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Apolipoprotein E-ε4 (APOE-ε4) carriers had elevated cerebrospinal fluid (CSF) presynaptic protein growth-associated protein-43 (GAP-43), but the underlying mechanism is not fully understood. We investigated how the APOE-ε4 genotype affects the baseline and longitudinal changes in CSF GAP-43 and their associations with β-amyloid positron emission tomography (Aβ PET), CSF phosphorylated tau 181 (p-Tau 181), neurodegeneration, and cognitive decline. Compared to APOE-ε4 non-carriers, APOE-ε4 carriers had higher baseline levels and faster rates of increases in Aβ PET, CSF p-Tau 181 , and CSF GAP-43. Both higher baseline levels and faster rates of increase in CSF GAP-43 were associated with greater baseline Aβ PET and CSF p-Tau 181 , which fully mediated the APOE-ε4 effect on CSF GAP-43 elevations. Independent of Aβ PET and CSF p-Tau 181 , APOE-ε4 carriage was associated with exacerbated GAP-43-related longitudinal hippocampal atrophy and cognitive decline, especially in Aβ+ participants (GAP-43 × time × APOE-ε4). These findings suggest that the APOE-ε4 effect on GAP-43-related presynaptic dysfunction is mediated by primary Alzheimer's pathologies and independently correlates to hippocampal atrophy and cognitive decline in the future. [ABSTRACT FROM AUTHOR]

Background : Epilepsy is one of the most common neurological disorders, and it places a significant economic strain on the healthcare system around the world. Although the exact mechanism of epilepsy has yet to be illustrated, various pathogenic cascades involving neurotransmitters and trace elements have been reported. We aimed to investigate the serum levels of growth-associated protein-43 (GAP-43) and neurotrophin-3 (NT-3) among cohort of Egyptian children with epilepsy and correlate these biomarkers with their zinc levels. Methods: This case–control study included 50 pediatric patients with epilepsy who were comparable with 50 controls. Neurological assessment and electroencephalogram (EEG) were done to all included children. Biochemical measurements of serum GAP-43 and NT-3 using enzyme linked immunosorbent assays (ELISA), and total antioxidant capacity (TAC) and zinc using colorimetric assays, were performed to all participants. Results: There was significantly frequent positive parental consanguinity among cases with significantly frequent generalized onset seizures (94%) than simple partial seizure (6%). There were significantly lower serum GAP-43 and zinc levels with significantly higher TAC among cases vs. the controls, p˂0.05 for all. There was no significant difference in the serum levels of NT-3 among epileptic children vs. the controls, p = 0.269. Serum Zn was positively correlated with GAP-43 level among epileptic children (r = 0.381, p = 0.006). Serum GAP-43 in diagnosing childhood epilepsy at cut-off point ≤ 0.6 ng/mL showed 78% sensitivity, 62% specificity, positive predictive value (PPV) = 50.6%, negative predictive value (NPP) = 84.9% with AUC = 0.574. Conclusion: GAP-43 can be considered a sensitive good negative biomarker in childhood epilepsy which correlated positively with the zinc status. [ABSTRACT FROM AUTHOR]

A previous study by our group found that inhibition of nischarin promotes neurite outgrowth and neuronal regeneration in Neuro-2a cells and primary cortical neurons. In recent years, more and more studies have shown that nanomaterials have good prospects in treatment of spinal cord injury. We proposed that small interfering RNA targeting nischarin (Nis-siRNA) delivered by polyethyleneimine-alginate (PEI-ALG) nanoparticles promoted motor function recovery in rats with spinal cord injury. Direct microinjection of 5 μL PEI-ALG/Nis-siRNA into the spinal cord lesion area of spinal cord injury rats was performed. From day 7 after surgery, Basso, Beattie and Bresnahan score was significantly higher in rats from the PEI-ALG/Nis-siRNA group compared with the spinal cord injury group and PEI-ALG/Control-siRNA group. On day 21 after injection, hematoxylin-eosin staining showed that the necrotic area was reduced in the PEI-ALG/Nis-siRNA group. Immunohistochemistry and western blot assay results confirmed successful inhibition of nischarin expression and increased protein expression of growth-associated protein-43 in the PEI-ALG/Nis-siRNA group. These findings suggest that a complex of PEI-ALG nanoparticles and Nis-siRNA effectively suppresses nischarin expression, induces expression of growth-associated protein-43, and accelerates motor function recovery after spinal cord injury.

Aims: The main objective was to investigate the effects of the transient receptor potential cation channel subfamily V member 1 (TRPV1) on nerve regeneration following sciatic transection injury by functional blockage of TRPV1 using AMG-517, a specific blocker of TRPV1. Methods: AMG-517 was injected into the area surrounding ipsilateral lumbar dorsal root ganglia 30 min after unilateral sciatic nerve transection. The number of sciatic axons and the expression of growth-associated protein-43 (GAP-43) and glial fibrillary acidic protein was examined using semithin sections, Western blot, and immunofluorescence analyses. Results: Blockage of TRPV1 with AMG-517 markedly promoted axonal regeneration, especially at two weeks after sciatic injury; the number of axons was similar to the uninjured control group. After sciatic nerve transection, expression of glial fibrillary acidic protein was decreased and GAP-43 was increased at the proximal stump. However, the expression of both glial fibrillary acidic protein and GAP-43 increased significantly in AMG-517-treated groups. Conclusions: TRPV1 may be an important therapeutic target to promote peripheral nerve regeneration after injury. [ABSTRACT FROM AUTHOR]

Diffuse axonal injury (DAI) is the most common and significant pathological features of traumatic brain injury (TBI). However, there are still no effective drugs to combat the formation and progression of DAI in affected individuals. FK506, also known as tacrolimus, is an immunosuppressive drug, which is widely used in transplantation medicine for the reduction of allograft rejection. Previous studies have identified that FK506 may play an important role in the nerve protective effect of the central nervous system. In the present study, apoptosis of neuronal cells was observed following the induction of experimental DAI. The results demonstrated that it was closely related with the upregulation of death-associated protein kinase 1 (DAPK1). It was hypothesized that FK506 may inhibit the activity of DAPK1 by inhibiting calcineurin activity, which may be primarily involved in anti-apoptosis following DAI induction. Through researching the expression of nerve regeneration associated proteins (NF-H and GAP-43) following DAI, the present study provides novel data to suggest that FK506 promotes axon formation and nerve regeneration following experimental DAI. Therefore, FK506 may be a potent therapeutic for inhibiting nerve injury, as well as promoting the nerve regeneration following DAI. [ABSTRACT FROM AUTHOR]

