Corrigendum to: Fasudil alleviates cerebral ischemia‑reperfusion injury by inhibiting inflammation and improving neurotrophic factor expression in rats.

An experimental animal study about neuronal loss and the expression of neurotrophic factors in the chronic compressive spinal cords. To investigate neuronal loss and the expression of neurotrophic factors in the chronic compressive spinal cords of rats, and to evaluate effects of decompressive procedures for the neuronal loss. Chronic compression of spinal cords induces the loss of motor neurons in the anterior horn. However, the precise mechanism of this neuronal loss is not still understood completely. Furthermore, it is uncertain whether decompressive procedures prevent this neuronal loss or not. A thin expanding polymer sheet was implanted microsurgically underneath T7 laminae of rats. After 6, 9, 12, and 15 weeks, the thoracic spinal cord was harvested and examined histopathologically. The expression of neurotrophic factors, including NGF, BDNF, NT-3, GDNF, CNTF, and VEGF, was analyzed using semiquantitative RT-PCR, enzyme immunoassay, and immunohistochemistry. Decompressive surgery was performed through the removal of T7 laminae and the compression materials 6, 9, and 12 weeks after starting compression. Three weeks later, respectively, the neuronal loss in the anterior horn was estimated. The spinal cords were progressively flattened by the expanding of the implanted polymer sheet, and the number of motor neurons in the anterior horn decreased, especially from 6 to 9 weeks after starting compression. Semiquantitative RT-PCR analysis showed that the expression of NGF and BDNF mRNAs was decreased significantly in the spinal cords of 12-week compression group compared with the 6-week compression group and that NGF mRNA expression was up-regulated significantly in the 6-week compression group relative to the 6-week control group. Any changes of expression of other neurotrophic factors were not significant. Since BDNF, not NGF, has been known to be one of the powerful survival factors for spinal motoneurons, we investigated the levels of BDNF protein in the compressive spinal cords using enzyme immunoassay and immunohistochemistry. We demonstrated the level of BDNF protein in the compressive spinal cords was increased 6 weeks after compression but declined after 12 weeks. The decompressive procedure in the 6 weeks after compression prevented neuronal loss, but the same procedure in the 9 or 12 weeks was ineffective. From the point of view of neuronal loss, decompressive surgery at an earlier stage, when compensatory mechanisms including the up-regulation of BDNF might be still effective, could provide better therapeutic results against chronic mechanical compressive spinal cord lesions.

Objective To investigate the effects of hyperbaric oxygen (HBO) combined with moxibustion on learning and memory functions and the expression of hippocampal neurotrophic factor in rats with Alzheimer′s disease (AD). Methods The AD rat model was established by a single injection of aggregated Aβ25-35 into the hippocampus, and the rats were divided into the model group, the moxibustion group and the HBO combined with moxibustion group. The sham surgical group was injected with the same volume of normal saline at the same site. The learning and memory capacity of the rats was detected by Morris water maze. The positive expression of brain-derived neurotrophic factor (BDNF) and nerve growth factor (NGF) in hippocampus was detected by immunohistochemistry, and the expression of BDNF and NGF proteins in hippocampus was detected by Western blotting. Results Compared with those of the sham surgical group, the escape latency and spatial exploration time of the model group significantly lowered (P<0.01), learning and memory capacity was severely impaired, the expression of BDNF and NGF in the hippocampus significantly decreased (P<0.01), with a neurotrophic deficiency. Following treatment with moxibustion or HBO combined with moxibustion, the learning and memory capacity of the model rats recovered to a certain extent (P<0.05 or P<0.01). The expression of BDNF and NGF in hippocampus was significantly up-regulated (P<0.01), with the therapeutic effects of the HBO combined with moxibustion group being obviously better than those of the moxibustion group (P<0.05). Conclusion HBO combined with moxibustion could significantly improve the learning and memory function of the AD model rats, up-regulate the expression of neurotrophic factor in hippocampus, and the effects were significantly superior to simple moxibustion treatment. Key words: Alzheimer′s disease; Hyperbaric oxygen; Moxibustion; Neurotrophic factor

