Neurotrophic factors and diabetic peripheral neuropathy

Recent evidence from animal models of diabetes and human diabetic subjects suggests that the reduced availability of neurotrophic factors may contribute to the pathogenesis of diabetic peripheral neuropathy (DPN). Of these proteins, nerve growth factor (NGF), brain-derived neurotrophic factor, neurotrophin (NT-3) and NT-4/5 appear to be important for the development and maintenance of peripheral neurons, but others, including insulin-like growth factors (IGFs), may also be involved. Studies with NGF, NT-3, IGF-I and IGF-II both in vitro and in animal models of neuropathies (including DPN) suggest that these factors ameliorate nerve degeneration. Recombinant human NGF is the first neurotrophic factor to enter clinical trials for DPN and is currently being tested in two phase III studies.     

Altered nerve growth factor level in the optic nerve of patients affected by multiple sclerosis

In this study we measured with a highly sensitive two-site immunoenzymatic assay the levels of nerve growth factor (NGF) in human optic nerve affected by multiple sclerosis (MS). The result of this study showed an elevated increase of NGF in the MS optic nerves, as compared to the level of NGF found in the optic nerves non-affected by this demyelinating disorder. Moreover, the results showed that the optic nerves also expressed trkA NGF receptor and NGFmRNA, most likely by oligodendrocytes, implying that NGF is locally produced and suggesting that the presence of NGF might be regulated by an autocrine mechanism. These and other ongoing studies on animal models indicate that altered NGF levels are among one of the early symptoms of these demyelinating diseases. The physiopathological role of NGF in the optic nerve during demyelinating disorders remains however to be defined.     

Ocular nerve growth factor administration counteracts the impairment of neural precursor cell viability and differentiation in the brain subventricular area of rats with streptozotocin‐induced diabetes

The ocular administration of nerve growth factor (NGF) as eye drops (oNGF) has been shown to exert protective effects in forebrain‐injured animal models, including adult diabetes induced by a single injection of streptozotocin (STZ) (60 mg/kg body weight). This type 1 diabetes model was used in this study to investigate whether oNGF might extend its actions on neuronal precursors localised in the subventricular zone (SVZ). NGF or saline was administrated as eye drops twice daily for 2 weeks in rats with STZ‐induced diabetes and healthy control rats. The expression of mature and precursor NGF and the NGF receptors, tropomyosin‐related kinase A and neurotrophin receptor p75, and the levels of DNA fragmentation were analysed by ELISA and western blotting. Incorporation of bromodeoxyuridine was used to trace newly formed cells. Nestin, polysialylated neuronal cell adhesion molecule (PSA‐NCAM), doublecortin (DCX) and glial fibrillary acidic protein antibodies were used to identify the SVZ cells by confocal microscopy. It was found that oNGF counteracts the STZ‐induced cell death and the alteration of mature/pro‐NGF expression in the SVZ. It also affects the survival and differentiation of SVZ progenitors. In particular, oNGF counteracts the reduction in the number of cells expressing PSA‐NCAM/DCX (neuroblast type A cells) and the related reductions in the number and distribution of nestin/DCX‐positive cells (C‐type cells), or glia‐committed cells (type B cells), observed in the SVZ of diabetic rats. These findings show that oNGF treatment counteracts the effect of type 1 diabetes on neuronal precursors in the SVZ, and further support the neuroprotective and reparative role of oNGF in the brain.     

Increased Concentrations of Nerve Growth Factor and Brain-Derived Neurotrophic Factor in the Rat Cerebellum After Exposure to Environmental Enrichment

The molecular mechanism of environmental enrichment (EE) on brain function and anatomy has been partially attributed to the up-regulation of proteins involved in neuronal survival and activity-dependent plasticity, such as the neurotrophins nerve growth factor (NGF) and brain-derived neurotrophic factor (BDNF), in the cerebral cortex and hippocampus of animal models. Nevertheless, at present, little indication is available on the influence of EE on neurotrophin levels in the cerebellum. Thus, in this study, we exposed male Wistar rats to EE from weaning to 5 months of age and evaluated the production of NGF and BDNF in the cerebellum and compared the neurotrophin changes in this region with those obtained in other brain structures where neurotrophins are produced or transported. We found that in rats exposed to EE from 21st until 140th postnatal day, a significant increase of both BDNF and NGF concentrations was observed in the cerebellum, as compared to rats reared in standard conditions. In addition, cerebellum was the brain region where NGF and BDNF levels were more influenced by EE as compared to the changes observed in other regions. EE also caused a concomitant increase in NGF levels in the striatum while in the same brain region, BDNF levels were reduced. In summary, this study shows that a prolonged exposure to EE is associated with an increase in cerebellar NGF and BDNF production, thus suggesting that the beneficial effects of EE on the cerebellum of adult animals could be mediated, at least in part, by neurotrophins.     