Chronic intermittent hypoxia (CIH) has been shown to alter the response of neurons in the nucleus of the solitary tract (NTS) to activation of cardiovascular inputs. Although the mechanisms involved in these effects are not known, they may involve pre- and/or post-synaptic activity-dependent changes in the chemoreceptor afferent pathway at the level of NTS. To investigate this possibility, Sprague–Dawley rats were exposed to 7 or 95 days of CIH or normoxia. Arterial pressure (AP) and heart rates (HR) were measured at these time intervals in the conscious animal, and at each time point protein was also extracted from the caudal medial NTS and analyzed by western blot for the expression of brain-derived neurotrophic factor (BDNF), tropomyosin receptor kinase B (TrkB), synaptophysin and growth-associated protein-43 (GAP-43). AP was found not to be different between the CIH and normoxic animals at 7 days, although by 95 days of CIH exposure, AP was significantly elevated (124±6 mmHg) compared to normoxic controls (107±4 mmHg). After 7 days of CIH exposure, protein expression of BDNF and its receptor TrkB (isoforms gp95 and gp145) were found to be significantly elevated in NTS compared to normoxic controls. However, no changes were observed in synaptophysin, and GAP-43 protein expression. After 95 days of CIH exposure, BDNF, TrkB (gp95), synaptophysin, and GAP-43 protein expression were less abundant in NTS than in the normoxic controls. These data suggest that CIH may have induced neuroplasticity changes within chemoreceptor reflex pathways at the level of NTS that may be associated with the development of autonomic dysregulation often seen in patients with CIH associated with chronic sleep apnea. [ABSTRACT FROM AUTHOR]

The aim of the present study was to examine the effect of growth-associated protein-43 (GAP-43) on bone marrow mesenchymal stem cell (BMSC) differentiation in a rat model of traumatic optic neuropathy (TON). GAP-43 and short hairpin (sh)RNA-GAP-43 were inserted into pGLV5 and pGLV3 lentiviral vectors, respectively. The stable control, GAP-43-overexpression and GAP-43-knockdown cell lines (GFP/BMSCs, GAP-43/BMSCs and shGAP-43/BMSCs, respectively) were established. The expression of GAP-43, neuron-specific enolase (NSE), nestin, neurofilament (NF), neuron-specific nuclear-binding protein (NeuN) and βIII-tubulin were detected in the GAP-43/BMSCs and shGAP-43/BMSCs with retinal cell-conditioned differentiation medium using semi-quantitative polymerase chain reaction (PCR), western blotting and cell immunofluorescence. In addition, the BMSCs were observed under fluorescence microscopy. The Sprague-Dawley rat models of TON were established and identified by retrograde labeling of retinal ganglion cells (RGCs) with fluoroGold (FG). The lentiviral-mediated GAP-43-modified BMSCs were then transplanted into the rat model of TON. The expression of GAP-43 was detected in the retinal tissues using qPCR and western blotting. The histopathology of the retinal tissues was observed using hematoxylin and eosin (H&E) staining. The GAP-43/BMSCs exhibited positive expression of NSE, NF, nestin and βIII-tubulin, and exhibited a neuronal phenotype. The shGAP-43/BMSCs markedly inhibited expression of NeuN, NSE, NF, nestin and βIII-tubulin induced by retinal cell-conditioned differentiation medium. The FG staining revealed that the number of labeled RGCs were significantly decreased in the TON model rats, compared with normal rats (P<0.05). The H&E staining revealed that the degree of pathological changes was improved in the GAP-43/BMSC group, compared with the GFP/BMSC and shGAP-43/BMSC groups. In conclusion, GAP-43 promoted BMSC differentiation into neuron-like cells, and intravitreally injected GAP-43/BMSCs promoted the process of nerve repair in a rat model of TON. [ABSTRACT FROM AUTHOR]

To investigate the possibility that leptin exerts an effect in NTS by inducing changes in the expression of pre- and/or post-synaptic proteins, experiments were done in Sprague–Dawley wild-type rats (WT) rats and leptin-deficient rats ( Lep Δ151 / Δ 151 ; KILO rat) exposed to 8 h of continuous intermittent hypoxia (IH) or normoxia. Protein was extracted from the caudal medial NTS and analyzed by western blot for the expression of brain-derived neurotrophic factor (BDNF), tropomyosin receptor kinase B (TrkB), synaptophysin, synaptopodin and growth-associated protein-43 (GAP-43). In WT rats, BDNF and GAP 43 protein expression levels were not altered after IH or normoxia, although there was a trend towards an increase in BDNF expression. On the other hand, after IH, protein expression of both isoforms of the BDNF receptor TrkB (gp95 and gp145) was higher. Furthermore, synaptophysin protein expression was lower compared to normoxic WT rats. In the KILO rat, no changes were observed in the protein expression of BDNF, TrkB, or GAP 43 after IH when compared to KILO normoxic controls. However, synaptophysin was lower in the IH exposed KILO rat compared to normoxic controls, as found in the WT rat. Expression of synaptopodin was not detected in NTS in either IH or normoxic animals of all groups. These results suggest that leptin released during IH may contribute to neurotrophic changes occurring within NTS and that these changes may be associated with altered chemoreceptor reflex function. [ABSTRACT FROM AUTHOR]

Introduction: Both target skeletal muscle (SKM) cells and neurotrophins (NTs) are essential for the maintenance of neuronal function and nerve-muscle communication. The effects of different NTs and SKM cells on growth-associated protein-43 (GAP-43) expression in dorsal root ganglion (DRG) neurons have not been clarified. Methods: The morphological relationship between DRG neurons and SKM cells in neuromuscular cocultures was observed by scanning electron microscopy. The levels of GAP-43 and its mRNA were determined after administration of different NTs. Results: DRG neurons demonstrated dense neurite outgrowth in the presence of NTs. Distinct NTs promoted GAP-43 and its mRNA expression in neuromuscular cocultures of DRG neurons and SKM cells. Conclusions: These results offer new clues for a better understanding of the effects of distinct NTs on GAP-43 expression in DRG sensory neurons in the presence of target SKM cells and implicate NTs and target SKM cells in DRG neuronal regeneration. Muscle Nerve 47: 909-915, 2013 [ABSTRACT FROM AUTHOR]

Highlights: [•] Dissociated embryonic rat DRG neuronal culture model was established. [•] NRG-1β on GAP-43 expression in DRG neurons with Glu-induced toxicity was determined. [•] The decreased GAP-43 levles induced by Glu could be partially reversed by NRG-1β. [•] PI3K and ERK1/2 inhibitors either alone or in combination blocked NRG-1β’s effects. [Copyright &y& Elsevier]

The article discusses the findings of a study on the effects of rho kinase inhibitor fasudil hydrochloride on blood-brain barrier permeability. It notes that fasudil hydrochloride has the capacity to reduce cerebral vasospasm, to inhibit inflammation and apoptosis and to promote the recovery of neurological function. The study found that fasudil hydrochloride can improve the function of blood-brain barrier.

