Identification of mitophagy-related hub genes during the progression of spinal cord injury by integrated multinomial bioinformatics analysis.

Spinal cord injury (SCI) is a disturbance of peripheral and central nerve conduction that causes disability in sensory and motor function. Currently, there is no effective treatment for SCI. Mitophagy plays a vital role in mitochondrial quality control during various physiological and pathological processes. The study aimed to elucidate the role of mitophagy and identify potential mitophagy-related hub genes in SCI pathophysiology. Two datasets (GSE15878 and GSE138637) were analyzed. Firstly, the differentially expressed genes (DEGs) were identified and mitophagy-related genes were obtained from GeneCards, then the intersection between SCI and mitophagy-related genes was determined. Next, we performed gene set enrichment analysis (GSEA), weighted gene co-expression network analysis (WGCNA), protein-protein interaction network (PPI network), least absolute shrinkage and selection operator (LASSO), and cluster analysis to identify and define the hub genes in SCI. Finally, the link between hub genes and infiltrating immune cells was investigated and the potential transcriptional regulation/small molecular compounds to target hub genes were predicted. In total, SKP1 and BAP1 were identified as hub genes of mitophagy-related DEGs during SCI development and regulatory T cells (Tregs)/resting NK cells/activated mast cells may play an essential role in the progression of SCI. LINC00324 and SNHG16 may regulate SKP1 and BAP1, respectively, through miRNAs. Eleven and eight transcriptional factors (TFs) regulate SKP1 and BAP1, respectively, and six small molecular compounds target BAP1. Then, the mRNA expression levels of BAP1 and SKP1 were detected in the injured sites of spinal cord of SD rats at 6 h and 72 h after injury using RT-qPCR, and found that the level were decreased. Therefore, the pathways of mitophagy are downregulated during the pathophysiology of SCI, and SKP1 and BAP1 could be accessible targets for diagnosing and treating SCI.

Safety of Every-Other-Day Fasting in the Treatment of Spinal Cord Injury: A Randomized Controlled Trial.

ABSTRACT: Every-other-day fasting is effective for a variety of major human diseases, but the safety of these interventions is uncertain for patients with spinal cord injury. A randomized controlled study was conducted to investigate the safety of every-other-day fasting in patients with spinal cord injury. Participants who met the diagnostic inclusion and exclusion criteria were randomly divided into the control and every-other-day fasting groups. In the every-other-day fasting group, fasting lasted from 09:00 p.m. on day 1 to 06:00 p.m. on the following day (day 2). Dinner on day 2 was restricted to approximately 30% of the average daily calorie intake. The changes in plasma glucose were recorded daily for 2 days and every other day from the third day after every-other-day fasting intervention. The changes in albumin, prealbumin, plasma potassium, serum sodium, blood calcium, body weight, and body mass index were monitored at the baseline and at the end of the every-other-day fasting intervention. The results showed that compared with the control group, the mean blood glucose levels were significantly decreased from the second week after every-other-day fasting intervention. The body weight of patients in the every-other-day fasting group was notably reduced compared with that at baseline, whereas in body mass index, no obvious differences were observed before and after treatment with every-other-day fasting. In general, every-other-day fasting could be considered as a safe approach for individuals with spinal cord injury.

Ketogenic regimens for acute neurotraumatic events.

Dietary modification would be the most translatable, cost-efficient, and, likely, the safest approach available that can reduce the reliance on pharmaceutical treatments for treating acute or chronic neurological disorders. A wide variety of evidence suggests that the ketogenic diet (KD) could have beneficial effects in acute traumatic events, such as spinal cord injury and traumatic brain injury. Review of existing human and animal studies revealed that KD can improve motor neuro-recovery, gray matter sparing, pain thresholds, and neuroinflammation and decrease depression. Although the exact mechanism by which the KD provides neuroprotection is not fully understood, its effects on cellular energetics, mitochondria function and inflammation are likely to have a role.

