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PubMed2005

Possible problems of moulding the regenerate in mandibular distraction osteogenesis -- experimental aspects in a canine model.

INTRODUCTION: Moulding of the regenerate created by distraction osteogenesis has been shown clinically to be efficient and good enough so that for complex three-dimensional deformities, final adjustments by moulding the regenerate may be part of the treatment plan. This study assessed possible drawbacks of moulding a regenerate, taking into consideration compressive and tensile forces acting simultaneously on the fresh callus. METHOD: Distraction osteogenesis in 15 Beagle mandibles was performed using custom made devices which allowed for lengthening as well as for angulation. After linear distraction of 10 mm, a defined 20 degrees angulation was performed in one step. The position of the fulcrum of the device allowed simultaneously compression and stretching of the regenerated bone. Effects on bone healing were assessed after 6 and 13 weeks of consolidation respectively and compared with a control group where only linear distraction was performed. RESULTS: Radiological and histological investigations demonstrated that no significant differences between the biological behaviour of the compressed and the stretched zones of the regenerate could be found. However, there were signs showing the more critical character of the stretched area. After 6 weeks of consolidation some specimens revealed delayed ossification of the stretched zone. Under stable conditions, this delay was compensated for after 13 weeks of consolidation and complete osseous healing occurred. CONCLUSION: Under stable conditions, a fresh regenerate can be moulded to a considerable extent without permanently endangering osseous healing. Nevertheless tensile forces acting on the regenerate should be minimized to prevent damage to the new bone. This can be achieved by overdistraction prior to callus moulding or by gradually changing the vector of distraction during the lengthening process.

Animals↗
PubMed2005

Beneficial effect of hyperbaric oxygenation on liver regeneration in cirrhosis.

BACKGROUND: Underlying hepatic injury and cirrhosis are leading factors that interfere with the post-operative liver regeneration and function. Hyperbaric oxygenation (HBO) has been reported to ameliorate the ischemia-reperfusion injury of the liver, to induce compensatory hypertrophy of the predicted remnant liver in rats after portal vein ligation and to augment liver regeneration after hepatectomy in non-cirrhotic rats. Our aim was to determine the effect of HBO treatment on liver regeneration after partial hepatectomy in normal and cirrhotic mice in this experimental study. MATERIALS AND METHODS: The effect of HBO on liver regeneration was studied in a mice model combining carbon tetrachloride induced cirrhosis and partial hepatectomy. Mice were divided into four groups: Control, cirrhotic, non-cirrhotic HBO-treated, and cirrhotic HBO-treated. All animals underwent 40% hepatectomy. Liver regeneration was evaluated by the proliferating cell nuclear antigen-labeling index. Serum aspartate aminotransferase and alanine aminotransferase levels were measured to evaluate liver injury. RESULTS: Serum alanine aminotransferase and aspartate aminotransferase levels were significantly decreased in HBO-treated cirrhotic group compared to cirrhosis group after hepatectomy (P = 0.001 and P = 0.014, respectively). The proliferating cell nuclear antigen labeling index was significantly higher in HBO treated cirrhotic group than in cirrhotic group after hepatectomy (P = 0.022). CONCLUSIONS: Our results suggest that HBO treatment improves liver functions and augments hepatocyte regeneration in cirrhotic mice after hepatectomy. Post-operative HBO treatment may have a beneficial effect on post-operative liver function and regeneration in cirrhotic patients.

Alanine Transaminase↗
PubMed2006

Comprehensive analysis of the regenerating mouse liver: an in vivo fluorescence microscopic and immunohistological study.