Low concentrations of capsaicin (CAP) stimulate and high concentrations of CAP can be toxic to the primary sensory neurons of the dorsal root ganglion (DRG). CAP induces the phosphorylation of extracellular signal-regulated protein kinases 1/2 (ERK1/2) in DRG neurons. The effect of the activation of ERK1/2 by different concentrations of CAP on growth-associated protein 43 (GAP-43) expression and calcitonin gene-related peptide (CGRP) depletion in DRG neurons remains unknown. In the present study, organotypic embryonic 15-day-old rat DRG explants were used to determine the effect of different concentrations of CAP on GAP-43 expression and CGRP depletion. The results showed that, compared to unstimulated control cultures, GAP-43 and pERK1/2 protein levels increased at a low concentration (2 μmol/L) of CAP and decreased at a higher concentration (10 μmol/L). The number of CGRP-immunoreactive (IR) migrating neurons also decreased in CAP-treated cultures. The increase in GAP-43 levels and CGRP depletion could be blocked by the administration of ERK1/2 inhibitor PD98059. The results of the present study imply that CAP at different concentrations has different effects on GAP-43 expression and CGRP depletion. These effects were involved in the activation of ERK1/2 in organotypically cultured DRG neurons stimulated with CAP. These data may provide new insights for further development potential therapeutic applications of CAP with moderate dose on neurogenic inflammation. [ABSTRACT FROM AUTHOR]

The aim of the present study was to clarify an involvement of growth-associated protein-43 (GAP-43) in the regeneration of primary afferent trigeminal ganglion (TG) neurons following inferior alveolar nerve transection (IANX). A larger number of GAP-43 immunoreactive (GAP-43 IR) TG neurons was observed in rats 3 d after IANX compared with sham rats. Growth-associated protein-43 IR TG neurons were also detected for 30 d after IANX, and the number of GAP-43 IR TG neurons was significantly higher in the IANX model until day 30. The relative number of large (>600 μm2) GAP-43 IR TG neurons was significantly lower, whereas the relative number of small (<400 /μm2) GAP-43 IR TG neurons was significantly higher than that at day 0 until 30 d after IANX. To evaluate the functional recovery of damaged IAN, the jaw opening reflex (JOR), elicited by the electrical stimulation of the IAN, was measured before and after IANX. Jaw opening reflex occurrence was gradually increased and the relative threshold of electrical stimulation eliciting JOR was gradually decreased over the 30-d duration of the study. On day 30 after IANX, the JOR occurrence and relative JOR threshold were similar to those in sham rats. The present findings suggest that changes in the expression of GAP-43 in TG neurons after IANX are involved in regeneration and functional recovery of the transected IAN. [ABSTRACT FROM AUTHOR]

Spinal cord injury ( SCI) represents a devastating central nervous system disease that still lacks sufficient therapies. Here, dogs are increasingly recognized as a preclinical animal model for the development of future therapies. The aim of this study was a detailed characterization of axonopathy in canine intervertebral disc disease, which produces a mixed contusive and compressive injury and functions as a spontaneous translational animal model for human SCI. The results revealed an early occurrence of ultrastructurally distinct axonal swelling. Immunohistochemically, enhanced axonal expression of β-amyloid precursor protein, non-phosphorylated neurofilament (n- NF) and growth-associated protein-43 was detected in the epicenter during acute canine SCI. Indicative of a progressive axonopathy, these changes showed a cranial and caudally accentuated spatial progression in the subacute disease phase. In canine spinal cord slice cultures, immunoreactivity of axons was confined to n- NF. Real-time quantitative polymerase chain reaction of naturally traumatized tissue and slice cultures revealed a temporally distinct dysregulation of the matrix metalloproteinases ( MMP)-2 and MMP-9 with a dominating expression of the latter. Contrasting to early axonopathy, diminished myelin basic protein immunoreactivity and phagocytosis were delayed. The results present a basis for assessing new therapies in the canine animal model for translational research that might allow partial extrapolation to human SCI. [ABSTRACT FROM AUTHOR]

Many cellular organelles must travel long distances in neurons to perform their specific functions, and this transport is highly dependent on the microtubule network within the axon. Hyperphosphorylation of microtubule-associated tau protein destabilizes microtubules and leads to neuronal cell death. This destabilization can be corrected in part by treatment with microtubule-stabilizing drugs such as paclitaxel and epothilone. The phosphatase inhibitor okadaic acid inhibits the outgrowth of neurites in neuronal cell cultures by hyperphosphorylating tau protein. In this study using neuronal cultures derived from the cerebral cortex of early postnatal Sprague-Dawley rats, we examined whether stabilization of microtubules by peloruside A, a microtubule-stabilizing agent that binds to a different site on β-tubulin from paclitaxel, could counter the deleterious effects of 8 h exposure to 15 n m okadaic acid. Peloruside A reversed the decrease in axonal outgrowth and branching seen in neuronal cultures treated with okadaic acid and rescued neurons from growth cone collapse. Although peloruside A had no effect on the hyperphosphorylation of tau caused by okadaic acid, it restored the levels of acetylated tubulin, a marker of stable microtubules, and reversed the okadaic acid-induced depression of growth-associated protein-43, an axonal growth regulator. Thus, microtubule-stabilizing drugs show promise as new therapeutic agents for treating damaged microtubule networks characteristic of neurodegenerative disease. [ABSTRACT FROM AUTHOR]

Emerging evidence has demonstrated that exposure to anesthetics early in life caused neurohistopathologic changes and persistent behavioral impairments. In this study, a maternal fetal rat model was developed to study the effects of isoflurane exposure during pregnancy on postnatal memory and learning in the offspring. Pregnant rats at gestational day 14 were either exposed to 1.3% isoflurane in a humidified 100% oxygen carrier gas or simply humidified 100% oxygen without any inhalational anesthetic for 2 h every day before delivery. Four weeks later, spatial learning and memory of the offspring were examined using the Morris Water Maze. The expression levels of GAP-43 and NPY in the hippocampal CA1 region of the pups were determined by immunohistochemistry and RT-PCR. Simultaneously, the ultrastructure changes in synapse of the hippocampus were also observed by transmission electron microscopy (TEM). Isoflurane exposure during pregnancy impaired postnatal spatial memory and learning in the offspring as shown by the longer escape latency and the fewer original platform crossings in the Morris Water Maze test. The number and optical densities of GAP-43 and NPY positive cells, as well as the levels of GAP-43 and NPY mRNA, decreased significantly in the hippocampus of isoflurane-exposed pups. Furthermore, TEM studies showed remarkable changes in synaptic ultrastructure of hippocampus. These results indicate that isoflurane exposure during pregnancy could cause postnatal spatial memory and learning impairments in offspring rats, which may be partially explained by the down-regulation of GAP-43 and NPY in the hippocampal area. [ABSTRACT FROM AUTHOR]

