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BACKGROUND: Buqi Huoxue Compounds have significant clinical efficacy in treating ischemic stroke with Qi deficiency and phlegm stasis; however, the exact mechanism of action is not clear. OBJECTIVE: To observe the effect of Buqi Huoxue Compounds on the expression of vascular endothelial growth factor, basic fibroblast growth factor, brain-derived neurotrophic factor and autophagy related protein Beclin1 and p62 in a rat model of cerebral ischemia/reperfusion. METHODS: Forty male Sprague-Dawley rats were randomly divided into sham operation group, model group, Buqi Huoxue Compounds group and autophagy inhibitor group, with 10 rats in each group. In the latter three groups, a rat model of cerebral ischemia/reperfusion injury was established. The Buqi Huoxue Compounds group was intragastrically given Buqi Huoxue Compounds (6.49 g/kg, administered three times a day) 2 hours after reperfusion; the autophagy inhibitor group was intragastrically given Buqi Huoxue Compounds (6.49 g/kg, administered three times a day) 2 hours after reperfusion and intraperitoneally given 3-methyladenine 2 hours before gavage and at days 1-3 of gavage. The sham operation group and model group were given equal amounts of saline by gavage for 7 consecutive days. Neurological function, cerebral infarct volume, brain tissue morphology and expression of vascular endothelial growth factor, basic fibroblast growth factor, brain-derived neurotrophic factor and autophagy-related proteins Beclin1 and p62 in the ischemic cortical region of rats were detected at 24 hours after the final administration. RESULTS AND CONCLUSION: Zea-Longa scoring results showed that the neurological function of rats was severely damaged after modeling and neurological deficit of rats in the Buqi Huoxue Compounds group was less than that in the model group and the autophagy inhibitor group (P < 0.05). TTC staining showed that cerebral infarct foci were observed in the model group, Buqi Huoxue Compounds group, and autophagy inhibitor group, and the cerebral infarct volume in the Buqi Huoxue Compounds group was lower than that in the model group and the autophagy inhibitor group (P < 0.05). The results of hematoxylineosin staining in ischemic brain tissues showed that there were large gaps between nerve cells in the model group and cell arrangement was not neat, and cytoplasmic agglutination and pyknosis were observed. Immunohistochemical staining results showed that vascular endothelial growth factor was mostly expressed in neuronal cells, glial cells and capillary endothelium; basic fibroblast growth factor and brain-derived neurotrophic factor were mostly expressed in neuronal cells and glial cells; and there was no significant difference in the expression of vascular endothelial growth factor, basic fibroblast growth factor, and brain-derived neurotrophic factor among the four groups (P > 0.05). The results of western blot assay showed that compared with the sham operation group, Beclin1 protein expression was decreased (P < 0.05) and p62 protein expression was elevated (P < 0.05) in the model group; compared with the model group, Beclin1 protein expression was increased (P < 0.05) and p62 protein expression was reduced (P < 0.05) in the Buqi Huoxue Compounds group; compared with the Buqi Huoxue Compounds group, Beclin1 protein expression was decreased (P < 0.05) and p62 protein expression was elevated (P < 0.05) in the autophagy inhibitor group. To conclude, Buqi Huoxue Compounds attenuate cerebral ischemia-reperfusion injury in rats by promoting autophagy. [ABSTRACT FROM AUTHOR]