Neuroprotective effects of a ketogenic diet in combination with exogenous ketone salts following acute spinal cord injury.

We have previously shown that induction of ketosis by ketogenic diet (KD) conveyed neuroprotection following spinal cord injury in rodent models, however, clinical translation may be limited by the slow raise of ketone levels when applying KD in the acute post-injury period. Thus we investigated the use of exogenous ketone supplementation (ketone sodium, KS) combined with ketogenic diet as a means rapidly inducing a metabolic state of ketosis following spinal cord injury in adult rats. In uninjured rats, ketone levels increased more rapidly than those in rats with KD alone and peaked at higher levels than we previously demonstrated for the KD in models of spinal cord injury. However, ketone levels in KD + KS treated rats with SCI did not exceed the previously observed levels in rats treated with KD alone. We still demonstrated neuroprotective effects of KD + KS treatment that extend our previous neuroprotective observations with KD only. The results showed increased neuronal and axonal sparing in the dorsal corticospinal tract. Also, better performance of forelimb motor abilities were observed on the Montoya staircase (for testing food pellets reaching) at 4 and 6 weeks post-injury and rearing in a cylinder (for testing forelimb usage) at 6 and 8 weeks post-injury. Taken together, the findings of this study add to the growing body of work demonstrating the potential benefits of inducing ketosis following neurotrauma. Ketone salt combined with a ketogenic diet gavage in rats with acute spinal cord injury can rapidly increase ketone body levels in the blood and promote motor function recovery. This study was approved by the Animal Care Committee of the University of British Columbia (protocol No. A14-350) on August 31, 2015.

Skilled reaching deterioration contralateral to cervical hemicontusion in rats is reversed by pregabalin treatment conditional upon its early administration.

INTRODUCTION: Gabapentinoids are first-line treatments for painful traumatic and nontraumatic central nervous system disorders. Evidence from a large human study suggests that early use of gabapentinoids after spinal cord injury improves motor scores. The underlying mechanism is unknown. OBJECTIVES: We sought to examine the effects of early pregabalin (PGB, a gabapentinoid) treatment on performance in a fine motor task (skilled reaching) after cervical hemicontusion. We also asked whether early PGB administration affected PGB responsiveness later on. METHODS: Rats received C4/5 cervical hemicontusions. Injury severities ranged from 80 to 150 kdyn. We monitored evidence of skin irritation (peri-incisional and elsewhere) and quantified food pellet retrieval using the Montoya staircase test. Behaviours were assessed in rats receiving early (for 3 weeks from injury induction) and/or late (resuming or beginning at week 8) PGB treatment in animals with 150-kdyn injuries. RESULTS: Contralateral skilled reaching waned in control animals with 150-kdyn injuries. This was prevented in animals, which received early PGB as long as treatment continued. Deterioration of skilled reaching was reversed by later (week 8) PGB only in animals that had received early treatment. Ipsilateral reaching impairment was not improved by PGB. Relief of skin irritation verified early PGB efficacy. CONCLUSION: Hemicontusive spinal cord injury produces a contralateral motor phenotype evocative of on-going neuropathic pain. Early PGB preserves sensitivity to subsequent PGB treatment, indicating that motor function is impaired by neuropathic pain and can be improved indirectly by early PGB administration. Direct effects of PGB on motor circuitry cannot be excluded but are not supported by our data.

Open Access Platforms in Spinal Cord Injury: Existing Clinical Trial Data to Predict and Improve Outcomes.

Recovery from acute spinal cord injury (SCI) is characterized by extensive heterogeneity, resulting in uncertain prognosis. Reliable prediction of recovery in the acute phase benefits patients and their families directly, as well as improves the likelihood of detecting efficacy in clinical trials. This issue of heterogeneity is not unique to SCI. In fields such as traumatic brain injury, Parkinson's disease, and amyotrophic lateral sclerosis, one approach to understand variability in recovery has been to make clinical trial data widely available to the greater research community. We contend that the SCI community should adopt a similar approach in providing open access clinical trial data.