Streptozotocin-induced diabetes causes metabolic changes and alterations in neurotrophin content and retrograde transport in the cervical vagus nerve.

Abnormal availability of neurotrophins, such as nerve growth factor (NGF), has been implicated in diabetic somatosensory polyneuropathy. However, the involvement of neurotrophins in diabetic neuropathy of autonomic nerves, particularly the vagus nerve which plays a critical role in visceral afferent and in autonomic motor functions, is unknown. To assess the effects of hyperglycemia on the neurotrophin content and transport in this system, cervical vagus nerves of streptozotocin (STZ)-induced diabetic rats were studied at 8, 16, and 24 weeks after the induction of diabetes. Elevations in vagus nerve hexose (glucose and fructose) and polyol levels (sorbitol), and their normalization with insulin treatment, verified that the STZ treatment resulted in hyperglycemia-induced metabolic abnormalities in the nerve. Neurotrophin (NGF and neurotrophin-3; NT-3) content and axonal transport were assessed in the cervical vagus nerves from nondiabetic control rats, STZ-induced diabetic rats, and diabetic rats treated with insulin. The NGF, but not the NT-3, content of intact vagus nerves from diabetic rats was increased at 8 and 16 weeks (but not at 24 weeks). Using a double-ligation model to assess the transport of endogenous neurotrophins, the retrograde transport of both NGF and NT-3 was found to be significantly reduced in the cervical vagus nerve at later stages of diabetes (16 and 24 weeks). Anterograde transport of NGF or NT-3 was not apparent in the vagus nerve of diabetic or control rats. These data suggest that an increase in vagus nerve NGF is an early, but transient, response to the diabetic hyperglycemia and that a subsequent reduction in neuronal access to NGF and NT-3 secondary to decreased retrograde axonal transport may play a role in diabetes-induced damage to the vagus nerve.     

Functional recovery after peripheral nerve injury via sustained growth factor delivery from mineral-coated microparticles

The gold standard for treating peripheral nerve injuries that have large nerve gaps where the nerves cannot be directly sutured back together because it creates tension on the nerve, is to incorporate an autologous nerve graft. However, even with the incorporation of a nerve graft, generally patients only regain a small portion of function in limbs affected by the injury. Although, there has been some promising results using growth factors to induce more axon growth through the nerve graft, many of these previous therapies are limited in their ability to release growth factors in a sustained manner and tailor them to a desired time frame. The ideal drug delivery platform would deliver growth factors at therapeutic levels for enough time to grow axons the entire length of the nerve graft. We hypothesized that mineral coated microparticles(MCMs) would bind, stabilize and release biologically active glial cell-derived neurotrophic factor(GDNF) and nerve growth factor(NGF) in a sustained manner. Therefore, the objective of this study was to test the ability of MCMs releasing growth factors at the distal end of a 10 mm sciatic nerve graft, to induce axon growth through the nerve graft and restore hind limb function. After sciatic nerve grafting in Lewis rats, the hind limb function was tested weekly by measuring the angle of the ankle at toe lift-off while walking down a track. Twelve weeks after grafting, the grafts were harvested and myelinated axons were analyzed proximal to the graft, in the center of the graft, and distal to the graft. Under physiological conditions in vitro, the MCMs delivered a burst release of NGF and GDNF for 3 days followed by a sustained release for at least 22 days. In vivo, MCMs releasing NGF and GDNF at the distal end of sciatic nerve grafts resulted in significantly more myelinated axons extending distal to the graft when compared to rats that received nerve grafts without growth factor treatment. The rats with nerve grafts incorporated with MCMs releasing NGF and GDNF also showed significant improvement in hind limb function starting at 7 weeks postoperatively and continuing through 12 weeks postoperatively when compared to rats that received nerve grafts without growth factor treatment. In conclusion, MCMs released biologically active NGF and GDNF in a sustained manner, which significantly enhanced axon growth resulting in a significant improvement of hind limb function in rats. The animal experiments were approved by University of Wisconsin-Madison Animal Care and Use Committee(ACUC, protocol# M5958) on January 3, 2018.     