Alzheimer's disease (AD) is the most common cause of dementia in adulthood, followed by cognitive and behavioral deficits. Today, mesenchymal stem cell (MSC)-based therapy is a suitable therapeutic option to improve regenerative medicine approaches against neurodegenerative disorders, including AD. This study aimed to investigate the effects of human Wharton's jelly-derived MSCs (WJ-MSCs) on AD-like rat models (rats treated with amyloid beta 1-42 (Aβ1-42)) by evaluating the expression of neurotrophic factors such as brain-derived neurotrophic factor (BDNF) and nerve growth factor (NGF), as well as the expression of apoptotic factors such as B-cell lymphoma 2 (BCL2, an anti-apoptotic factor to inhibit apoptosis) and BCL2-associated X protein (BAX, a pro-apoptotic factor to regulate apoptosis). After treatment of AD rat models with WJ-MSCs, behavioral tests (i.e., passive avoidance and Morris water maze) showed cognitive improvements, and amelioration of cells in the CA1 area of the hippocampus was detected by cresyl violet staining. Additionally, real-time polymerase chain reaction (RT-PCR) of the hippocampus indicated an increase in the expression level of the BDNF, NGF, and BCL2 genes and a decrease in the expression level of the BAX gene. Overall, the WJ-MSCs improved the cognitive function in AD rat models by increasing the neurotrophic and anti-apoptotic factors and decreasing the pro-apoptotic factor. This graphical abstract depicts the process of isolating mesenchymal stem cells (MSCs) from human Wharton's jelly (WJ) and their subsequent use in an Alzheimer's disease (AD) rat model. The left side of the image illustrates the steps involved in isolating MSCs from WJ. The right side of the image shows how AD rat models are generated under stereotaxic injection of Aβ. In the middle, intranasally administration of MSCs is shown and then how their effects are evaluated using behavioral tests, nissl staining, and RT-qPCR. [ABSTRACT FROM AUTHOR]

Stroke causes irreversible damage, particularly to the hippocampus. Evidence suggests that exercise training may mitigate adverse structural and functional consequences of an ischemic lesion in the brain. The purpose of this study was to investigate the effects of preconditioning exercise on expression of neurotrophic factor genes and proteins in hippocampalCA1 region and their relationship with sensorimotor recovery following global ischemia/reperfusion (Is/Re) injury in a rat model of stroke. Male Wistar rats were randomly assigned to Exercise+Ischemia/Reperfusion (Ex+Is/Re),Control+Ischemia/Reperfusion (Co+Is/Re), and Sham treatments. Rats in the exercise groups ran on a treadmill for 45 min/d for five days/week for 8 consecutive weeks prior to Is/Re lesion.Ischemia was induced by common carotid artery occlusion (CCAO). The ladder rung walking task was used to assess functional impairments and recovery following ischemic lesion.Tissue from hippocampal area CA1 was inspected for ischemia-induced cell loss and gene and protein expression linked to neurotrophins NT-3, NT-4, and their receptorsTrkB and TrkC. CCAO caused hippocampal cell death in CA1 and resulted in significant sensori motor impairments in the ladder rung walking task. In contrast, pre-ischemic exercise considerably reduced cell death and supported sensorimotor recovery following CCAO.In addition, NT-3, NT-4,TrkB and TrkC gene expression and their protein levels were significantly increased inthe Ex+Is/Re group compared to Co+Is/Re (p < 0.05). The findings showed that pre-ischemic exercise can exert neuroprotective effects via NT-3 and NT-4 pathways against ischemia in hippocampal CA1 neurons and promote post-injury sensorimotor recovery. • The preconditioning exercise reduce structural damage after cerebral ischemia. • The preconditioning exercise restrict neuronal apoptosis following cerebral ischemia. • The preconditioning exercise ameliorate sensorimotor function loss through neurotropic actions of NT-3 and NT-4, and their receptors after cerebral ischemia. [ABSTRACT FROM AUTHOR]

Objective(s): Celastrol is an herbal compound with neuroprotective properties. Our research aimed to assess the neuroprotective properties of celastrol on sciatic nerve transection in rats. Materials and Methods: The rats' left sciatic nerve was cut and sutured directly. The animals were then given 1 or 2 mg/kg celastrol intraperitoneally for two weeks. The sensory and locomotor behaviors of the animals were then evaluated for 16 weeks. Immunohistochemistry, ELISA, and real-time PCR were also utilized to evaluate macrophage polarization, cytokine secretion, and neurotrophin expression in injured nerves. Results: Results showed that both doses of celastrol significantly accelerated nerve regeneration and improved sensorimotor functional recovery when compared with controls. Nevertheless, administration of 2 mg/kg of celastrol significantly outperforms treatment with a dose of 1 mg/kg. Celastrol treatment-induced M2 polarization in macrophages decreased proinflammatory cytokines at the injury site. It also increased the expression of BDNF mRNA. Conclusion: These findings suggest that a two-week treatment with celastrol had neuroprotective effects in a rat sciatic nerve transection model, most likely by inducing macrophage M2 polarization and anti-inflammatory effects. [ABSTRACT FROM AUTHOR]