Schwann cells generated from neonatal skin-derived precursors or neonatal peripheral nerve improve functional recovery after acute transplantation into the partially injured cervical spinal cord of the rat.

The transplantation of Schwann cells (SCs) holds considerable promise as a therapy for spinal cord injury, but the optimal source of these cells and the best timing for intervention remains debatable. Previously, we demonstrated that delayed transplantation of SCs generated from neonatal mouse skin-derived precursors (SKP-SCs) promoted repair and functional recovery in rats with thoracic contusions. Here, we conducted two experiments using neonatal rat cells and an incomplete cervical injury model to examine the efficacy of acute SKP-SC transplantation versus media control (Experiment 1) and versus nerve-derived SC or dermal fibroblast (Fibro) transplantation (Experiment 2). Despite limited graft survival, by 10 weeks after injury, rats that received SCs from either source showed improved functional recovery compared with media- or fibroblast-treated animals. Compared with media treatment, SKP-SC-transplanted rats showed enhanced rubrospinal tract (RST) sparing/plasticity in the gray matter (GM) rostral to injury, particularly in the absence of immunosuppression. The functional benefits of SC transplantations over fibroblast treatment correlated with the enhanced preservation of host tissue, reduced RST atrophy, and/or increased RST sparing/plasticity in the GM. In summary, our results indicate that: (1) early transplantation of neonatal SCs generated from skin or nerve promotes repair and functional recovery after incomplete cervical crush injury; (2) either of these cell types is preferable to Fibros for these purposes; and (3) age-matched SCs from these two sources do not differ in terms of their reparative effects or functional efficacy after transplantation into the injured cervical spinal cord.

Ketogenic diet improves forelimb motor function after spinal cord injury in rodents.

High fat, low carbohydrate ketogenic diets (KD) are validated non-pharmacological treatments for some forms of drug-resistant epilepsy. Ketones reduce neuronal excitation and promote neuroprotection. Here, we investigated the efficacy of KD as a treatment for acute cervical spinal cord injury (SCI) in rats. Starting 4 hours following C5 hemi-contusion injury animals were fed either a standard carbohydrate based diet or a KD formulation with lipid to carbohydrate plus protein ratio of 3:1. The forelimb functional recovery was evaluated for 14 weeks, followed by quantitative histopathology. Post-injury 3:1 KD treatment resulted in increased usage and range of motion of the affected forepaw. Furthermore, KD improved pellet retrieval with recovery of wrist and digit movements. Importantly, after returning to a standard diet after 12 weeks of KD treatment, the improved forelimb function remained stable. Histologically, the spinal cords of KD treated animals displayed smaller lesion areas and more grey matter sparing. In addition, KD treatment increased the number of glucose transporter-1 positive blood vessels in the lesion penumbra and monocarboxylate transporter-1 (MCT1) expression. Pharmacological inhibition of MCTs with 4-CIN (α-cyano-4-hydroxycinnamate) prevented the KD-induced neuroprotection after SCI, In conclusion, post-injury KD effectively promotes functional recovery and is neuroprotective after cervical SCI. These beneficial effects require the function of monocarboxylate transporters responsible for ketone uptake and link the observed neuroprotection directly to the function of ketones, which are known to exert neuroprotection by multiple mechanisms. Our data suggest that current clinical nutritional guidelines, which include relatively high carbohydrate contents, should be revisited.

Intermittent fasting in mice does not improve hindlimb motor performance after spinal cord injury.