Insulin-like growth factor-1 (IGF-1) is a neurotrophic factor and plays an important role in promoting axonal growth from dorsal root ganglion (DRG) neurons. Whether IGF-1 influences growth-associated protein 43 (GAP-43) expression and activates the extracellular signal-regulated protein kinase (ERK1/2) and the phosphatidylinositol 3-kinase (PI3K)/Akt signaling pathways in DRG neurons with excitotoxicity induced by glutamate (Glu) remains unknown. In this study, embryonic 15-day-old rat DRG explants were cultured for 48 h and then exposed to IGF-1, Glu, Glu + IGF-1, Glu + IGF-1 + PD98059, Glu + IGF-1 + LY294002, Glu + IGF-1 + PD98059 + LY294002 for additional 12 h. The DRG explants were continuously exposed to growth media as control. The levels of GAP-43 mRNA were detected by real time-PCR analysis. The protein levels of GAP-43, phosphorylated ERK1/2, phosphorylated Akt, total ERK1/2, and total Akt were detected by Western blot assay. GAP-43 expression in situ was determined by immunofluorescent labeling. Apoptotic cell death was monitored by Hoechst 33342 staining. IGF-1 alone increased GAP-43 and its mRNA levels in the absence of Glu. The decreased GAP-43 and its mRNA levels caused by Glu could be partially reversed by the presence of IGF-1. IGF-1 rescued neuronal cell death caused by Glu. Neither the ERK1/2 inhibitor PD98059 nor the PI3K inhibitor LY294002 blocked the effect of IGF-1, but both inhibitors together were effective. To validate the impact of GAP-43 expression by IGF-1, GAP-43 induction was blocked by administration of dexamethasone (DEX). IGF-1 partially rescued the decrease of GAP-43 and its mRNA levels induced by DEX. DEX induced an increase of cell apoptosis. IGF-1 may play an important role in neuroprotective effects on DRG neurons through regulating GAP-43 expression with excitotoxicity induced by Glu and the process was involved in both ERK1/2 and PI3K/Akt signaling pathways. [ABSTRACT FROM AUTHOR]

Chondroitin sulphate proteoglycans (CSPGs) with the major component NG2 have an inhibitory effect on regeneration of damaged axons after spinal cord injury. In this study, we investigate whether the digestion of CSPGs by chondroitinase ABC (ChABC) may decrease the NG2 expression and promote axon regrowth through the lesion site. Rats underwent spinal cord compression injury and were treated with ChABC or vehicle through an intrathecal catheter delivery at 2, 3, and 4 days after injury. In addition, animals were behaviorally scored using BBB test in weekly intervals after SCI. Based on immunocytochemical analyses, we have quantified distribution of NG2 glycoprotein and GAP-43 in spinal cord tissue in both experimental groups. Multiple injections of ChABC caused decrease of NG2 expression at lesion site at 5 and 7 days, but not at 14 and 28 days in comparison with vehicle-treated rats and significantly enhanced GAP-43 expression during the entire survival. The densitometry analysis showed significantly higher GAP-43 immunoreactivity (1.8-2.2-fold) in the regrowing axons and cell bodies within the central lesion cavity when compared with vehicle group. Longitudinally oriented and disorganized GAP-43-labeled axons were able to infiltrate and penetrate damaged tissue. The outgrowth of GAP-43 axons after CHABC delivery was significantly longer (≤0.457 mm) when compared with the length of axons in vehicle-treated rats (≤0.046 mm). Present findings suggest that degradation of NG2 with acute IT ChABC treatment may promote ongoing (long-lasting) axonal regenerative processes at late survival (14 and 28 days), but with no significant impact on the improvement of motor function. [ABSTRACT FROM AUTHOR]

Objective: Sucralose, a high-intensity sweetener, has been approved as a general-purpose sweetener in all food since the late 1990s. Due to its good taste and physiochemical profile, its use has increased and sucralose is considered a way of managing health and an option to improve the quality of life in the diabetic population. Recently high concentrations of sucralose have been found in the environment. Other environmental pollutants have been shown to induce neurotoxic effects when administered during a period of rapid brain growth and development. This period of rapid brain growth and development is postnatal in mice and rats, spanning the first 3–4 wk of life, reaching its peak around postnatal day 10, whereas in humans, brain growth and development is perinatal. The proteins calcium/calmodulin-dependent protein kinase II, growth-associated protein-43, synaptophysin, and tau play important roles during brain growth and development. Methods: In the present study, mice were orally exposed to 5–125 mg of sucralose per kilogram of body weight per day during postnatal days 8–12. Twenty-four hours after last exposure, brains were analyzed for calcium/calmodulin-dependent protein kinase II, growth-associated protein-43, synaptophysin, and tau, and at the age of 2 mo the animals were tested for spontaneous behavior. Results: The protein analysis showed no alterations in calcium/calmodulin-dependent protein kinase II, growth-associated protein-43, synaptophysin, or tau. Furthermore, there were no disturbances in adult behavior or habituation after neonatal sucralose exposure. Conclusion: The present study shows that repeated neonatal exposure to the artificial sweetener sucralose does not result in neurotoxicity, which supports that sucralose seems to be a safe alternative for people who want or need to reduce or substitute glucose in their diet. [Copyright &y& Elsevier]

Background and Aims: This study is concerned with the expressions of growth-associated protein-43 (GAP-43) mRNA and protein in the anterior horn of the spinal cord after brachial plexus injury. Methods: Animals were killed 1, 7, 14 days after injury and were divided into three injury groups: group 1, right C7 ventral motor root avulsion; group 2, right C7 ventral motor root avulsion and cut right C5-T1 dorsal sensitive roots; and group 3, right C7 ventral motor root avulsion plus right hemisection between C5 and C6 segment of the spinal cord. The combined behavioral scores (CBS) 1, 7 and 14 days after surgery were used in behavioral testing. Expressions of both GAP-43 mRNA and protein were analyzed using QRT-PCR and immunohistochemistry 14 days after surgery. Results: Among the injury groups, rats in group 3 had the highest score and those in group 1, the lowest score. On day 14 after surgery, the expressions of GAP-43 mRNA and protein were evidently up-regulated compared to the control group, with the highest in group 3 and the lowest in group 1, showing significant differences among the three injury groups (p <0.01). Conclusions: Our study suggests that the expressions of GAP-43 mRNA and protein may be upregulated after brachial plexus injury, and GAP-43 protein is possibly associated with the axon regeneration and function reconstruction. [Copyright &y& Elsevier]

Abstract: Protein kinase C (PKC) has been suggested as a molecular target related to the pathogenetic and therapeutic mechanisms of mood disorders in which electroconvulsive seizure (ECS) is effective. However, the reports concerning the effects of ECS on PKC are anecdotal and need further clarification. In this study, we examined the effects of ECS treatment on the phosphorylation of PKC substrates, including GAP-43, MARCKS, and neurogranin. Immunoblot using anti-p-PKC substrate antibodies revealed that a single ECS treatment induced temporal changes in the phosphorylation level of PKC substrates in rat brain, reflecting the effects on PKC activity. Phosphorylation of GAP-43 and MARCKS, representative PKC substrates related to synaptic remodeling, increased from 5 to 30min, after a transient decrease at 0min immediately after ECS, and returned to basal levels at 60min in rat frontal cortex, hippocampus, and cerebellum. Phosphorylation of neurogranin, another PKC substrate, showed a similar pattern of temporal changes in the frontal cortex and hippocampus. Immunohistochemical analysis revealed that p-GAP-43 and p-MARCKS were densely stained throughout the neuronal cells of the prefrontal cortex and hippocampus, and the Purkinje cells of cerebellum, after ECS treatment. Brief and transient activation of PKC may be translated into long-term biochemical changes, resulting in synaptic plasticity. Taken together, the acute effects of ECS on PKC activity, which could be an underpinning of long-term biochemical changes induced by ECS, may contribute to understand the molecular mechanism of ECS. [Copyright &y& Elsevier]