Chronic parasite infection in mice induces brain granulomas and differentially alters brain nerve growth factor levels and thermal responses in paws

Schistosoma mansoni infection, both in humans and in animal models, is known to induce granulomas in the liver and intestine. It has also been reported that in humans the eggs of this parasite can reach the brain, causing psychiatric and neuropathological disorders. Whether this also occurs in rodents is unknown. To answer this question, mice were infected with this parasite and the central nervous system (CNS) examined at various time intervals. The results show that schistosomiasis induced granulomas in several regions of the CNS and increased nerve growth factor (NGF) levels in the cortex, hypothalamus and brain stem, but not in the hippocampus. The infection also caused paw hyperalgesia, as determined by the hot-plate test, and a local increase in NGF, but not in substance P. These findings indicate that the murine model of infection can be used for studying mechanisms leading to human neuroschistosomiasis and suggest that the neuropathological disorders and the sensory deficits observed in human schistosomiasis are associated with impaired levels of NGF in the peripheral and central nervous system. Received: 18 January 1996 / Revised, accepted: 16 April 1996     

Effect of NGF and neurotrophin-3 treatment on experimental diabetic autonomic neuropathy

Peripheral neuropathy is a significant complication of diabetes resulting in increased patient morbidity and mortality. Deficiencies of neurotrophic substances (e.g. NGE NT-3, and IGF-I) have been proposed as pathogenetic mechanisms in the development of distal symmetrical sensory diabetic polyneuropathy, and salutary effects of exogenous NGF administration have been reported in animal models. In comparison, relatively little is known concerning the effect of NGF on experimental diabetic sympathetic autonomic neuropathy. We have developed an experimental animal model of diabetic autonomic neuropathy characterized by the regular occurrence of pathologically distinctive dystrophic axons in prevertebral sympathetic ganglia and ileal mesenteric nerves of rats with chronic streptozotocin (STZ)-induced diabetes. Treatment of STZ-diabetic rats for 2-3 months with pharmacologic doses of NGF or NT-3, neurotrophic substances with known effects on the adult sympathetic nervous system, did not normalize established neuroaxonal dystrophy (NAD) in diabetic rats in the prevertebral superior mesenteric ganglia (SMG) and ileal mesenteric nerves as had pancreatic islet transplantation and IGF-I in earlier experiments. NGF treatment of control animals actually increased the frequency of NAD in the SMG. New data suggests that, in adult sympathetic ganglia. NGF may contribute to the pathogenesis of NAD rather than its amelioration, perhaps as the result of inducing intraganglionic axonal sprouts in which dystrophic changes are superimposed. NT-3 administration did not alter the frequency of NAD in diabetic animals, although it resulted in a significant decrease in NAD in control SMG. Although deficiencies of neurotrophic substances may represent the underlying pathogenesis of a variety of experimental neuropathies, delivery of excessive levels of selected substances may produce untoward effects.     

Regulation of myelinated nociceptor function by nerve growth factor in neonatal and adult rats

The role of nerve growth factor (NGF) as a survival factor for sensory neurons during embryonic life has been well documented. Here we examine the actions of NGF or antisera against NGF (anti-NGF) on physiologically identified sensory neurons with myelinated axons later in life, after the dependence on NGF for survival ends. We find that the effects of NGF and anti-NGF are specific for sensory neurons which are nociceptors. Treatments were found to affect the biophysical properties, the development, or the physiological function of myelinated nociceptors. They also affect the animal's behavioral response to noxious stimulation, depending upon when the treatments were given: neonatally, from 2–5 weeks of age, or chronically, beginning at birth. Thus, we find that the actions of NGF are specific for nociceptors but that the function of this neurotrophic factor changes according to the developmental age of the animal.     