Previously, we reported that every-other-day-fasting (EODF) in Sprague-Dawley rats initiated after cervical spinal cord injury (SCI) effectively promoted functional recovery, reduced lesion size, and enhanced sprouting of the corticospinal tract. More recently, we also showed improved behavioral recovery with EODF after a moderate thoracic contusion injury in rats. In order to make use of transgenic mouse models to study molecular mechanisms of EODF, we tested here whether this intermittent fasting regimen was also beneficial in mice after SCI. Starting after SCI, C57BL/6 mice were fed a standard rodent chow diet either with unrestricted access or feeding every other day. Over a 14-week post-injury period, we assessed hindlimb locomotor function with the Basso Mouse Scale (BMS) open-field test and horizontal ladder, and the spinal cords were evaluated histologically to measure white and grey matter sparing. EODF resulted in an overall caloric restriction of 20% compared to animals fed ad libitum (AL). The EODF-treated animals exhibited a ∼ 14% reduction in body weight compared to AL mice, and never recovered to their pre-operative body weight. In contrast to rats on an intermittent fasting regimen, mice exhibited no increase in blood ketone bodies by the end of the second, third, and fourth day of fasting. EODF had no beneficial effect on tissue sparing and failed to improve behavioral recovery of hindlimb function. Hence this observation stands in stark contrast to our earlier observations in Sprague-Dawley rats. This is likely due to the difference in the metabolic response to intermittent fasting as evidenced by different ketone levels during the first week of the EODF regimen.

Intermittent fasting improves functional recovery after rat thoracic contusion spinal cord injury.

Spinal cord injury (SCI) often results in a loss of motor and sensory function. Currently there are no validated effective clinical treatments. Previously we found in rats that dietary restriction, in the form of every-other-day fasting (EODF), started prior to (pre-EODF), or after (post-EODF) an incomplete cervical SCI was neuroprotective, increased plasticity, and promoted motor recovery. Here we examined if EODF initiated prior to, or after, a T10 thoracic contusion injury would similarly lead to enhanced functional recovery compared to ad libitum feeding. Additionally, we tested if a group fed every day (pair-fed), but with the same degree of restriction as the EODF animals (∼25% calorie restricted), would also promote functional recovery, to examine if EODF's effect is due to overall calorie restriction, or is specific to alternating sequences of 24-h fasts and ad libitum eating periods. Behaviorally, both pre- and post-EODF groups exhibited better functional recovery in the regularity indexed BBB ambulatory assessment, along with several parameters of their walking pattern measured with the CatWalk device, compared to both the ad-libitium-fed group as well as the pair-fed group. Several histological parameters (intensity and symmetry of serotonin immunostaining caudal to the injury and gray matter sparing) correlated with functional outcome; however, no group differences were observed. Thus besides the beneficial effects of EODF after a partial cervical SCI, we now report that alternating periods of fasting (but not pair-fed) also promotes improved hindlimb locomotion after thoracic spinal cord contusion, demonstrating its robust effect in two different injury models.

A systematic review of cellular transplantation therapies for spinal cord injury.

Cell transplantation therapies have become a major focus in pre-clinical research as a promising strategy for the treatment of spinal cord injury (SCI). In this article, we systematically review the available pre-clinical literature on the most commonly used cell types in order to assess the body of evidence that may support their translation to human SCI patients. These cell types include Schwann cells, olfactory ensheathing glial cells, embryonic and adult neural stem/progenitor cells, fate-restricted neural/glial precursor cells, and bone-marrow stromal cells. Studies were included for review only if they described the transplantation of the cell substrate into an in-vivo model of traumatic SCI, induced either bluntly or sharply. Using these inclusion criteria, 162 studies were identified and reviewed in detail, emphasizing their behavioral effects (although not limiting the scope of the discussion to behavioral effects alone). Significant differences between cells of the same "type" exist based on the species and age of donor, as well as culture conditions and mode of delivery. Many of these studies used cell transplantations in combination with other strategies. The systematic review makes it very apparent that cells derived from rodent sources have been the most extensively studied, while only 19 studies reported the transplantation of human cells, nine of which utilized bone-marrow stromal cells. Similarly, the vast majority of studies have been conducted in rodent models of injury, and few studies have investigated cell transplantation in larger mammals or primates. With respect to the timing of intervention, nearly all of the studies reviewed were conducted with transplantations occurring subacutely and acutely, while chronic treatments were rare and often failed to yield functional benefits.