Abstract: Methamphetamine (METH) is a most commonly abused drug which damages nerve terminals by causing formation of reactive oxygen species (ROS), apoptosis, and finally neuronal damage. Fetal exposure to neurotoxic METH causes significant behavioral effects. The developing fetus is substantially deficient in most antioxidative enzymes, and may therefore be at high risk from both endogenous and drug-enhanced oxidative stress. Little is known about the effects of METH on vesicular proteins such as synaptophysin and growth-associated protein 43 (GAP-43) in the immature brain. The present study attempted to investigate the effects of METH-induced neurotoxicity in the dopaminergic system of the neonatal rat brain. Neonatal rats were subcutaneously exposed to 5–10mg/kg METH daily from postnatal day 4–10 for 7 consecutive days. The results showed that tyrosine hydroxylase enzyme levels were significantly decreased in the dorsal striatum, prefrontal cortex, nucleus accumbens and substantia nigra, synaptophysin levels decreased in the striatum and prefrontal cortex and growth-associated protein-43 (GAP-43) levels significantly decreased in the nucleus accumbens of neonatal rats. Pretreatment with 2mg/kg melatonin 30min prior to METH administration prevented METH-induced reduction in tyrosine hydroxylase, synaptophysin and growth-associated protein-43 protein levels in different brain regions. These results suggest that melatonin provides a protective effect against METH-induced nerve terminal degeneration in the immature rat brain probably via its antioxidant properties. [Copyright &y& Elsevier]

Abstract: We have prepared an aqueous extract of Achyranthes bidentata Blume, a commonly prescribed Chinese medicinal herb, and reported, in previous studies, that A. bidentata extract benefits nerve growth and prevents neuron apoptosis. In this study, we investigated the actions of A. bidentata extract on survival and growth of primarily cultured rat hippocampal neurons. The morphological observation revealed that neurite growth from hippocampal neurons was significantly enhanced by A. bidentata extract with similar effects to those induced by nerve growth factor (NGF), and the greatest neurite growth appeared on treatment with A. bidentata extract at 1μg/ml for 24h. DNA microarray analysis indicated that there were 25 upregulated genes and 47 downregulated genes exhibiting significantly differential expression in hippocampal neurons treated with A. bidentata extract at 1μg/ml for 6h when compared to those in untreated hippocampal neurons. Real-time quantitative RT-PCR and Western blot analysis demonstrated that the expression of growth-associated protein-43 in hippocampal neurons was upregulated at both mRNA and protein levels after treatment with A. bidentata extract, and the optimal dosage of the extract was also 1μg/ml. These data confirm that A. bidentata extract could promote in vitro hippocampal neuronal growth in a dose- and time-dependent manner. [Copyright &y& Elsevier]

The present study examined the role of phospholipase D2 (PLD2) in the regulation of depolarization-induced neurite outgrowth and the expression of growth-associated protein-43 (GAP-43) and synapsin I in rat pheochromocytoma (PC12) cells. Depolarization of PC12 cells with 50 mmol/L KCl increased neurite outgrowth and elevated mRNA and protein expression of GAP-43 and synapsin I. These increases were suppressed by inhibition of Ca2+-calmodulin-dependent protein kinase II (CaMKII), PLD, or mitogen-activated protein kinase kinase (MEK). Knockdown of PLD2 by small interfering RNA (siRNA) suppressed the depolarization-induced neurite outgrowth, and the increase in GAP-43 and synapsin I expression. Depolarization evoked a Ca2+ rise that activated various signaling enzymes and the cAMP response element-binding protein (CREB). Silencing CaMKIIδ by siRNA blocked KCl-induced phosphorylation of proline-rich protein tyrosine kinase 2 (Pyk2), Src kinase, and extracellular signal-regulated kinase (ERK). Inhibition of Src or MEK abolished phosphorylation of ERK and CREB. Furthermore, phosphorylation of Pyk2, ERK, and CREB was suppressed by the PLD inhibitor, 1-butanol and transfection of PLD2 siRNA, whereas it was enhanced by over-expression of wild-type PLD2. Depolarization-induced PLD2 activation was suppressed by CaMKII and Src inhibitors, but not by MEK or protein kinase A inhibitors. These results suggest that the signaling pathway of depolarization-induced PLD2 activation was downstream of CaMKIIδ and Src, and upstream of Pyk2(Y881) and ERK/CREB, but independent of the protein kinase A. This is the first demonstration that PLD2 activation is involved in GAP-43 and synapsin I expression during depolarization-induced neuronal differentiation in PC12 cells. [ABSTRACT FROM AUTHOR]

Abstract: Strong evidence suggests that antidepressants work by induction of neuroplastic changes mediated through regulation of brain-derived neurotrophic factor (BDNF). This study was undertaken to investigate the time-course of the effect of three antidepressants; fluoxetine, imipramine and venlafaxine, which differentially affect monoamine reuptake, on BDNF mRNA expression in the hippocampus. The consequences of increased BDNF in the hippocampus are still indefinite. Here, we also determined the effects on the expression of two other genes (synaptophysin and growth-associated protein-43 (GAP-43)) known to be involved in synapse formation and axonal growth and likely regulated by BDNF. The effects were determined in rats after sub-chronic (7 days) and chronic (14 and 21 days) treatment using semi-quantitative in situ hybridisation. BDNF mRNA levels in the dentate gyrus (DG) were increased after treatment with venlafaxine (7, 14 and 21 days) and imipramine (14 and 21 days), but not after treatment with fluoxetine, indicating that stimulation of BDNF mRNA expression is dependent on the pharmacological profile and on the time-course of drug treatment. A transient increase in synaptophysin mRNA was observed after treatment with venlafaxine and fluoxetine whereas imipramine had no effect. In the CA3 region a reduction of GAP-43 mRNA was observed after treatment with imipramine (21 days) and fluoxetine (7 and 14 days). These results suggest that venlafaxine and imipramine, but not fluoxetine, induce neuroplastic effects in the hippocampus through stimulation of BDNF mRNA expression, and that the effect on BDNF is not directly translated into regulation of synaptophysin and GAP-43 mRNA. [Copyright &y& Elsevier]

Abstract: Diabetes mellitus (DM) may give rise to cognitive impairment, but the pathological mechanism involved was still unknown. We employed streptozotocin (STZ)-induced diabetic rats and test their capacity for learning and memory by three-arm radial maze. We determined the expression level of growth-associated protein-43 (GAP-43) and mitogen activated protein kinase phosphatase-1 (MKP-1) in the hippocampus by immunohistochemistry. MKP-1 mRNA level in the CA1 and dentate gyrus (DG) Hippocampal area is further determined by RT-PCR method. We also observed the ultrastructures of Hippocampal neurons by transmission electron microscopy (TEM). All data were analyzed by the independent samples t-test. Four weeks after STZ induction, the diabetic rats showed decreased capacity for learning and memory as indicated by the increase in the error number and reaction time in three-arm radial maze test. TEM results showed the ultrastructures of diabetic hippocampus, including area CA1 and DG, neurons were characterized by swollen mitochondria, increased heterochromatin accumulation and reduced synaptic contacts. The optical density as well as the positive neuron number for GAP-43 and MKP-1 decreased significantly in the CA1 and DG Hippocampal area in diabetic rats (P <0.01). RT-PCR results also showed MKP-1 mRNA in the CA1 and DG Hippocampal area was decreased in the diabetic rats. These results indicated that DM could down-regulate GAP-43 and MKP-1 expression in Hippocampal area that is in charge of memory and cognition. As indicated by our study, the changes in GAP-43 and MKP-1 expression in hippocampus may play a role in the pathogenesis of diabetic dementia. [Copyright &y& Elsevier]