This study aims to investigate the mechanism by which Histidine triad nucleotide-binding protein 1 (HINT1) promotes hippocampal neuronal apoptosis, triggering schizophrenia (SZ)- like behavior in rats. By establishing a rat SZ-like model, we assessed learning, memory, emotional response, and cognitive function through the Morris Water Maze, auditory startle response, and open field tests. HINT1 expression in the hippocampus was analyzed via RT-PCR and Western blot. We also created a HINT1 overexpression model in hippocampal neuronal cells to analyze its effects on cell proliferation and apoptosis. This analysis was conducted using the CCK-8 assay and flow cytometry, along with the quantification of apoptosis-related proteins and neurotrophic factors. Our findings indicated that the SZ-like model rats exhibited diminished learning and memory abilities, altered emotional reactions, and impaired cognitive functions, alongside a notable increase in HINT1 mRNA and protein levels. HINT1 overexpression was observed to inhibit hippocampal neuronal cell proliferation and promote apoptosis, with an increase in the expression of pro-apoptotic proteins and a decrease in neurotrophic factors. These results suggest HINT1's role in the onset and development of SZ-like behavior through its upregulation and induction of apoptosis in hippocampal neuronal cells, underlining its potential as a therapeutic target. • HINT1 promotes hippocampal neuronal apoptosis and triggers SZ-like behavior in rats. • Increased pro-apoptotic proteins and decreased neurotrophic factors with HINT1 upregulation. • HINT1 may be a therapeutic target for SZ-like behavior. [ABSTRACT FROM AUTHOR]

A low-molecular-weight nerve growth factor mimetic, compound GK-2 (bis-(N-monosuccinyl- L-glutamyl-L-lysine)hexamethylenediamide) that previously demonstrated antidiabetic activity in rats with streptozotocin-induced type 2 diabetes mellitus was studied on the model of diabetic neuropathy. It was found that in 8 weeks after diabetes mellitus development, untreated diabetic rats demonstrated impaired tactile sensitivity in von Frey test, while GK-2 therapy (7.5 mg/kg orally for 28 days) restored this parameter. The decrease of tactile sensitivity in diabetic neuropathy closely correlated with the severity of hyperglycemia (r=0.76). Our findings are consistent with the concept on the role of glucose toxicity and nerve growth factor deficiency in the pathogenesis of diabetic neuropathy and attest to feasibility of further studies of nerve growth factor mimetic GK-2 as a potential treatment for diabetes and diabetic neuropathy. [ABSTRACT FROM AUTHOR]

Background/aim: This study was conducted to elucidate the effects of lutein/zeaxanthin isomers (L/Zi) on lipid metabolism, oxidative stress, NF-κB/Nrf2 pathways, and synaptic plasticity proteins in trained rats. Materials and methods: Wistar rats were distributed into four groups: 1) control, 2) L/Zi: rats received L/Zi at the dose of 100 mg/kg by oral gavage, 3) exercise, 4) exercise+L/Zi: rats exercised and received L/Zi (100 mg/kg) by oral gavage. The duration of the study was eight weeks. Results: Exercise combined with L/Zi reduced lipid peroxidation and improved antioxidant enzyme activities of muscle and cerebral cortex in rats (p < 0.001). In the Exercise + L/Zi group, muscle and cerebral cortex Nrf2 and HO-1 levels increased, while NF-κB levels decreased (p <0.001). Also, L/Zi improved BDNF, synapsin I, SYP, and GAP-43 levels of the cerebral cortex of trained rats (p < 0.001). The highest levels of BDNF, synapsin SYP, and GAP-43 in the cerebral cortex were determined in the Exercise+L/Zi group. Conclusion: These results suggested that exercise combined with L/Zi supplementation might be effective to reduce neurodegeneration via improving neurotrophic factors and synaptic proteins, and oxidative capacity in the cerebral cortex. [ABSTRACT FROM AUTHOR]