Neurotrophic factors play an essential role in the ontogeny of the newborn brain, determining the vectors for the development of the regulatory systems of the organism. Changes in the expression of neurotrophic factors under conditions of elevated glucocorticoid levels or stress, according to the results of clinical observations and animal studies, are associated with the etiology of psychoemotional disorders and neurodegenerative pathologies. The hippocampus is a link for the manifestation of the modifying effects of glucocorticoids and stress effects on the processes of neuroplasticity and behavioral regulation in the brain. The manifestation of psychopathological and neurodegenerative changes is accompanied by modulation of the expression of key neurotrophic factors in the hippocampus, including after glucocorticoid induction, while the balance of expression of proforms and mature proteins of neurotrophins is extremely important. Thus, the main problem of this mini-review is to highlight the modification of expression of brain-derived neurotrophic factors, mature and immature forms of BDNF, NGF and NT3 mainly in the neonatal CNS, in particular in the hippocampus, under the influence of glucocorticoids, neuropathologies or effects of stress of various etiologies based on literature and our own data. It was established that, after dexamethasone induction, proBDNF, and not proNT3 and proNGF, has its own expression pattern in the hippocampus of neonatal rats, which is different from its mature form, and the manifestation of the proapoptotic effect of this proneurotrophin is accompanied by an increase in the proBDNF/BDNF ratio and an increase in the number of cells with detectable active caspase-3.

Delivery of multiple neurotrophic factors (NTFs), especially with time-restricted release kinetics, holds great potential for nerve repair. In this study, we utilized the tetracycline-regulatable Tet-On 3G system to control the expression of c-Jun, which is a common regulator of multiple NTFs in Schwann cells (SCs). In vitro, Tet-On/c-Jun-modified SCs showed a tightly controllable secretion of multiple NTFs, including glial cell line-derived NTF, nerve growth factor, brain-derived NTF, and artemin, by the addition or removal of doxycycline (Dox). When Tet-On/c-Jun-transduced SCs were grafted in vivo, the expression of NTFs could also be regulated by oral administration or removal of Dox. Fluoro-Gold retrograde tracing results indicated that a biphasic NTF expression scheme (Dox+3/-9, NTFs were up-regulated for 3 wk and declined to physiologic levels for another 9 wk) achieved more axonal regeneration than continuous up-regulation of NTFs (Dox+12) or no NTF induction (Dox-12). More importantly, the Dox+3/-9-group animals showed much better functional recovery than the animals in the Dox+12 and Dox-12 groups. Our findings, for the first time, demonstrated drug-controllable expression of multiple NTFs in nerve repair cells both in vitro and in vivo. These findings provide new hope for developing an optimal therapeutic alternative for nerve repair through the time-restricted release of multiple NTFs using Tet-On/c-Jun-modified SCs.-Huang, L., Xia, B., Shi, X., Gao, J., Yang, Y., Xu, F., Qi, F., Liang, C., Huang, J., Luo, Z. Time-restricted release of multiple neurotrophic factors promotes axonal regeneration and functional recovery after peripheral nerve injury.

Cerebral hypoperfusion is an important factor in the pathogenesis of cerebrovascular diseases and neurodegenerative disorders. We investigated the effects of memantine and rosuvastatin on both neovascularization and synaptic function in a rat model of chronic cerebral hypoperfusion, which was established by the bilateral common carotid occlusion (2VO) method. We tested learning and memory ability, synaptic function, circulating endothelial progenitor cell (EPC) number, expression of neurotrophic factors, and markers of neovasculogenesis and cell proliferation after memantine and/or rosuvastatin treatment. Rats treated with memantine and/or rosuvastatin showed significant improvement in Morris water maze task and long-term potentiation (LTP) in the hippocampus, compared with untreated 2VO model rats. Circulating EPCs, expression of brain-derived neurotrophic factor, and vascular endothelial growth factor, markers of microvessel density were increased by each of the three interventions. Rosuvastatin also increased cell proliferation in the hippocampus. Combined treatment with memantine and rosuvastatin showed greater effect on enhancement of LTP and expression of neurotrophic factors than either single medication treatment alone. Both memantine and rosuvastatin improved learning and memory, enhanced neovascularization and synaptic function, and upregulated neurotrophic factors in a rat model of chronic cerebral hypoperfusion.