A systematic review of directly applied biologic therapies for acute spinal cord injury.

An increasing number of therapies for spinal cord injury (SCI) are emerging from the laboratory and seeking translation into human clinical trials. Many of these are administered as soon as possible after injury with the hope of attenuating secondary damage and maximizing the extent of spared neurologic tissue. In this article, we systematically reviewed the available preclinical research on such neuroprotective therapies that are administered in a non-invasive manner for acute SCI. Specifically, we reviewed treatments that have a relatively high potential for translation due to the fact that they are already used in human clinical applications or are available in a form that could be administered to humans. These included: erythropoietin, NSAIDs, anti-CD11d antibodies, minocycline, progesterone, estrogen, magnesium, riluzole, polyethylene glycol, atorvastatin, inosine, and pioglitazone. The literature was systematically reviewed to examine studies in which an in vivo animal model was utilized to assess the efficacy of the therapy in a traumatic spinal cord injury paradigm. Using these criteria, 122 studies were identified and reviewed in detail. Wide variations exist in the animal species, injury models, and experimental designs reported in the preclinical literature on the therapies reviewed. The review highlights the extent of investigation that has occurred in these specific therapies, and points out gaps in our knowledge that would be potentially valuable prior to human translation.

Platelet-derived growth factor-responsive neural precursors give rise to myelinating oligodendrocytes after transplantation into the spinal cords of contused rats and dysmyelinated mice.

Spinal cord injury (SCI) results in substantial oligodendrocyte death and subsequent demyelination leading to white-matter defects. Cell replacement strategies to promote remyelination are under intense investigation; however, the optimal cell for transplantation remains to be determined. We previously isolated a platelet-derived growth factor (PDGF)-responsive neural precursor (PRP) from the ventral forebrain of fetal mice that primarily generates oligodendrocytes, but also astrocytes and neurons. Importantly, human PRPs were found to possess a greater capacity for oligodendrogenesis than human epidermal growth factor- and/or fibroblast growth factor-responsive neural stem cells. Therefore, we tested the potential of PRPs isolated from green fluorescent protein (GFP)-expressing transgenic mice to remyelinate axons in the injured rat spinal cord. PRPs were transplanted 1 week after a moderate thoracic (T9) spinal cord contusion in adult male rats. After initial losses, PRP numbers remained stable from 2 weeks posttransplantation onward and those surviving cells integrated into host tissue. Approximately one-third of the surviving cells developed the typical branched phenotype of mature oligodendrocytes, expressing the marker APC-CC1. The close association of GFP cells with myelin basic protein as well as with Kv1.2 and Caspr in the paranodal and juxtaparanodal regions of nodes of Ranvier indicated that the transplanted cells successfully formed mature myelin sheaths. Transplantation of PRPs into dysmyelinated Shiverer mice confirmed the ability of PRP-derived cells to produce compact myelin sheaths with normal periodicity. These findings indicate that PRPs are a novel candidate for CNS myelin repair, although PRP-derived myelinating oligodendrocytes were insufficient to produce behavioral improvements in our model of SCI.

Prophylactic dietary restriction may promote functional recovery and increase lifespan after spinal cord injury.

Functional recovery after spinal cord injury (SCI) is limited, and the injury results in a dramatic reduction in long-term lifespan. Prophylactic dietary restriction (DR) robustly extends animal lifespan, and is beneficial in models of neuronal insult. In rats, we found that one form of DR, every-other-day-fasting (EODF), which started 1 month prior to a cervical SCI improved functional recovery, resulted in greater numbers of neurons surrounding the injury site, and a approximately 45% reduction in lesion size compared to the control group. In the light of the low-risk implementation of prophylactic EODF, the clinical translation as a treatment prior to elective subacute or chronic interventions is attractive. There are numerous secondary complications after human SCI, including a 13- to 25-year reduction in lifespan. DR consistently increases median and maximal lifespan in a large range of organisms, including non-human primates. Animal research suggests that EODF might reduce many of the secondary complications people with SCI suffer from. Dietary interventions may provide the possibility to improve the quality and span of life for individuals with SCI.