Abstract: Learned helplessness rats are thought to be an animal model of depression. To study the role of synapse plasticity in depression, we examined the effects of learned helplessness and antidepressant treatments on synapsin I (a marker of presynaptic terminals), growth-associated protein-43 (GAP-43; a marker of growth cones), and microtubule-associated protein-2 (MAP-2; a marker of dendrites) in the hippocampus by immunolabeling. (1) Learned helplessness rats showed significant increases in the expression of synapsin I two days after the attainment of learned helplessness, and significant decreases in the protein expression eight days after the achievement of learned helplessness. Subchronic treatment of naïve rats with imipramine or fluvoxamine significantly decreased the expression of synapsin I. (2) Learned helplessness increased the expression of GAP-43 two days and eight days after learned helplessness training. Subchronic treatment of naïve rats with fluvoxamine but not imipramine showed a tendency to decrease the expression of synapsin I. (3) Learned helplessness rats showed increased expression of MAP-2 eight days after the attainment of learned helplessness. Naïve rats subchronically treated with imipramine showed a tendency toward increased expression of MAP-2, but those treated with fluvoxamine did not. These results indicate that the neuroplasticity-related proteins synapsin I, GAP-43, and MAP-2 may play a role in the pathophysiology of depression and the mechanisms of antidepressants. [Copyright &y& Elsevier]

Abstract: In spinal cord injury, the injury could trigger some inhibitory signal cascades to promote chondroitin sulfate proteoglycans (CSPGs), the structures of scar tissues, formation. CSPGs could limit axonal regeneration mainly through the glycosaminoglycan (GAG) chain in the lesion site were suggested. We hypothesized that the digestion of CSPGs by chondroitinase ABC (ChABC) might decrease the inhibitory effects of limiting axonal re-growth after spinal cord injury. We compared the digesting products of CSPGs such as 2B6 by ChABC with the untreated control group and found no immunostaining of 2B6 in control group. The smaller size scars of ChABC-treatment were observed via CS-56, a type of CSPGs, 8 weeks after transection by immunohistochemistry. The inhibitory effects of CSPGs withdraw GAGs following ChABC-treatment would reduce, and immunopositive GAP-43 newly outgrown fibers were identified. In the animal trials, ChABC-treatment could improve motor function through BBB locomotor’s test and reduce limiting ability of scar tissues to promote axonal regeneration via changing the structure of CSPGs by immunohistochemistry with GAP-43. [Copyright &y& Elsevier]

We previously reported that the transplantation of neural stem/progenitor cells (NSPCs) can contribute to the repair of injured spinal cord in adult rats and monkeys. In some cases, however, most of the transplanted cells adhered to the cavity wall and failed to migrate and integrate into the host spinal cord. In this study we focused on chondroitin sulfate proteoglycan (CSPG), a known constituent of glial scars that is strongly expressed after spinal cord injury (SCI), as a putative inhibitor of NSPC migration in vivo. We hypothesized that the digestion of CSPG by chondroitinase ABC (C-ABC) might promote the migration of transplanted cells and neurite outgrowth after SCI. An in vitro study revealed that the migration of NSPC-derived cells was inhibited by CSPG and that this inhibitory effect was attenuated by C-ABC pre-treatment. Consistently, an in vivo study of C-ABC treatment combined with NSPC transplantation into injured spinal cord revealed that C-ABC pre-treatment promoted the migration of the transplanted cells, whereas CSPG-immunopositive scar tissue around the lesion cavity prevented their migration into the host spinal cord in the absence of C-ABC pre-treatment. Furthermore, this combined treatment significantly induced the outgrowth of a greater number of growth-associated protein-43-positive fibers at the lesion epicentre, compared with NSPC transplantation alone. These findings suggested that the application of C-ABC enhanced the benefits of NSPC transplantation for SCI by reducing the inhibitory effects of the glial scar, indicating that this combined treatment may be a promising strategy for the regeneration of injured spinal cord. [ABSTRACT FROM AUTHOR]

Abstract: Chronic cerebral hypoperfusion causes cognitive impairment, but the underlying molecular mechanism is not well understood. We used permanent occlusion of bilateral common carotid arteries (2-VO) to induce chronic cerebral hypoperfusion in male Wistar rats. Cognitive impairment and the expression patterns of MAP-2, GAP-43, and synaptophysin were examined. We found that both learning capacity and memory were gradually impaired in the rats with chronic cerebral hypoperfusion concomitant with increased duration of 2-VO treatment. Four weeks of 2-VO treatment resulted in down-regulation of synaptophysin expression at the protein levels, and a further decrease was observed at 10–20 weeks, although mRNA levels remained the same. Ten weeks of 2-VO treatment lead to down-regulation of MAP-2 expression at both the mRNA and protein levels with a further decrease at 20 weeks. Interestingly, GAP-43 mRNA was significantly up-regulated by 2-VO treatment, although the protein levels were not altered. Therefore, the cognitive impairment caused by chronic cerebral hypoperfusion may be partially explained by reduced expression of synaptophysin and MAP-2 at the protein level. The reduction in MAP-2 expression may be attributed to the inhibition of transcription, while the reduction in synaptophysin expression might be due to the inhibition of translation. Up-regulation of GAP-43 mRNA in the rat hippocampus with 2-VO treatment suggests that a compensatory mechanism may antagonize ischemic challenges. [Copyright &y& Elsevier]

We have recently reported that albumin, a serum protein present in the developing brain, stimulates the synthesis of oleic acid by cultured astrocytes by inducing stearoyl-CoA 9-desaturase, the rate-limiting enzyme in oleic acid synthesis, through activation of the sterol regulatory element-binding protein-1. In this work, we offer evidence supporting the in vivo occurrence of this process during the postnatal development of the rat brain. Our results show that albumin reaches maximal brain level by day 1 after birth, coinciding with activation of the sterol response element binding protein-1, which is responsible for the transcription of the enzymes required for oleic acid synthesis. In addition, the developmental profile of stearoyl-CoA 9-desaturase-1 mRNA expression follows that of sterol regulatory element-binding protein-1 activation, indicating that these phenomena are tightly linked. In a previous work, we showed that oleic acid induces neuronal differentiation, as indicated by the expression of growth associated protein-43. Here, we report that the expression of growth associated protein-43 mRNA peaks at about day 7 after birth, following the maximal expression of stearoyl-CoA 9-desaturase-1 mRNA that occurs between days 3 and 5 postnatally. In conclusion, our results support the hypothesis that the synthesis of oleic acid is linked to neuronal differentiation during rat brain development. [Copyright &y& Elsevier]