Rapid quantitative immunohistochemical assessment of human peripheral neuropathies using a monoclonal antibody against nerve growth factor receptor

Summary An analysis of nerve growth factor (NGF) receptor expression and density in human sural nerve biopsies was performed by immunocytochemistry with a murine monoclonal antibody against the human NGF receptor. Quantitative assessment of immunostaining density was made by histospectrophotometry on frozen sections. Although there was enhanced expression of NGF receptor within endoneurium in all patients with clinical neuropathies, expression was highest in nerves with axonal disease, consistent with the proposal that disruption of axon-Schwann cell interactions triggers the reexpression of the NGF receptor. These results with human nerves, together with previous studies with animal models, suggest that NGF and NGF receptor play important roles in the general response to neuronal injury.     

Chronic nicotine improves working and reference memory performance and reduces hippocampal NGF in aged female rats

The cholinergic system is involved in cognition and several forms of dementia, including Alzheimer's disease, and nicotine administration has been shown to improve cognitive performance in both humans and rodents. While experiments with humans have shown that nicotine improves the ability to handle an increasing working memory load, little work has been done in animal models evaluating nicotine effects on performance as working memory load increases. In this report, we demonstrate that in aged rats nicotine improved the ability to handle an increasing working memory load as well as enhanced performance on the reference memory component of the water radial arm maze task. The dose required to exert these effects (0.3mg/kg/day) was much lower than doses shown to be effective in young rats and appears to be a lower maintenance dose than is seen in light to moderate smokers. In addition, our study reports a nicotine-induced reduction in nerve growth factor (NGF) protein levels in the hippocampus of the aged rat. The effects of nicotine on hippocampal NGF levels are discussed as a potential mechanism of nicotine-induced improvements in working and reference memory.     

Altered plasma levels of nerve growth factor and transforming growth factor-beta2 in type-1 diabetes mellitus

Nerve growth factor (NGF) and transforming growth factor-beta2 (TGF-beta2) are cytokines which have known immunological effects. An elevated level of NGF has been reported in certain autoimmune diseases, whereas TGF-beta2 is an immunosuppressor which is known to play a role in regulating cell proliferation. A role of this cytokine has been proposed in the pathogenesis of type-1 diabetes mellitus (IDDM), but no clinical studies have yet measured its serum level in this disease. In this study we measured the levels of NGF and TGF-beta2 in the sera of patients with IDDM (n = 26) and values were compared to those of age-matched normal subjects (n = 27) and also to patients with type-2 diabetes mellitus (NIDDM) (n = 26) with similar HbA1c levels and an equal duration of diabetes. Serum NGF levels were significantly elevated in IDDM patients compared to those of age-matched controls (p <.001) and NIDDM controls (p <.01). TGF-beta2 levels were lower in IDDM patients when compared with the healthy control (p <.001) and the NIDDM control (p <.05). There was no correlation between the levels of NGF and TGF-beta2. The duration of diabetes and the level of HbA1c did not affect the NGF and TGF-beta2 levels in the IDDM patients. We conclude that an increase in NGF and a suppression in TGF-beta2 levels are present in patients with type-1 diabetes mellitus and that both cytokines may play independent roles in the pathogenesis of this disease.     

Chronic 1,25-dihydroxyvitamin D3-mediated induction of nerve growth factor mRNA and protein in L929 fibroblasts and in adult rat brain

We have proposed that elevating levels of nerve growth factor (NGF) in the CNS is a rational strategy for treating certain neurodegenerative disorders. The present studies were conducted to determine: (1) if pharmacologically induced levels of NGF could be sustained for an extended time, and (2) if correlations exist between increases in NGF mRNA and NGF protein in L929 cells and in vivo. Short-term treatment of L929 cells with 1,25-dihydroxyvitamin D₃ resulted in a two-fold increase in both NGF mRNA and NGF protein. These increases were sustained for up to 48 h with continuous exposure to 1,25-dihydroxyvitamin D₃. In rats, 1,25-dihydroxyvitamin D₃ (2.5 nmol; i.c.v.) induced NGF mRNA transiently, with peak two-fold increased observed 4 h post-injection. In contrast to L929 cells, 1,25-dihydroxyvitamin D₃ did not elicit an increase in NGF protein after a single administration in vivo. However, consistent with long-term exposure in L929 cells, chronic 6 day infusion of 1,25-dihydroxyvitamin D₃ resulted in induction of both NGF mRNA and NGF protein in the brain. These results indicate that 1,25-dihydroxyvitamin D₃-mediated NGF induction in cultured L929 cells may predict of NGF induction in vivo, suggesting that L929 cells may have utility in studying underlying mechanisms of NGF induction by 1,25-dihydroxyvitamin D₃. On the basis of NGF's ability to increase cholinergic function in animal models of cholinergic degeneration, these results are supportive of a role for NGF inducers as potential drugs for neurodegenerative disorders.     