To investigate a possible therapeutic mechanism of cell therapy in the field of cerebral palsy using granulocyte-colony stimulating factor (G-CSF)-mobilized peripheral blood mononuclear cells (mPBMCs), we compared the expression of inflammatory cytokines and neurotrophic factors in PBMCs and mPBMCs from children with cerebral palsy to those from healthy adult donors and to cord blood mononuclear cells donated from healthy newborns. No significant differences in expression of neurotrophic factors were found between PBMCs and mPBMCs. However, in cerebral palsy children, the expression of interleukin-6 was significantly increased in mPBMCs as compared to PBMCs, and the expression of interleukin-3 was significantly decreased in mPBMCs as compared to PBMCs. In healthy adults, the expression levels of both interleukin-1β and interleukin-6 were significantly increased in mPBMCs as compared to PBMCs. The expression of brain-derived neurotrophic factors in mPBMC from cerebral palsy children was significantly higher than that in the cord blood or mPBMCs from healthy adults. The expression of G-CSF in mPBMCs from cerebral palsy children was comparable to that in the cord blood but significantly higher than that in mPBMCs from healthy adults. Lower expression of pro-inflammatory cytokines (interleukin-1β, interleukin-3, and -6) and higher expression of anti-inflammatory cytokines (interleukin-8 and interleukin-9) were observed from the cord blood and mPBMCs from cerebral palsy children rather than from healthy adults. These findings indicate that mPBMCs from cerebral palsy and cord blood mononuclear cells from healthy newborns have the potential to become seed cells for treatment of cerebral palsy.

Cell-based therapy is a promising strategy for the repair of spinal cord injury (SCI), and the synergic effects of donor cells are emphasized in recent years. In this study, epidermal neural crest stem cells (EPI-NCSCs) and olfactory ensheathing cells (OECs) were transplanted into the contused spinal cord of rats separately or jointly at 1week after injury. At 3 and 9weeks posttransplantation, migration of the donor cells, expression of brain-derived neurotrophic factor (BDNF) and glial cell line-derived neurotrophic factor (GDNF) and functional recovery of the contused cord were determined by techniques of histopathology, quantitative real-time polymerase chain reaction (qPCR), immunohistochemistry and Basso-Beattie-Bresnahan (BBB) score. The results showed that the migration and distribution of EPI-NCSCs in vivo were promoted by OECs at 3weeks after transplantation, but they vanished at 9weeks. The expression of BDNF and GDNF was significantly increased by co-transplantation at molecular and protein level. Although the expression of both factors in EPI-NCSCs- and OECs-injected group was lower than in co-injected group, it was higher than in control groups. Similarly, the best locomotor recovery of the contused cord was acquired from co-injected animals. As we know, this is the first time to study the synergic effects of EPI-NCSCs and OECs, and the data indicates that donor cells migration, expression of neurotrophic factors (NTFs), and recovery of motor function can be improved by EPI-NCSCs and OECs synergistically.

Purpose: To measure the expression level and pattern of neurotrophic factors and their receptors in keratoconus (KC) cornea using quantitative RT-PCR (qPCR) and immunostaining.Materials and Methods: Twenty-one recipient corneal buttons after keratoplasty from KC cornea and four age-matched normal corneas were obtained. The 25 corneal tissues were divided into two pieces; one fragment of each sample was used for immunostaining whereas the other fragment was used for qPCR. Using primary antibodies and specific qPCR primer, immunostaining and qPCR were performed to analyze the expression level of the neurotrophic factors and receptors.Results: Nerve growth factor and its receptors (TrkA and p75NTR) were not expressed in the center of normal cornea. However, TrkA and the p75NTR were clearly expressed in a membrane bound staining pattern and the mRNA levels were significantly higher in KC (p < 0.001). The mRNA expression of brain-derived neurotrophic factor (BDNF), ciliary neurotrophic factor (CNTF) and neurotrophin (NT)-4 mRNA was also elevated in KC (p < 0.001). BDNF was expressed in epithelium of normal cornea. However, in KC, its expression was found to be extending into the anterior stromal layer. CNTF was hardly expressed in normal cornea. In KC, the entire epithelium expressed CNTF, especially in perinuclear area. NT-4 was expressed throughout the epithelium and stroma in KC.Conclusion: The change in expression of neurotrophic factors in KC may suggest that these factors play an important role in the pathogenesis of KC and serve as new markers for the progression of KC.