BACKGROUND: Regeneration of tissue is a fundamental parameter of the liver's response to injury and is essential for post-operative recovery from hepatic resection. An adequate microvascular supply of both remnant tissue and newly formed cell clusters is necessary for the accurate restoration of the organ. However, a comprehensive analysis of hepatic architecture and microcirculation during liver regeneration is missing. METHODS: Using intravital high resolution multifluorescence microscopy and histological techniques we analyzed the regenerating liver of mice at days 3, 5, and 8 after 68% hepatectomy. RESULTS: Within the 8-day course of regeneration, liver weight restored to approximately 90% of its original mass. During the 8-day period of observation density of hepatocytes and Ito cells was constantly found reduced from 4,200 and 800 cells/mm(2) in non-hepatectomized control livers to approximately 2,500 and approximately 500 cells/mm(2). A transient decline of sinusoidal density was partly compensated by recruiting all sinusoids for perfusion with a final perfusion index of 79, 89, and 98% at days 3, 5, and 8 after resection. Increase of sinusoidal diameters preserved functional vessel area after resection, guaranteeing an adequate tissue oxygenation, as verified by low parenchymal NADH autofluorescence. The number of PCNA expressing hepatocytes rose 11-, 4-, and 2-fold at days 3, 5, and 8 after resection, followed by a maximum proliferation of sinusoidal lining cells at day 5. Cell apoptosis slightly increased, most probably in response to the restoration and to eliminate redundant cells. Liver regeneration was not associated with enhanced leukocyte-endothelial cell interaction, disproving inflammation as a relevant trigger for the regeneration. CONCLUSION: The present data contribute to a better understanding of the complex vascular and cellular mechanisms during liver regeneration to develop strategies fighting against impeded liver growth.

Animals↗
PubMed2004

Stimulated regeneration of the crushed adult rat optic nerve correlates with attenuated expression of the protein tyrosine phosphatases RPTPalpha, STEP, and LAR.

We have evaluated the spatial and temporal expression patterns of three protein tyrosine phosphatases (PTPs), receptor PTPalpha (RPTPalpha), striatal enriched phosphatase (STEP), and leucocyte common antigen-related phosphatase (LAR), in the retina and optic nerve (ON) of adult rats in which the crushed ON was either regenerating after retinal ganglion cell (RGC) stimulation with intravitreal peripheral nerve (PN) grafting or lens injury (LI), or not regenerating (no treatment). In intact adult rats, all three PTPs were expressed by RGCs and ON glia. In both the regenerating and non-regenerating models, a postlesion rise in RPTPalpha, STEP, and LAR expression occurred in the RGC somata and in the ON. However, for RPTPalpha and LAR in the RGCs, and for RPTPalpha, STEP, and LAR in the ON, this postlesion increase was attenuated in the regenerating versus the non-regenerating models. ON PTP expression changes were localized to glia in the proximal and distal stumps, and to macrophages and extracellular matrix of the glial scar at the lesion site. Interestingly, neither RPTPalpha, STEP, nor LAR localized to intact or regenerating axons. One explanation of these findings is that RPTPalpha and LAR may modulate RGC survival, and that RPTPalpha, STEP, and LAR may modulate axon growth.

Age Factors↗
PubMed2006

Temporal requirement for bone morphogenetic proteins in regeneration of the tail and limb of Xenopus tadpoles.

Bone morphogenetic protein (BMP) signalling is necessary for both the development of the tail bud and for tail regeneration in Xenopus laevis tadpoles. Using a stable transgenic line in which expression of the soluble BMP inhibitor noggin is under the control of the temperature inducible hsp70 promoter, we have investigated the timing of the requirement for BMP signalling during tail regeneration. If noggin expression is induced followed by partial amputation of the tail, then wound closure and the formation of the neural ampulla occur normally but outgrowth of the regeneration bud is inhibited. Furthermore, we show that BMP signalling is also necessary for limb bud regeneration, which occurs in Xenopus tadpoles prior to differentiation. When noggin expression is induced, limb bud regeneration fails at an early stage and a stump is formed. The situation appears similar to the tail, with formation of the limb bud blastema occurring but renewed outgrowth inhibited. The transcriptional repressor Msx1, a direct target of BMP signalling with known roles in vertebrate appendage regeneration, fails to be re-expressed in both tail and limb in the presence of noggin. DNA labelling studies show that proliferation in the notochord and spinal cord of the tail, and of the blastema in the limb bud, is significantly inhibited by noggin induction, suggesting that in the context of these regenerating appendages BMP is mainly required, directly or indirectly, as a mitogenic factor.