Introduction: This study evaluates the effects of 8 weeks of resistance exercises on the expression of neurotrophins and Trk receptors in Alzheimer model male Wistar rats. Methods: For this purpose, 32 mature male Wistar rats with a mean weight of 230-280 g were chosen and divided into Alzheimer and Sham groups. The rats in the sham group received normal saline, while the ones in the Alzheimer group received streptomycin via intraventricular injection. These rats were then divided into the following four subgroups: 1) resting sham, 2) exercising sham, 3) resting Alzheimer, and 4) exercising Alzheimer. The two exercising rat subgroups exercised three times a week for 8 weeks. A weight was attached to their tails, and they had to carry it on a 26-step ladder in each cycle. Resting groups were handled every day to minimize the effects of stress. At the end of the eighth week and 24 hours after the last exercise session (to avoid the effects of the last exercise session), the rats were put under deep anesthesia and beheaded. Hippocampus tissues were precisely extracted, and samples were sent to the laboratory for molecular and cellular tests. To investigate gene expression, quantitative RTPCR was used. Results: The tests for comparing the mean values of BDNF, NT3, NGF, TrkA, and TrkB in two rat groups showed that with error levels of less than 5%, there is a significant difference in the amounts of BDNF, NT3, NGF, TrkA, and TrkB between exercising rats and resting ones. These amounts were much higher in the exercising Alzheimer rats group. Conclusion: Eight weeks of resistance exercises increased the expression of BDNF, NT3, and NGF genes and TrkA and TrkB receptors in Alzheimer model Wistar rats. [ABSTRACT FROM AUTHOR]

Experiments on Wistar rats using a model of type 2 diabetes induced by streptozotocin (STZ) at a dose of 40 mg/kg addressed the effects of the proline-containing dipeptide noopept (the ethyl ester of N-phenylacetyl-L-prolylglycine) on nerve growth factor (NGF) and brain-derived neurotrophic factor (BDNF) contents. Untreated diabetic rats showed 59% and 33% decreases in NGF content in the pancreas and liver, respectively, while BDNF contents decreased by 30% and 40% in the pancreas and liver, respectively, as compared with controls. Noopept given to diabetic rats at a dose of 0.5 mg/kg for 14 days increased the NGF content in the pancreas by 48% compared with untreated diabetic rats and produced a 19% increase in the NGF content in the liver as compared with the control group. Noopept given to diabetic rats normalized BDNF content in the pancreas but had no effect on the decreased level in the liver. The data obtained here identify one of the mechanisms of the antidiabetic action of noopept described in our previous reports. [ABSTRACT FROM AUTHOR]

In the critical period of neurodevelopment (gestation and lactation), maternal consumption of essential fatty acids (FAs) can alter the offspring cognitive function permanently causing damage. Lipids can regulate neurotrophin and compose brain tissue. However, the effects of maternal consumption of a mixture of conjugated linoleic acid (CLA) on an offspring nervous system are not completely clear. We aimed to investigate the impacts of different CLA concentrations mixed into the maternal diet during early life on neonatal reflex maturation and cognitive functions of the offspring. Three groups were formed: control (CG): receiving a standard diet; CLA1: receiving a diet containing 1% of CLA, and CLA3: receiving a diet containing 3% of CLA, offered during gestation and lactation. After birth, the reflex responses of the offspring were observed from the 1st to the 21st day. After weaning, the animals' anxiety and memory were assessed using open field (OF) and novel object recognition tests. Fatty acids in the breast milk and the offspring's brain were also quantified. The data were analyzed using one-way ANOVA and the Kruskal–Wallis test. CLA1 presented accelerated palmar grasp disappearance versus CLA3 and negative-geotaxis versus CG; and the CLA3 presented increases for most reflexes (cliff-avoidance, vibrissa-placing, negative-geotaxis, and auditory-startle response), and decrease in reflexes palmar grasp and free-fall righting versus CG (p < 0.05). CLA3 group explored less of the OF in the second exposure. CLA1 and CLA3 presented an increased exploration ratio for new objects, which indicates memory improvement. The milk tested from CLA3 demonstrated an increase in polyunsaturated fatty acids (PUFAs), and a decrease in monounsaturated fatty acids. The amount of CLA in milk was greater in CLA1 and CLA3 and in the brain offspring both presented moderated amounts of CLA. Maternal treatment with the CLA mixture induced anticipated reflex maturation and improved memory in the offspring. Even though CLA was detected in the brains in only trace amounts, offspring's brain PUFA and SFA levels were increased. Further studies aimed to delineate the effect of maternal CLA supplementation on offspring's brain lipid metabolism and long-term neurologic outcome are needed to confirm these findings. [ABSTRACT FROM AUTHOR]