Fingolimod increases oligodendrocytes markers expression in epidermal neural crest stem cells

Studies have suggested that neurotrophic factors (NTFs) are involved in the status epilepticus development. This indicates their essential role in mediating acquired epileptic conditions. Therefore, modulating the expression of NTFs may inhibit seizure-induced cell loss in the epileptic lesions. In this study, we examined the anti-apoptotic, anti-necrotic and regulatory effects of lovastatin on the expression of NTFs in the pilocarpine rat model of temporal lobe epilepsy (TLE). A total of 32 male Wistar rats were divided into 4 groups (n = 8 per group): i) normal; ii) non-treated epileptic group [intraperitoneal (i.p.) administration of 350-400mg/kg pilocarpine]; iii) treatment group (pilocarpine-treated rats treated followed by 5mg/kg lovastatin); and iv) vehicle epileptic rats treated with Carboxymethyl cellulose (CMC). Animals that had a behavioral score of 4-5 according to the Racine scale were selected for study participation. Three days after the first seizure, pilocarpine-treated rats received i.p. injections of lovastatin for 14days. The rats were killed and prepared for histopathologic analysis as well as real-time RT-PCR 17days after the first seizure. The results of this study showed increased mRNA expression of glial cell line-derived neurotrophic factor (GDNF) and Ciliary neurotrophic factor (CNTF) and decreased expressions of Brain-derived neurotrophic factor (BDNF), Neurotrophin-3 (NT-3), and Neurotrophin-4 (NT-4) mRNA in the epileptic rats treated with lovastatin. Histological analysis of neurodegeneration in the brain sections showed that the number of hippocampal apoptotic and necrotic cells significantly decreased in the treatment groups. Furthermore, numerical density of neurons per area was significantly higher in the treated groups compared with the untreated groups. Collectively, the results of this study have shown that lovastatin could attenuate seizure-induced expression of neurotrophic factors and consequently reduce hippocampal cell death in the pilocarpine rat model of TLE.

Comparison of the capability of GDNF, BDNF, or both, to protect nigrostriatal neurons in a rat model of Parkinson's disease

Modulation of neurogenesis via neurotrophic factors in acupuncture treatments for neurological diseases

Continued Administration of Ciliary Neurotrophic Factor Protects Mice from Inflammatory Pathology in Experimental Autoimmune Encephalomyelitis

Fasudil enhances the phagocytosis of myelin debris and the expression of neurotrophic factors in cuprizone-induced demyelinating mice

Background: Recent studies have shown that the cerebellum directly interacts with the ventral tegmental area, a critical component of the reward system. Objectives: This study aimed to explore potential changes in the expression of neurotrophic factors and various types of voltage-gated calcium channels in the cerebellum following morphine dependence and withdrawal. Methods: This study involved three groups of male Wistar rats. For ten consecutive days, the second and third groups were administered morphine (10 mg/kg), while the first group received saline (1 mL/kg). Analgesic responses were assessed using a hotplate test on days 1 and 10 of the repeated injections and after a 30-day withdrawal period. Rats were sacrificed on day 10 of the injections or on day 30 of withdrawal, and their cerebellum were dissected for analysis. Gene expression was analyzed using the real-time PCR method. Results: The study found that morphine analgesia decreased during the 10 days of repeated injections but partially recovered after a 30-day withdrawal period. Morphine dependence led to a decrease in the expression of Cav1.1, which increased after withdrawal. The expression of Cav1.2 in the cerebellum consistently rose after both morphine dependence and withdrawal. There were no significant changes in the expression of Cav2.2 due to morphine dependence or withdrawal. An increase in the expression of Cav3.1 was observed following morphine dependence, which decreased after withdrawal. There were significant reductions in the mRNA levels of neurotrophic factors (BDNF, GDNF, and NGF) and their receptors (TrkB, GFRA1, and NGFR) following morphine dependence. However, the expression of almost all neurotrophic factors increased after morphine withdrawal. Conclusions: The findings suggest that changes in neurotrophic factors, their receptors, and specific types of voltage-gated calcium channels in the cerebellum play roles in the processes of morphine dependency and withdrawal.