Animals↗
PubMed2005

The role of prostaglandins in triggering the liver regeneration cascade.

Following injury or surgical resection, the liver has the remarkable ability to regenerate. Despite over 100 years of research, the trigger of the liver regeneration cascade has only recently been identified. Shear stress-induced nitric oxide (NO), released secondary to a hemodynamic event following partial hepatectomy (PHX), has been implicated as the trigger of the liver regeneration cascade. However, it is also known that prostaglandins (PGs) are released following PHX, and in response to shear stress. Therefore, it is hypothesized that PGs, released secondary to an increase in the blood flow-to-liver mass ratio following PHX, trigger the liver regeneration cascade, and that NO and PGs interact during the triggering event. An index of initiation of the liver regeneration cascade, c-fos mRNA expression 15 min after PHX, has been employed. As expected, c-fos mRNA expression increased 15 min after PHX and this increase was inhibited by the NO synthase antagonist, l-NAME. This inhibition was reversed by the NO donors, SIN-1 and SNAP, and by the PGs, PGE2 and PGI2. Also, the increase in c-fos mRNA expression was inhibited by indomethacin, a cyclooxygenase antagonist. This inhibition was also reversed by the NO donors, SIN-1 and SNAP, and by the PGs, PGE2 and PGI2. These results suggest that there is interaction between NO and PGs in triggering the liver regeneration cascade, and that in a situation where either NO or COX is inhibited, provision of excess exogenous NO or PGs can reverse the inhibition. This suggests that exogenous NO and/or PGs may play a role in potentiation of the liver regeneration cascade.

Animals↗
PubMed2004

MRI and histology of collagen template disc implantation and regeneration in rabbit temporomandibular joint: preliminary report.

INTRODUCTION: We aimed to evaluate regeneration of injured temporomandibular joint (TMJ) discs following reconstituted collagen template implantation in rabbits using contrast-enhanced magnetic resonance imaging (MRI) and to correlate these findings with histology. METHODS: Twenty-four adult rabbits were divided into five groups: group A, partial discectomy without implantation (n = 6); group B, partial discectomy with collagen template implantation (n = 6); group C, partial discectomy with subdermal graft implantation (n = 6); group D, sham operation (n = 4); and group E, control (n = 2). All rabbits received baseline MRI scans before surgery and follow-up MRI studies at 3 months after surgery. All rabbits were sacrificed for histologic analysis after the follow-up MRI. RESULTS: In group A, follow-up MRI showed marked joint effusion in all six injured TMJs, which was accompanied by bony erosion at the tympanic fossa and mandibular condyle. In group B, MRI showed a homogenous low signal intensity in five of six discs, suggestive of regeneration. One disc showed higher signal intensity at its lateral portion than that of the original disc, indicating partial regeneration. MRI of group C depicted a low signal intensity, bandlike regenerative structure in four of the six discs. One disc with partial regeneration demonstrated relatively high signal intensity. The disc in the sixth animal of this group showed no evidence of regeneration. All of the MRI findings were in agreement with the histologic findings. CONCLUSION: TMJ discs can regenerate following implantation of a reconstituted collagen template in discectomied rabbits. Contrast-enhanced MRI can be used to monitor and determine the degree of disc regeneration.

Animals↗
PubMed2003

reg6 is required for branching morphogenesis during blood vessel regeneration in zebrafish caudal fins.