Denervation of the skin following section of the inferior alveolar nerve leads to increased NGF accumulation without change in NGF mRNA expression

Following inferior alveolar nerve section and capping of the nerve to prevent regeneration, amounts of nerve growth factor (NGF) and NGF mRNA have been quantified in the chin skin, a discrete target of the nerve. NGF protein in the target region increases rapidly following nerve section and to levels known to induce sprouting. NGF on the ipsilateral side increased many-fold above unoperated control and the contralateral side also increased above control. Measurement of NGF mRNA levels using quantitative Northern analysis revealed, however, that there was no change in the expression levels of NGF mRNA, indicating that the large increase in protein occurs due to a cessation of transport back to the cell bodies of the innervating neurons.     

Early life stress as a risk factor for mental health: role of neurotrophins from rodents to non-human primates

Early adverse events can enhance stress responsiveness and lead to greater susceptibility for psychopathology at adulthood. The epigenetic factors involved in transducing specific features of the rearing environment into stable changes in brain and behavioural plasticity have only begun to be elucidated. Neurotrophic factors, such as nerve growth factor (NGF) and brain-derived neurotrophic factor (BDNF), are affected by stress and play a major role in brain development and in the trophism of specific neuronal networks involved in cognitive function and in mood disorders. In addition to the central nervous system, these effectors are produced by peripheral tissues, thus being in a position to integrate the response to external challenges. In this paper we will review data, obtained from animal models, indicating that early maternal deprivation stress can affect neurotrophin levels. Maladaptive or repeated activation of NGF and BDNF, early during postnatal life, may influence stress sensitivity at adulthood and increase vulnerability for stress-related psychopathology.     

Recent preclinical evidence advancing cell therapy for Alzheimer's disease

Alzheimer's disease (AD) causes brain degeneration, primarily depleting cholinergic cells, and leading to cognitive and learning dysfunction. Logically, to augment the cholinergic cell loss, a viable treatment for AD has been via drugs boosting brain acetylcholine production. However, this is not a curative measure. To this end, nerve growth factor (NGF) has been examined as a possible preventative treatment against cholinergic neuronal death while enhancing memory capabilities; however, NGF brain bioavailability is challenging as it does not cross the blood-brain barrier. Investigations into stem cell- and gene-based therapy have been explored in order to enhance NGF potency in the brain. Along this line of research, a genetically modified cell line, called HB1.F3 transfected with the cholinergic acetyltransferase or HB1.F3.ChAT cells, has shown safety and efficacy profiles in AD models. This stem cell transplant therapy for AD is an extension of the neural stem cells' use in other neurological treatments, such as Parkinson's disease and stroke, and recently extended to cancer. The HB1 parent cell and its associated cell lines have been used as a vehicle to deliver genes of interest in various neurological models, and are highly effective as they can differentiate into neurons and glial cells. A focus of this mini-review is the recent demonstration that the transplantation of HB1.F3.ChAT cells in an AD animal model increases cognitive function coinciding with upregulation of acetylcholine levels in the cerebrospinal fluid. In addition, there is a large dispersion throughout the brain of the transplanted stem cells which is important to repair the widespread cholinergic cell loss in AD. Some translational caveats that need to be satisfied prior to initiating clinical trials of HB1.F3.ChAT cells in AD include regulating the host immune response and the possible tumorigenesis arising from the transplantation of this genetically modified cell line. Further studies are warranted to test the safety and effectiveness of these cells in AD transgenic animal models. This review highlights the recent progress of stem cell therapy in AD, not only emphasizing the significant basic science strides made in this field, but also providing caution on remaining translational issues necessary to advance this novel treatment to the clinic.     