Highlights • CUMS-induced depressive behaviors via COTR-microglia M1/M2-astrocytes/BDNF pathway. • CUMS elevated IL-17 and TGF-β1 concentrations in the hippocampus. • Minocycline improved depressive behaviors via anti-inflammation. Abstract Activated microglia-induced neuroinflammation can stimulate the hypothalamic- pituitary-adrenal (HPA) axis to release glucocorticoids and suppress astrocyte functions, such as reducing neurotrophin production, which occur in depression. However, the balance between M1 (pro-inflammation) and M2 (anti-inflammation) microglial phenotypes and the interaction between these two glial cells are unclear in the depression. Hence, the chronic unpredictable mild stress (CUMS)-induced depression model was chosen to study depression- and anxiety-like behaviors, the concentration of corticosterone and relevant hippocampal cytokines, mRNA and protein expressions of microglial and astrocyte markers. To demonstrate the role of M1 phenotype activation in depression, the effect of microglial inhibitor minocycline on these aspects was also evaluated. Six weeks after CUMS exposure, behaviors were tested. Compared to the control group, CUMS increased serum corticosterone concentration and depression-like behaviors, like anhedonia, helplessness and anxiety. Moreover, CUMS increased microglia M1 marker CD11b expression and tumor necrosis factor (TNF)-α, interferon (INF)-γ, interleukin (IL)-1β and IL-17 concentrations, but decreased the concentration of M2 cytokines, IL-4, IL-10 and IL-13. Meanwhile, CUMS inhibited the expressions of astrocyte marker glial fibrillary acidic protein (GFAP), brain-derived neurotrophic factor (BDNF) and TrKB. Minocycline (40 mg/kg, 45 days) treatment significantly attenuated CUMS-induced behavioral abnormalities, which were associated with the suppressed M1 response, restored GFAP, BDNF and its receptor expression. In conclusion, CUMS-induced depression- and anxiety-like behavior may result from an imbalance between M1 and M2 and suppressed astrocyte function. Minocycline treatment reversed M1 response, which was associated with behavioral normalization. [ABSTRACT FROM AUTHOR]

Objective: Neurotrophin-3 (NT3) plays a key role in the development and function of locomotor circuits including descending serotonergic and corticospinal tract axons and afferents from muscle and skin. We have previously shown that gene therapy delivery of human NT3 into affected forelimb muscles improves sensorimotor recovery after stroke in adult and elderly rats. Here, to move toward the clinic, we tested the hypothesis that intramuscular infusion of NT3 protein could improve sensorimotor recovery after stroke.Methods: Rats received unilateral ischemic stroke in sensorimotor cortex. To simulate a clinically feasible time to treatment, 24 hours later rats were randomized to receive NT3 or vehicle by infusion into affected triceps brachii for 4 weeks using implanted catheters and minipumps.Results: Radiolabeled NT3 crossed from the bloodstream into the brain and spinal cord in rodents with or without strokes. NT3 increased the accuracy of forelimb placement during walking on a horizontal ladder and increased use of the affected arm for lateral support during rearing. NT3 also reversed sensory impairment of the affected wrist. Functional magnetic resonance imaging during stimulation of the affected wrist showed spontaneous recovery of peri-infarct blood oxygenation level-dependent signal that NT3 did not further enhance. Rather, NT3 induced neuroplasticity of the spared corticospinal and serotonergic pathways.Interpretation: Our results show that delayed, peripheral infusion of NT3 can improve sensorimotor function after ischemic stroke. Phase I and II clinical trials of NT3 (for constipation and neuropathy) have shown that peripheral high doses are safe and well tolerated, which paves the way for NT3 as a therapy for stroke. ANN NEUROL 2019;85:32-46. [ABSTRACT FROM AUTHOR]