Postnatal neovascularization is essential for wound healing, cancer progression, and many other physiological functions. However, its genetic mechanism is largely unknown. In this report, we study neovascularization in regenerating adult zebrafish fins using transgenic fish that express EGFP in blood vessel endothelial cells. We first describe the morphogenesis of regenerating vessels in wild-type animals and then the phenotypic analysis of a genetic mutation that disrupts blood vessel regeneration. In wild-type zebrafish caudal fins, amputated blood vessels heal their ends by 24 h postamputation (hpa) and then reconnect arteries and veins via anastomosis, to resume blood flow at wound sites by 48 hpa. The truncated vessels regenerate by first growing excess vessels to form unstructured plexuses, resembling the primary capillary plexuses formed during embryonic vasculogenesis. Interestingly, this mode of vessel growth switches by 8 days postamputation (dpa) to growth without a plexus intermediate. During blood vessel regeneration, vessel remodeling begins during early plexus formation and continues until the original vasculature pattern is reestablished at approximately 35 dpa. Temperature-sensitive mutants for reg6 have profound defects in blood vessel regeneration. At the restrictive temperature, reg6 regenerating blood vessels first fail to make reconnections between severed arteries and veins, and then form enlarged vascular sinuses rather than branched vascular plexuses. Reciprocal temperature-shift experiments show that reg6 function is required throughout plexus formation, but not during later growth. Our results suggest that the reg6 mutation causes defects in branch formation and/or angiogenic sprouting.

Animals↗
PubMed2004

A stepwise model system for limb regeneration.

The amphibian limb is a model that has provided numerous insights into the principles and mechanisms of tissue and organ regeneration. While later stages of limb regeneration share mechanisms of growth control and patterning with limb development, the formation of a regeneration blastema is controlled by early events that are unique to regeneration. In this study, we present a stepwise experimental system based on induction of limb regeneration from skin wounds that will allow the identification and functional analysis of the molecules controlling this early, critical stage of regeneration. If a nerve is deviated to a skin wound on the side of a limb, an ectopic blastema is induced. If a piece of skin is grafted from the contralateral side of the limb to the wound site concomitantly with nerve deviation, the ectopic blastema continues to grow and forms an ectopic limb. Our analysis of dermal cell migration, contribution, and proliferation indicates that ectopic blastemas are equivalent to blastemas that form in response to limb amputation. Signals from nerves are required to induce formation of both ectopic and normal blastemas, and the diversity of positional information provided by blastema cells derived from opposite sides of the limb induces outgrowth and pattern formation. Hence, this novel and convenient stepwise model allows for the discovery of necessary and sufficient signals and conditions that control blastema formation, growth, and pattern formation during limb regeneration.

Ambystoma mexicanum↗
PubMed2005

Proximodistal patterning during limb regeneration.

Regeneration is an ability that has been observed extensively throughout metazoan phylogeny. Amongst vertebrates, the urodele amphibians stand out for their exceptional capacity to regenerate body parts such as the limb. During this process, only the missing portion of the limb is precisely replaced--amputation in the upper arm results in regeneration of the entire limb, while amputation at the wrist produces a hand. Limb regeneration occurs through the formation of a local proliferative zone called the blastema. Here, we examine how proximodistal identity is established in the blastema. Using cell marking and transplantation experiments, we show that distal identities have already been established in the earliest stages of blastemas examined. Transplantation of cells into new environments is not sufficient to respecify cell identity. However, overexpression of the CD59, a cell surface molecule previously implicated in proximodistal identity during limb regeneration, causes distal blastema cells to translocate to a more proximal location and causes defects in the patterning of the distal elements of the regenerate. We suggest a model for the limb regeneration blastema where by 4 days post-amputation the blastema is already divided into distinct growth zones; the cells of each zone are already specified to give rise to upper arm, lower arm, and hand.

Ambystoma mexicanum↗
PubMed2005

Impaired proliferation of non-parenchymal cells participates in an impairment of liver regeneration in db/db mice.