GADD45A protects against cell death in dorsal root ganglion neurons following peripheral nerve injury

A significant loss of neurons in the dorsal root ganglia (DRG) has been reported in animal models of peripheral nerve injury. Neonatal sensory neurons are more susceptible than adult neurons to axotomy- or nerve growth factor (NGF) withdrawal-induced cell death. To develop therapies for preventing irreversible sensory cell loss, it is essential to understand the molecular mechanisms responsible for DRG cell death and survival. Here we describe how the expression of the growth arrest- and DNA damage-inducible gene 45α (GADD45A) is correlated with neuronal survival after axotomy in vivo and after NGF withdrawal in vitro. GADD45A expression is low at birth and does not change significantly after spinal nerve ligation (SNL). In contrast, GADD45A is robustly up-regulated in the adult rat DRG 24 hr after SNL, and this up-regulation persists as long as the injured fibers are prevented from regenerating. In vitro delivery of GADD45A protects neonatal rat DRG neurons from NGF withdrawal-induced cytochrome c release and cell death. In addition, in vivo knockdown of GADD45A expression in adult injured DRG by small hairpin RNA increased cell death. Our results indicate that GADD45A protects neuronal cells from SNL-induced cell death.     

AGGRESOME FORMATION IN NEUROPATHY MODELS BASED ON PERIPHERAL MYELIN PROTEIN 22 MUTATIONS

Peripheral neuropathy is a common and debilitating complication of diabetes. In animal models, neurotrophic factors can prevent progression of the neuropathy, but adverse effects prevent systemic administration in adequate doses to treat human disease. We examined whether gene transfer with replication-defective genomic herpes simplex virus (HSV) vectors modified to express nerve growth factor (NGF) could be used to prevent progression of neuropathy in mice. Diabetes induced by streptozotocin (STZ) resulted in a sensory neuropathy manifest by a decrease in the foot sensory nerve amplitude (FSA; control = 20 +/− 0.1 muV, treated = 14 +/− 0.1 muV). Transduction of dorsal root ganglia in vivo with an HSV-based vector expressing NGF under the control of the human cytomegalovirus immediate early promoter (vector SHN) or the HSV latency active promoter 2 (vector SLN) by footpad inoculation 2 weeks after STZ administration protected against the decrease in FSA (22 +/− 1.4 muV and 21 +/− 1.7 muV, respectively) measured 4 weeks later. Injection of SHN into inguinal adipose tissue 2 weeks after onset of diabetes also prevented the decrease in FSA (20 +/− 3.3 muV). These results suggest that gene transfer with an NGF-producing herpes-based vector may prove useful in the treatment of diabetic neuropathy.     

糖尿病大鼠周围神经NGF的动态表达及巴曲酶对其影响

目的探讨神经生长因子（NGF）在糖尿病周围神经病（DPN）大鼠中的动态变化规律,初步证实巴曲酶对NGF的影响并探讨其机制,为临床上治疗DPN提供理论依据。方法将大鼠腹腔注射链脲佐菌素制作实验性糖尿病模型,再分别于成模后2个月和3个月时腹腔注射巴曲酶进行干预。通过免疫组织化学和原位杂交双重检测NGF在坐骨神经中的表达。结果DM造模后2个月时坐骨神经中NGF的含量明显减少,且随时间变化有统计学差异,而巴曲酶治疗后NGF的表达明显增加。结论DPN大鼠坐骨神经中NGF表达减少可能参与DPN的发病机制。巴曲酶对DPN有保护作用,其机制可能包括对NGF的调节。     

外源性神经生长因子诱导下自体静脉桥接修复神经缺损

背景：采用自体神经游离移植修复神经缺损效果比较理想,但有其弊端。为此寻求一种更佳修复神经缺损的治疗方法。 目的：验证及外源性神经生长因子诱导下自体静脉桥接神经缺损对神经再生的影响。 方法：采用Wistar大鼠建立周围神经缺损模型。随机将大鼠分为3组。实验组采用自体静脉桥接并注入神经生长因子;对照组采用自体静脉桥接并注入生理盐水;标准组采用自体神经桥接。分别于术后1,3个月,对实验动物进行活体观察,电生理检测及组织学检测。 结果与结论：3组实验动物均有神经再生及修复表现,但程度不同。实验组失神经表现恢复的较对照组早,电生理检测运动神经传导速度快,组织学检查再生神经纤维数量及质量明显高于对照组(P < 0.05);与“金标准”的自体神经桥接组比较无显著性意义(P > 0.05)。结果提示采用自体静脉桥接+神经生长因子诱导对周围神经缺损后的再生、修复具有有促进作用,可以使再生神经纤维的数量增加并显著提高再生神经纤维质量。