Cardiometabolic risk factors in experimental spinal cord injury.

Cardiometabolic risk factors are sorely underreported after spinal cord injury (SCI), despite the high prevalence of metabolic disorders and cardiovascular mortality in this population. Body-composition analysis and serum-lipid profiling are two assessments that are beginning to be more widely used to document metabolic changes after clinical SCI. Individuals with SCI have been reported to carry increased visceral fat and to exhibit altered serum-lipid levels. However, little is known about the development of these cardiometabolic risk factors in animal models. Using a combination of magnetic resonance imaging (MRI) and adipose tissue dissection, we show that visceral and subcutaneous adipose tissue were both increased at 1 month, but not at 1 week, after complete T3 SCI in rats. Additionally, at 1 month post injury, T3 SCI rats exhibited nonfasting serum hypertriglyceridemia, a result obtained using both standard clinical methods and a home cholesterol monitoring device (CardioChek). Interestingly, at 1 month post injury, rats with complete T10 SCI did not show an increase in either visceral adiposity or serum triglyceride levels. The fact that complete high-thoracic SCI disrupts lipid metabolism and perturbs fat storage in the subacute period, while low-thoracic SCI does not, suggests that differences in descending sympathetic control of adipose tissue might play a role in these changes. These results provide the first evidence of cardiometabolic risk factors in experimental animals with SCI, and are a starting point for investigations of the etiology of obesity and metabolic dysfunctions that often accompany SCI.

Dietary restriction started after spinal cord injury improves functional recovery.

Spinal cord injury typically results in limited functional recovery. Here we investigated whether therapeutic dietary restriction, a multi-faceted, safe, and clinically-feasible treatment, can improve outcome from cervical spinal cord injury. The well-established notion that dietary restriction increases longevity has kindled interest in its potential benefits in injury and disease. When followed for several months prior to insult, prophylactic dietary restriction triggers multiple molecular responses and improves outcome in animal models of stroke and myocardial infarction. However, the efficacy of the clinically-relevant treatment of post-injury dietary restriction is unknown. Here we report that "every-other-day fasting" (EODF), a form of dietary restriction, implemented after rat cervical spinal cord injury was neuroprotective, promoted plasticity, and improved behavioral recovery. Without causing weight loss, EODF improved gait-pattern, forelimb function during ladder-crossing, and vertical exploration. In agreement, EODF preserved neuronal integrity, dramatically reduced lesion volume by >50%, and increased sprouting of corticospinal axons. As expected, blood beta-hydroxybutyrate levels, a ketone known to be neuroprotective, were increased by 2-3 fold on the fasting days. In addition, we found increased ratios of full-length to truncated trkB (receptor for brain-derived neurotrophic factor) in the spinal cord by 2-6 folds at both 5 days (lesion site) and 3 weeks after injury (caudal to lesion site) which may further enhance neuroprotection and plasticity. Because EODF is a safe, non-invasive, and low-cost treatment, it could be readily translated into the clinical setting of spinal cord injury and possibly other insults.

Brain-derived neurotrophic factor gene transfer with adeno-associated viral and lentiviral vectors prevents rubrospinal neuronal atrophy and stimulates regeneration-associated gene expression after acute cervical spinal cord injury.