In this study, we examined the possibility that impaired proliferation of non-parenchymal cells affects in an impairment of liver regeneration in db/db mice, which are congenitally deficient in receptors for leptin. Liver regeneration after a two thirds partial hepatectomy (2/3 PH) was impaired in 10-week-old female db/db mice. The proliferation of both hepatocytes and non-parenchymal cells estimated from a bromodeoxyuridine (BrdU) labeling index was suppressed, and the protein expression of vascular endothelial growth factor was blocked in db/db mice. Although the extent of fatty change and the level of epidermal growth factor receptor protein expression in the liver were improved in 5-week-old db/db mice, the regeneration of liver was impaired after 2/3 PH in both 5- and 10-week-old db/db mice. These results suggested that suppressed proliferation of non-parenchymal cells contributes to the impairment of liver regeneration in db/db mice. As leptin has also the angiogenic effect, the angiogenic inhibitor FR-118487 was administered to ICR mice to examine liver regeneration after 2/3 PH, and the rate of regeneration was affected. In conclusion, it is suggested that the suppressed proliferation of non-parenchymal cells contributes to the impairment of liver regeneration probably through a disrupted angiogenesis in db/db mice.

Angiogenesis Inhibitors↗
PubMed2002

Expression of vascular endothelial growth factor and vascular endothelial growth factor receptor-2 (KDR/Flk-1) in ischemic skeletal muscle and its regeneration.

Vascular endothelial growth factor (VEGF) is a hypoxia-inducible endothelial cell mitogen and survival factor. Its receptor VEGFR-2 (KDR/Flk-1) mediates these effects. We studied the expression of VEGF and VEGFR-2 in ischemic human and rabbit skeletal muscle by immunohistochemistry and in situ hybridization. Human samples were obtained from eight lower limb amputations because of acute or chronic critical ischemia. In chronically ischemic human skeletal muscle VEGF and VEGFR-2 expression was restricted to atrophic and regenerating skeletal myocytes, whereas in acutely ischemic limbs VEGF and VEGFR-2 were expressed diffusely in the affected muscle. Hypoxia-inducible factor-1alpha was associated with VEGF and VEGFR-2 expression both in acute and chronic ischemia but not in regeneration. Hindlimb ischemia was induced in 20 New Zealand White rabbits by excising the femoral artery. Magnetic resonance imaging and histological sections revealed extensive ischemic damage in the thigh and leg muscles of ischemic rabbit hindlimbs with VEGF expression similar to acute human lower limb ischemia. After 1 and 3 weeks of ischemia VEGF expression was restricted to regenerating myotubes and by 6 weeks regeneration and expression of VEGF was diminished. VEGFR-2 expression was co-localized with VEGF expression in regenerating myotubes. Macrophages and an increased number of capillaries were associated with areas of ischemic muscle expressing VEGF and VEGFR-2. In conclusion, two patterns of VEGF and VEGFR-2 expression in human and rabbit ischemic skeletal muscle are demonstrated. In acute skeletal muscle ischemia VEGF and VEGFR-2 are expressed diffusely in the affected muscle. In chronic skeletal muscle ischemia and in skeletal muscle recovering from ischemia VEGF and VEGFR-2 expression are restricted to atrophic and regenerating muscle cells suggesting the operation of an autocrine pathway that may promote survival and regeneration of myocytes.

Aged↗
PubMed2002

Regeneration therapy of pancreatic beta cells: towards a cure for diabetes?

Regeneration therapy is an approach which could potentially move us towards a cure for type 1 diabetes. It is classified into three categories: (1) In vitro regeneration therapy using transplanted cultured cells, including ES cells, pancreatic stem cells, and beta-cell lines, in conjunction with immunosuppressive therapy or immunoisolation. (2) In ex vivo regeneration therapy, patients' own cells, such as bone marrow stem cells, are transiently removed and induced to differentiate into beta cells in vitro. At present, however, insulin-producing cells cannot be generated from bone marrow stem cells. (3) In in vivo regeneration therapy, impaired tissues regenerate from patients' own cells in vivo. beta-Cell neogenesis from non-beta-cells and beta-cell proliferation in vivo have been considered, particularly as regeneration therapies for type 2 diabetes. Regeneration therapy of pancreatic beta cells can be combined with various other therapeutic strategies, including islet transplantation, cell-based therapy, gene therapy, and drug therapy to promote beta-cell proliferation and neogenesis, and it is hoped that these strategies will, in the future, provide a cure for diabetes.