Low power laser irradiation (LPLI) has been used in the treatment of peripheral nerve injury. In this study, we verified its therapeutic effect on neuronal regeneration by finding elevated immunoreactivities (IRs) of growth-associated protein-43 (GAP-43), which is up-regulated during neuronal regeneration. Twenty Sprague–Dawley rats received a standardized crush injury of the sciatic nerve, mimicking the clinical situations accompanying partial axonotmesis. The injured nerve received calculated LPLI therapy immediately after injury and for 4 consecutive days thereafter. The walking movements of the animals were scored using the sciatic functional index (SFI). In the laser treated rats, the SFI level was higher in the laser treated animals at 3–4 weeks while the SFIs of the laser treated and untreated rats reached normal levels at 5 weeks after surgery. In immunocytochemical study, although GAP-43 IRs increased both in the untreated control and the LPLI treated groups after injury, the number of GAP-43 IR nerve fibers was much more increased in the LPLI group than those in the control group. The elevated numbers of GAP-43 IR nerve fibers reached a peak 3 weeks after injury, and then declined in both the untreated control and the LPLI groups at 5 weeks, with no differences in the numbers of GAP-43 IR nerve fibers of the two groups at this stage. This immunocytochemical study using GAP-43 antibody study shows for the first time that LPLI has an effect on the early stages of the nerve recovery process following sciatic nerve injury. [Copyright &y& Elsevier]

It has previously been shown that the capsaicin-lesioned peptidergic sensory neurons and the 6-hydroxydopamine (6-OHDA)-lesioned sympathetic noradrenergic neurons represent a useful model to study neurotrophin-induced nerve regeneration in the adult rat. The present study was aimed at investigating if the immunosuppressant drug FK506 (tacrolimus) has neuroregeneratory properties in these capsaicin- or 6-OHDA-lesioned peripheral nerves. FK506 was injected in a dose of 0.5 mg/kg/day for 10 days or in a dose of 1.5 mg/kg/day for 7 days. One day after the last FK506 injection neurotransmitter content was investigated in selected tissues. The content of the sensory neuron marker peptide calcitonin gene-related peptide (CGRP) was reduced after the capsaicin treatment in the hind paw skin by 35–40% and in the dorsal lumbar spinal cord by 48%. The treatment with FK506 did not induce a recovery of the CGRP content. Following the 6-OHDA treatment the noradrenaline content was reduced by 50–62% in the hind paw skin and by 73% in the heart atrium. FK506 alone did not increase the noradrenaline levels, whereas an additional local intraplantar treatment with nerve growth factor recovered noradrenaline levels almost completely. The expression of a marker protein for growth processes in cells of sympathetic or sensory ganglia, growth-associated protein-43, was significantly increased by the FK506 treatment. This study demonstrated that despite a stimulatory effect of FK506 on the expression of a growth-associated protein a recovery of the transmitter content is not evident in peripheral small diameter sensory or postganglionic sympathetic neurons of the adult rat.Copyright © 2002 S. Karger AG, Basel. [ABSTRACT FROM AUTHOR]

During cerebral ischemia-reperfusion, the enhanced production of oxygen-derived free radicals contributes to neuronal death. The antioxidants α-lipoic acid and vitamin E have shown synergistic effects against lipid peroxidation by oxidant radicals in several pathological conditions. A thromboembolic stroke model in rats was used to analyze the effects of this mixture under two oral treatments: intensive and prophylactic. Neurological functions, glial reactivity and neuronal remodeling were assessed after experimental infarction. Neurological recovery was only found in the prophylactic group, and both antioxidant schemes produced down-regulation of astrocytic and microglial reactivity, as well as higher neuronal remodeling in the penumbra area, as compared with controls. The beneficial effects of this antioxidant mixture suggest that it may be valuable for the treatment of cerebral ischemia in humans. [Copyright &y& Elsevier]

Unlike in the adult brain, the newborn brain specifically takes up serum albumin during the postnatal period, coinciding with the stage of maximal brain development. Here we report that albumin stimulates oleic acid synthesis by astrocytes from the main metabolic substrates available during brain development. Oleic acid released by astrocytes is used by neurons for the synthesis of phospholipids and is specifically incorporated into growth cones. Oleic acid promotes axonal growth, neuronal clustering, and expression of the axonal growth-associated protein-43, GAP-43; all these observations indicating neuronal differentiation. The effect of oleic acid on GAP-43 synthesis is brought about by the activation of protein kinase C, since it was prevented by inhibitors of this kinase, such as H-7, polymyxin or sphingosine. The expression of GAP-43 was significantly increased in neurons co-cultured with astrocytes by the presence of albumin indicating that neuronal differentiation takes place in the presence of oleic acid synthesized and released by astrocytes in situ. In conclusion, during brain development the presence of albumin could play an important role by triggering the synthesis and release of oleic acid by astrocytes, which induces neuronal differentiation. [ABSTRACT FROM AUTHOR]

Gracile neuroaxonal dystrophy (NAD) is an distinctive morphological alteration of central projecting axon terminals of dorsal root ganglion neurons. Experimentally, lower limb amputation has been shown to accelerate the formation of gracile NAD, suggesting that the transganglionic response to peripheral axotomy may play a role in its development. To determine if a similar response occurs in the human sensory nervous system following peripheral nerve injury, we have performed postmortem histopathological examinations of the dorsal column nuclei of three patients (aged 15, 55, and 77 years old); all of whom had undergone accidental or therapeutic unilateral limb amputation (1 year, 38 years, and 1 year 8 months prior to death, respectively). In a 15-year-old man who underwent therapeutic leg amputation, the gracile nuclei on the transected side revealed reactive gliosis and many small axonal spheroids. The spheroids and fine neurites were immunolabelled with antibodies for growth-associated protein-43, ubiquitin and neuropeptide Y (NPY). Neither routine histological nor immunohistochemical methods demonstrated comparable changes in the contralateral gracile nucleus. In a 77-year-old man who underwent leg amputation, the gracile nucleus on the amputated side was gliotic and showed several NPY and ubiquitin-immunoreactive spheroids, which were not seen in the contralateral non-transected side. A 55-year-old man with a history of accidental arm amputation showed well-developed NAD in the cuneate nucleus only on the transected side. This study clearly demonstrates the occurrence of transganglionic response to limb amputation in human dorsal column nuclei. The extent of the regenerative and/or degenerative responses may vary depending on the age of the patient and the time interval following the peripheral axotomy. [ABSTRACT FROM AUTHOR]