STUDY DESIGN: Experimental animal study. OBJECTIVE: To determine if viral vectors carrying the gene for brain-derived neurotrophic factor (BDNF) could be used to promote an axonal regenerative response in rubrospinal neurons after an acute cervical spinal cord injury. SUMMARY OF BACKGROUND DATA: Following axotomy in the cervical spinal cord, rubrospinal neurons undergo severe atrophy and fail to up-regulate important genes for regeneration. This can be attenuated or reversed with the infusion of BDNF to the injured cell bodies. This infusion technique, however, causes substantial parenchymal damage around the red nucleus and is limited by occlusion of the infusion pumps. This study examined whether viral vectors could be used to deliver the BDNF gene in a less damaging fashion and whether this could promote a regenerative response in injured rubrospinal neurons. METHODS: Following a cervical spinal cord injury, the viral vectors were injected into the vicinity of the injured red nucleus. The extent of parenchymal damage around the red nucleus was assessed, as was the immunoreactivity to BDNF and cellular transfection patterns. Rubrospinal neuronal cross-sectional area was measured to determine if atrophy had been reversed, and in situ hybridization for GAP-43 and Talpha1 tubulin was performed to determine if there genes, which are important for axonal regeneration, were up-regulated. RESULTS: Parenchymal damage associated with viral injection was significantly less than with previous infusion techniques. BDNF immunoreactivity around the red nucleus indicated that the BDNF transgene was expressed. Both viral vectors reversed rubrospinal neuronal atrophy and promoted the expression of GAP-43 and Talpha1 tubulin. CONCLUSIONS: Viral-mediated transfer of the BDNF gene was successful at promoting a regenerative response in rubrospinal neurons following acute cervical spinal cord injury, with significantly less parenchymal damage than previously observed when infusing the BDNF protein.

The astrocytic barrier to axonal regeneration at the dorsal root entry zone is induced by rhizotomy.

After dorsal rhizotomy, sensory axons fail to regenerate beyond the astrocytic glia limitans at the dorsal root entry zone (DREZ) but this inhibition can be overcome with the delivery of exogenous neurotrophin-3. We investigated whether axonal inhibition at the DREZ is constitutive or induced after dorsal rhizotomy. Primary afferent neurones from enhanced green fluorescent protein-expressing mice were transplanted into adult rat dorsal root ganglia in the presence or absence of dorsal rhizotomy. In the absence of dorsal rhizotomy mouse axons freely extended into the rat central nervous system. After host dorsal rhizotomy, mouse axons were unable to cross the DREZ. However, in rats that received a dorsal rhizotomy concomitant with intrathecal neurotrophin-3, the mouse axons were able to cross the DREZ. These results indicate that, under normal circumstances, the adult DREZ is permissive to the regeneration of adult sensory axons and that it only becomes inhibitory once dorsal root axons have been injured and astrocytes at the DREZ have become reactive.

Promoting axonal regeneration in the central nervous system by enhancing the cell body response to axotomy.

Neurons projecting into the peripheral nervous system (PNS) regenerate their axons after injury, in contrast to those confined to the central nervous system (CNS). Both neuronal and nonneuronal factors contribute to the lack of CNS regeneration. In this review we concentrate on the differential gene expression response to axotomy in PNS vs. CNS neurons. In general CNS neurons fail to up-regulate or sustain the expression of regeneration-associated proteins (RAGs), including trophic factors and their receptors. The presumed lack of trophic support of axotomized CNS neurons provided the rationale for the exogenous application of trophic factors, either to the lesion site or to the cell bodies. Here, we review our data on the application of trophic factors to rubrospinal and corticospinal neurons. Cell body treatment of axotomized rubrospinal neurons with brain-derived neurotrophic factor (BDNF) reversed atrophy, increased GAP-43 and Talpha-1 tubulin mRNA expression, and promoted axonal regeneration into peripheral nerve grafts. Importantly, BDNF cell body treatment was still effective in the chronic setting, i.e., when initiated 1 year after injury, but BDNF had no effect when applied to the chronic spinal cord injury site. The ability to promote regeneration in chronically injured neurons will hopefully contribute to the development of treatment strategies for chronic spinal injuries.