Cell Differentiation↗
PubMed2001

Inhibition by interferon alpha-2b of rat liver regeneration: effect on ornithine decarboxylase and total protein synthesis.

Polyamines are key factors in macromolecule synthesis during liver regeneration. It has been postulated that interferon-alpha (IFNalpha) decreases putrescine levels in regenerating liver by inhibiting ornithine decarboxylase (ODC) activity, the main enzyme in polyamine biosynthesis. In the present study, we analysed the effects of a pharmacological dose of IFNalpha on polyamine and ODC levels during the regenerative process following partial hepatectomy in rats. Synthesis of ODC by isolated hepatocytes from IFN-treated rats with regenerating livers was also assessed. Furthermore, we investigated the effect of IFNalpha-2b on DNA and total protein synthesis in 24-hr regenerating livers. No effect on DNA synthesis was observed at the dose of IFNalpha-2b used, but total protein synthesis decreased significantly in IFNalpha-2b-treated rats undergoing liver regeneration (7.0 +/- 2.0 and 12.1 +/- 1.7%. min(-1) in hepatectomized rats treated with IFNalpha-2b and saline, respectively). ODC levels were also reduced significantly (by 50%) in hepatectomized rats treated with IFNalpha-2b versus saline. In parallel with the ODC decrease, the concentrations of putrescine and spermidine (63 +/- 25 vs 101 +/- 15 nmol/g liver and 1.08 +/- 0.35 vs 2.14 +/- 0.22 micromol/g liver, respectively, in IFNalpha-2b- and saline-treated hepatectomized rats) showed similar, significant diminutions. Moreover, the incorporation of [35S]methionine into ODC was decreased dramatically in isolated hepatocytes from IFNalpha-2b-treated hepatectomized rats 12 hr after surgery. In conclusion, the protein synthesis rate in regenerating liver was impaired by therapeutic doses of IFNalpha-2b. In addition, the results presented in this study suggest that IFNalpha-2b negatively regulates ODC synthesis, causing a reduction in polyamine levels during liver regeneration.

Animals↗
PubMed1986

Cadmium acclimation and hormesis in Fundulus heteroclitus during fin regeneration.

We have previously demonstrated that exposure to cadmium at 0.1 and 0.5 mg/liter will retard the rate of fin regeneration in Fundulus heteroclitus. Since there is a body of literature indicating that preexposure to low levels of metals may increase tolerance during subsequent exposure, these experiments were designed to investigate the effects of preexposure to cadmium, using fin regeneration as the parameter of effect. Fish were exposed for 1 week to 0, 0.01, or 0.05 mg/liter Cd. Following this preexposure, the lower third of the caudal fin was amputated, and regrowth of the fins measured by ocular micrometer twice weekly for 2 weeks. During regeneration fish were maintained in either clean water (25% S, 23-25 degrees C) or in water with 0.1 mg/liter Cd. Fish newly placed in Cd (C----0.1 Cd) regenerated at the slowest rate, while the 0.01----0.1 Cd group approached the growth of control fish regenerating in clean water, indicating a protective effect or acclimation brought about by the preexposure. The 0.05----0.1 Cd group regenerated even more rapidly than controls, a phenomenon which has been termed "hormesis" and is believed to be due to an overcompensation by homeostatic regulatory mechanisms. In a second set of experiments in which regeneration took place in 0.5 mg/liter rather than 0.1 mg/liter, a protective effect of preexposure was again seen, but no hormesis was observed. Uptake data indicated that preexposed groups took up less Cd than the groups not preexposed.

Animals↗
PubMed2003

Axonal regeneration of Clarke's neurons beyond the spinal cord injury scar after treatment with chondroitinase ABC.

