TGF-beta1-incorporated into acidic gelatin hydrogels to induce bone regeneration was evaluated in a rabbit calvarial defect model. Eight weeks after treatment, the gelatin hydrogels with water contents of 90 and 95 wt% induced significantly high bone regeneration compared with those with lower and higher water contents and free TGF-beta1. This indicates that the sustained release of TGF-beta1 from the hydrogel with suitable in vivo degradability is necessary to effectively enhance its osteoinductive function. Rapid hydrogel degradation will result in a retention time of TGF-beta1 which is too short to induce bone regeneration. It is possible that the slow degradation of the hydrogel physically blocked TGF-beta1-induced bone regeneration at the skull defect. It can be concluded that the gelatin hydrogel is a promising matrix of TGF-beta1 release to induce skull bone regeneration.

Absorbable Implants↗
PubMed2001

Differential expression of CD44 isoforms during liver regeneration in rats.

BACKGROUND: CD44 is a transmembrane glycoprotein known to bind hyaluronic acid (HA). This molecule is a multifunctional cell surface glycoprotein involved in lymphocyte homing and activation, tumor growth and metastasis. We have investigated the qualitative modification of CD44 in the regenerating liver as a model for studying cellular proliferation in vivo. Molecules involved in cell adhesion and the extracellular matrix (ECM), which influence differentiation, growth, cell-cell interactions and cellular polarity, play an important role in the liver regeneration. We studied the modulation of CD44 gene expression and its post-transcriptional modifications, analyzing the expression of different isoforms containing exon v6 in the regenerating liver, in sham operated liver and in the hepatoma cells H-35. METHODS: The expression of CD44 and CD44v6 were analyzed in RNA extracted from regenerating liver at different times after partial hepatectomy (PH), and H-35 hepatoma cells by Northern blot, RT-PCR and Southern blot, and in protein extracts from regenerating liver by Western blot. H-35 hepatoma cells were assayed with the antibody cross-linked technique with CD44 antibodies. RESULTS: The standard CD44 form is expressed in regenerating liver and its levels were not modified following PH. However, our analysis revealed CD44 isoforms containing v6 in the first hours after PH as well as in the H-35 hepatoma cell line. H-35 cells treated with cross-linked anti-CD44 antibodies or HA show an increased rate of incorporation of [3H]thymidine (30 and 25%, respectively) with respect to the control. CONCLUSION: These findings suggest that CD44 may play a role in the proliferation of residual hepatocytes following PH.

Animals↗
PubMed1997

Hepatic expression of regeneration marker genes following partial hepatectomy in the rat. Influence of 1,25-dihydroxyvitamin D3 in hypocalcemia.

BACKGROUND/AIMS: Vitamin D (D) depletion is a common feature of chronic liver diseases. In past years, disturbances in calcium metabolism involving inadequate D and parathyroid hormone status have been reported to significantly impair the hepatic regeneration process following partial hepatectomy in the rat. The purpose of this study was to investigate how hypocalcemia and D deficiency affect specific cell markers of hepatic compensatory growth. METHODS: Steady-state mRNA levels of gene markers of the regeneration process were investigated following 2/3 partial hepatectomy. The response of hypocalcemic D-depleted rats was compared to that of animals whose calcium status had been normalized by repletion with the active D hormone 1,25-dihydroxyvitamin D3 (1,25(OH)2D3). RESULTS: The transcript for the major hepatic mitogen HGF increased in both groups after partial liver resection but the increase was significantly lower as well as delayed in livers obtained from calcium deficient rats in the prereplicative phase of the regeneration process. TGF alpha mRNA levels were also found to be significantly lower in calcium deficient rats at all time-points following partial hepatectomy, while the relative behavior of the tandem TGF alpha-EGFR indicated an early dominant effect in normocalcemic 1,25(OH)2D3-repleted animals. HGF-c-met mRNA levels also indicated that the 1,25(OH)2D3-repleted animals reacted more promptly to the regeneration stimuli. Indeed, while relative (1,25(OH)2D3/D-Ca- ratio) maximum mRNA levels were observed 12 h following liver resection in 1,25(OH)2D3-treated animals, relative peak levels were only apparent 24 h post-surgery in hypocalcemic rats. Maximum cyclin D1 (a marker of the G1 phase of the cell cycle) mRNA occurred between 8-18 h after partial hepatectomy in 1,25(OH)2D3-repleted animals to return to base-line value thereafter, but in hypocalcemic rats the transcript levels remained significantly below 1,25(OH)2D3-repleted animals during the prereplicative period with increases above initial values between 12-24 h post-surgery. Both cyclin A (an S phase marker) transcripts (1.8 and 2.9 kb) were influenced by the regeneration process. The transcripts significantly and sharply increased in hypocalcemia between 30-36 h following partial hepatectomy to decrease thereafter, while the increase was observed between 24-30 h, and at 48 h (1.8 kb) in 1,25(OH)2D3-repleted animals. Liver weight recovery was also found to be decreased in D-depleted rats over the 48 h period of observation. CONCLUSIONS: Our data further confirm the presence of an impaired regeneration process in hypocalcemia of D deficiency which seems to be associated with gene markers indicating an inefficient transit across the G1 phase of the cell cycle.