Abstract: We have previously shown that the RNA-binding protein HuD binds to a regulatory element in the growth-associated protein (GAP)-43 mRNA and that this interaction involves its first two RNA recognition motifs (RRMs). In this study, we investigated the functional significance of this interaction by overexpression of human HuD protein (pcHuD) or its truncated form lacking the third RRM (pcHuD I+II) in PC12 cells. Morphological analysis revealed that pcHuD cells extended short neurites containing GAP-43-positive growth cones in the absence of nerve growth factor (NGF). These processes also contained tubulin and F-actin filaments but were not stained with antibodies against neurofilament M protein. In correlation with this phenotype, pcHuD cells contained higher levels of GAP-43 without changes in levels of other NGF-induced proteins, such as SNAP-25 and tau. In mRNA decay studies, HuD stabilized the GAP-43 mRNA, whereas HuD I+II did not have any effect either on GAP-43 mRNA stability or on the levels of GAP-43 protein. Likewise, pcHuD I+II cells showed no spontaneous neurite outgrowth and deficient outgrowth in response to NGF. Our results indicate that HuD is sufficient to increase GAP-43 gene expression and neurite outgrowth in the absence of NGF and that the third RRM in the protein is critical for this function. [ABSTRACT FROM AUTHOR]

Objectives: Spinal cord injury (SCI) is a disabling central nervous system disorder. This study aimed to explore the effects of repetitive trans-spinal magnetic stimulation (rTSMS) of different spinal cord segments on movement function and growth-associated protein-43 (GAP43) and 5-hydroxytryptamine (5-HT) expression in rats after acute SCI and to preliminarily discuss the optimal rTSMS treatment site to provide a theoretical foundation and experimental evidence for clinical application of rTSMS in SCI., Methods: A rat T10 laminectomy SCI model produced by transient application of an aneurysm clip was used in the study. The rats were divided into group A (sham surgery), group B (acute SCI without stimulation), group C (T6 segment stimulation), group D (T10 segment stimulation), and group E (L2 segment stimulation)., Results: In vivo magnetic stimulation protected motor function, alleviated myelin sheath damage, decreased NgR and Nogo-A expression levels, increased GAP43 and 5-HT expression levels, and inhibited terminal deoxynucleotidyl transferase dUTP nick end labeling-positive cells and apoptosis-related protein expression in rats at 8 weeks after the surgery., Conclusions: This study suggests that rTSMS can promote GAP43 and 5-HT expression and axonal regeneration in the spinal cord, which is beneficial to motor function recovery after acute SCI.

Aims The main objective was to investigate the effects of the transient receptor potential cation channel subfamily V member 1 (TRPV1) on nerve regeneration following sciatic transection injury by functional blockage of TRPV1 using AMG-517, a specific blocker of TRPV1. Methods AMG-517 was injected into the area surrounding ipsilateral lumbar dorsal root ganglia 30 min after unilateral sciatic nerve transection. The number of sciatic axons and the expression of growth-associated protein-43 (GAP-43) and glial fibrillary acidic protein was examined using semithin sections, Western blot, and immunofluorescence analyses. Results Blockage of TRPV1 with AMG-517 markedly promoted axonal regeneration, especially at two weeks after sciatic injury; the number of axons was similar to the uninjured control group. After sciatic nerve transection, expression of glial fibrillary acidic protein was decreased and GAP-43 was increased at the proximal stump. However, the expression of both glial fibrillary acidic protein and GAP-43 increased significantly in AMG-517-treated groups. Conclusions TRPV1 may be an important therapeutic target to promote peripheral nerve regeneration after injury.

A previous study by our group found that inhibition of nischarin promotes neurite outgrowth and neuronal regeneration in Neuro-2a cells and primary cortical neurons. In recent years, more and more studies have shown that nanomaterials have good prospects in treatment of spinal cord injury. We proposed that small interfering RNA targeting nischarin (Nis-siRNA) delivered by polyethyleneimine-alginate (PEI-ALG) nanoparticles promoted motor function recovery in rats with spinal cord injury. Direct microinjection of 5 μL PEI-ALG/Nis-siRNA into the spinal cord lesion area of spinal cord injury rats was performed. From day 7 after surgery, Basso, Beattie and Bresnahan score was significantly higher in rats from the PEI-ALG/Nis-siRNA group compared with the spinal cord injury group and PEI-ALG/Control-siRNA group. On day 21 after injection, hematoxylin-eosin staining showed that the necrotic area was reduced in the PEI-ALG/Nis-siRNA group. Immunohistochemistry and western blot assay results confirmed successful inhibition of nischarin expression and increased protein expression of growth-associated protein-43 in the PEI-ALG/Nis-siRNA group. These findings suggest that a complex of PEI-ALG nanoparticles and Nis-siRNA effectively suppresses nischarin expression, induces expression of growth-associated protein-43, and accelerates motor function recovery after spinal cord injury., Competing Interests: None declared

Ginsenoside Rb1 has been reported to exert anti-aging and anti-neurodegenerative effects. In the present study, we investigate whether ginsenoside Rb1 is involved in neurite outgrowth and neuroprotection against damage induced by amyloid beta (25-35) in cultured hippocampal neurons, and explore the underlying mechanisms. Ginsenoside Rb1 significantly increased neurite outgrowth in hippocampal neurons, and increased the expression of phosphorylated-Akt and phosphorylated extracellular signal-regulated kinase 1/2. These effects were abrogated by API-2 and PD98059, inhibitors of the signaling proteins Akt and MEK. Additionally, cultured hippocampal neurons were exposed to amyloid beta (25-35) for 30 minutes; ginsenoside Rb1 prevented apoptosis induced by amyloid beta (25-35), and this effect was blocked by API-2 and PD98059. Furthermore, ginsenoside Rb1 significantly reversed the reduction in phosphorylated-Akt and phosphorylated extracellular signal-regulated kinase 1/2 levels induced by amyloid beta (25-35), and API-2 neutralized the effect of ginsenoside Rb1. The present results indicate that ginsenoside Rb1 enhances neurite outgrowth and protects against neurotoxicity induced by amyloid beta (25-35) via a mechanism involving Akt and extracellular signal-regulated kinase 1/2 signaling.

Focal cerebral infarction causes secondary damage in the ipsilateral ventroposterior thalamic nucleus (VPN). Chondroitin sulfate proteoglycans (CSPGs) are a family of putative inhibitory components, and its degradation by chondroitinase ABC (ChABC) promotes post-injury neurogenesis. This study investigated the role of ChABC in the primary and secondary injury post stroke in hypertension. Renovascular hypertensive Sprague-Dawley rats underwent middle cerebral artery occlusion (MCAO), and were subjected to continuous intra-infarct infusion of ChABC (0.12 U/d for 7 days) 24 h later. Neurological function was evaluated by a modified neurologic severity score. Neurons were counted in the peri-infarct region and the ipsilateral VPN 8 and 14 days after MCAO by Nissl staining and NeuN labeling. The expressions of CSPGs, growth-associated protein-43 (GAP-43) and synaptophysin (SYN) were detected with immunofluorescence or Western blotting. The intra-infarct infusion of ChABC, by degrading accumulated CSPGs, rescued neuronal loss and increased the levels of GAP-43 and SYN in both the ipsilateral cortex and VPN, indicating enhancd neuron survival as well as augmented axonal growth and synaptic plasticity, eventually improving overall neurological function. The study demonstrated that intra-infarct ChABC infusion could salvage the brain from both primary and secondary injury by the intervention on the neuroinhibitory environment post focal cerebral infarction., (© 2013 Published by Elsevier B.V.)