We have previously demonstrated that enzymatic digestion of chondroitin sulfate proteoglycan (CSPG) at the scar promotes the axonal regrowth of Clarke's nucleus (CN) neurons into an implanted peripheral nerve graft after hemisection of the spinal cord. The present study examined whether degradation of CSPG using chondroitinase ABC promoted the regeneration of CN neurons through the scar into the rostral spinal cord in neonatal and adult rats. Following hemisection of the spinal cord at T11, either vehicle or chondroitinase ABC was applied onto the lesion site. The postoperative survival periods were 2 and 4 weeks. The regenerated CN neurons were retrogradely labeled by Fluoro-Gold injected at spinal cord level C7. In the sham group, there was no regeneration of injured CN neurons in both neonatal and adult rats. Treatment with 2.5 unit/ml chondroitinase ABC in neonates resulted in 11.8 and 8.3% of the injured CN neurons regenerated into the rostral spinal cord at 2 and 4 weeks, respectively. In adults, 9.4 and 12.3%, at 2 and 4 weeks, respectively, of the injured CN neurons regenerated their axons to the rostral spinal cord. The immunoreactivity for the carbohydrate epitope of CSPG was dramatically decreased around the lesion site after treatment with chondroitinase ABC compared to sham control in both neonatal and adult animals. Our results show that axonal regeneration in the spinal cord can be promoted by degradation of CSPG with chondroitinase ABC. This result further suggests that CSPG is inhibitory to the regeneration of neurons in the spinal cord after traumatic injury.

Age Factors↗
PubMed2004

Intraocular injection of dibutyryl cyclic AMP promotes axon regeneration in rat optic nerve.

The optic nerve is a CNS pathway containing molecules capable of inhibiting axon elongation. The growth program in embryonic retinal ganglion cell (RGC) neurons enables axons to regenerate in the optic nerve through at least two mechanisms. Namely, high cyclic AMP (cAMP) levels abrogate the ability of CNS molecules to inhibit elongation, and the pattern of gene expression enables axons to undergo rapid, sustained, and lengthy elongation. In adult mammals, recovery of visual function after optic nerve injury is limited by both the death of most RGC neurons and the inability of surviving axons to regenerate. We now report that a single intraocular injection of the membrane-permeable cAMP analogue dibutyryl cAMP (db cAMP) promotes the regeneration of RGC axons in the optic nerves of adult rats, but does not prevent the death of RGC neurons. This regeneration in optic nerves crushed within the orbit (2 mm from the eye) was equally effective either 1 day before or 1 day after db cAMP injection. The number of regenerating axons, which was maximal 14 days after crush, declined with increasing time after injury (i.e., 28, 56, and 112 days) and distance beyond the crush site (i.e., 0.25, 0.5, and 1.0 mm). Thus, db cAMP promotes optic nerve regeneration without increasing the survival of axotomized RGC neurons. Furthermore, since db cAMP does not enable axons to undergo rapid, sustained, and lengthy elongation, strategies that increase survival and promote these changes in elongation may critically complement the ability of db cAMP to promote regeneration.

Animals↗
PubMed1997

Delayed neurite regeneration and its improvement by nerve growth factor (NGF) in dorsal root ganglia from MRL-lpr/lpr mice in vitro.

We studied neurite regeneration in MRL-lpr/lpr mice, a murine model of systemic lupus erythematosus, using a culture system to investigate the influences of immunological abnormalities on neurons. The regeneration of cultured dorsal root ganglion (DRG) neurons from MRL-lpr/lpr mice was delayed compared with control MRL-+/+ mice. This modification of regeneration was age-dependent. MRL-lpr/lpr mice older than 16 weeks of age exhibited less neurite regeneration than controls but those younger than 6 weeks of age showed equal regeneration. Regeneration was improved by adding nerve growth factor (NGF) to culture medium. Following immunocytochemical staining, we counted the low affinity NGF receptor p75-positive DRG neurons in MRL mice. The percentage of p75-positive neurons in MRL-lpr/lpr mice older than 16 weeks of age was higher than that in MRL-+/+ mice. These neuronal abnormalities were thought not to be directly dependent on the genetic defect of Fas antigen, which is related to apoptosis in MRL-lpr/lpr mice, but to be the result of immunological abnormalities. The present study is the first to demonstrate a modification of neurite regeneration by immunological dysfunction in autoimmune mice.

Aging↗