Animals↗
PubMed2002

Opsin expression in adult, developing, and regenerating newt retinas.

Japanese common newts (Cynops pyrrhogaster) have an ability to regenerate their neural retina even as adults. Although extensive research has been carried out attempting to understand this retinal regeneration, the molecules characterized in newt retina are limited. We isolated cDNAs encoding three putative opsins (Cp-Rh, -LWS and -SWS1), in addition to Cp-SWS2 [Takahashi et al., FEBS Lett. 501 (2001) 151-155] from a cDNA library of adult newt retina. Our immunohistochemical and in situ hybridization studies demonstrated that Cp-Rh is selectively expressed in rods, whereas the other opsins are expressed in cones. The distribution of opsin mRNAs in normal and regenerated retinas is very similar. In both developing and regenerating retinas, Cp-Rh and its mRNA first appeared in immature rods at the beginning or just after the formation of plexiform layers. Cp-Rh was initially found isotropically in the plasma membrane, and then translocalized to the apical region along with the maturation of regenerating rods. This suggests that reorganization of the intracellular structure takes place during maturation of the regenerating newt photoreceptors.

Amino Acid Sequence↗
PubMed1997

Brain-derived neurotrophic factor promotes axonal regeneration and long-term survival of adult rat spinal motoneurons in vivo.

This study shows that in adult rat spinal motoneurons brain-derived neurotrophic factor exerts a neuroprotective effect which extends several weeks beyond the duration of treatment. In addition, brain-derived neurotrophic factor strongly enhances regeneration of avulsed motor axons across the border between the central and peripheral nervous systems. Treatment with brain-derived neurotrophic factor is known to rescue adult rat spinal motoneurons from retrograde cell death induced by ventral root avulsion. The present experiments were designed to test whether this survival effect remains over an extended period of time following cessation of treatment and, also, whether brain-derived neurotrophic factor promotes regeneration of avulsed motor axons. After avulsion of a spinal ventral root, four weeks of treatment with brain-derived neurotrophic factor (10 microg/day) or vehicle was initiated. By using different retrograde tracers to obtain pre- and postoperative labelling of avulsed and regenerating motoneurons, respectively, the number of surviving motoneurons as well as the extent of motor axonal regeneration could be analysed. The expression of nitric oxide synthase in the lesioned motoneurons was also studied. In the vehicle-treated rats, only 10% of the avulsed motoneurons remained at 12 weeks postoperatively, 20-40% of which displayed nitric oxide synthase activity. Treatment with brain-derived neurotrophic factor during the initial four postoperative weeks resulted in 45% motoneuron survival and a complete blockage of nitric oxide synthase expression at 12 weeks postoperatively. Brain-derived neurotrophic factor also induced abundant regeneration of the avulsed motor axons, which formed extensive fibre bundles along the surface of the spinal cord and adjacent ventral roots. The long-term effect by brain-derived neurotrophic factor seemed to be even stronger on motor axonal regeneration than on motoneuron survival. The present results indicate a therapeutic potential for brain-derived neurotrophic factor in the early treatment of traumatic injuries to spinal nerves and roots.

Animals↗
PubMed1999

Electrically mediated regeneration and guidance of adult mammalian spinal axons into polymeric channels.

An extracellular electric field has been shown to influence the regeneration of nerve fibers within the adult mammalian spinal cord. However, in these studies, few axons were labeled by local application of intracellular markers relative to the number of axons transected. This has limited an evaluation of the robustness of the response, and the direction of growth of regenerating axons that might be influenced by the orientation of the applied voltage gradient. In this study, a hollow silicone rubber tube (c. 6 mm x 1 mm outside diameter) containing a cathodal (negative) electrode was inserted longitudinally into the dorsal half of the adult guinea-pig spinal cord. The electric field ( approximately 100 microV/mm) was imposed within the damaged spinal cord with an implanted d.c. stimulator for about three weeks. Based on previous studies, this orientation of the electric field would be expected to both initiate axonal regeneration and guide growing axons to, and into, the silicone guidance channel. In experimental animals (n = 20), a robust regeneration of axons into the tube was observed in more than half the cases. These axons were traced from surrounding white and gray matter by anterograde and retrograde labeling using a tetramethylrhodamine-conjugated dextran as an intracellular marker. Control animals (n = 16) received tubes with inactive electrodes. It was rare to find any axons within control guidance channels, since adult mammalian central nervous system axons do not regenerate. This report provides evidence for not only the facilitated regeneration of adult mammalian central axons, but also their guidance, by an imposed electric field.

Animals↗