The mechanisms underlying the pronociceptive effect of paradoxical sleep deprivation (PSD) are not fully established. The modulation of BDNF signaling-mediated descending facilitation from the rostral ventromedial medulla (RVM) of brain stem has been demonstrated in persistent pain models of inflammatory pain, but not in incisional pain model. Recent study has shown that PSD increases the expression of brain-derived neurotrophic factor (BDNF) in the brainstem structure. Therefore, in the current study, we asked whether the BDNF signaling-mediated descending facilitation was involved in the PSD-induced pronociceptive effect on incisional pain and delay the recovery period of postoperative pain in rats. Our results found that a preoperative 24 h PSD significantly aggravated the pain hypersensitivity after incision and prolonged the duration of postoperative pain. The lesions of ipsilateral dorsolateral funiculus partly reversed the PSD-induced pronociceptive effect on incisional pain. Interestingly, the 24 h PSD, but not incision significantly enhanced the levels of BDNF protein expression in the RVM areas of rats. Furthermore, at 1 day or 4 days after incision, intra-RVM microinjection of a BDNF antibody partly reversed the PSD-induced pronociceptive effects in incisional rats, while it did not change the cumulative pain scores and paw withdrawal thresholds in rats receiving only plantar incision. These findings suggest that the preoperative PSD may aggravate and prolong the incision-induced pain hypersensitivity via BDNF signaling-mediated descending facilitation. [ABSTRACT FROM AUTHOR]

Purpose: The aim of the study was to evaluate the effects of prenatal hypothyroidism on neonatal rats by the way of activity-dependent neuroprotective factor (ADNF) expression. Methods: Twenty-one Wistar albino neonatal rats were divided into two subgroups; a control group and neonatal rats with experimental maternal hypothyroidism. Hypothyroidism was induced by using propylthiouracil (PTU). Neonatal rats obtained PTU from breast milk continuously for 1 week after birth. The rats from the control group were fed only normal feed and water. After birth, body weight and blood thyroid hormone levels were tested. Glial fibrillary acidic protein (GFAP), Slug, Numb, Notch-1 and ADNF antibodies were used for immunohistochemical analysis. Real-time polymerase chain reaction (RT-PCR) and Western blotting analyses were used to evaluate ADNF gene expression levels from 1-week-old rat's brain. Results: There was no difference between the two groups for birth weights. The thyroxine (T4) level from the experimental group was <0.4 ng/mL, and it was 0.8 ng/mL for the control group. It was shown that, the results from the experimental group samples had significantly lower ADNF mRNA levels than control group (p < 0.05). The increase from GFAP and Numb expression and decrease from Slug expression were shown in the experimental group. Local differences were identified for ADNF and a decrease was shown in both sides of brain. There was no difference for Notch-1 expression for both groups. Conclusion: In this study, decreasing ADNF expression might contribute to developing neurological problems in congenital hypothyroidism. [ABSTRACT FROM AUTHOR]

We studied the effects of light and non-specific sound stimulation of domestic chick embryos on their filial preference as well as on the expression of two transcriptional factors c-Fos and Egr-1 and neurotrophin BDNF in the embryo brain. Prenatal light stimulation increased preference of the "natural" object, thus producing a priming effect. In the brain of E19 embryos, c-Fos and Egr-1 were expressed at a high basal level and neither light nor sound stimulation affected the number of cells expressing these factors. BDNF mRNA was also present in a number of brain areas of non-stimulated embryos, but light and sound stimulation enhanced the expression of BDNF mRNA in brain structures associated with filial imprinting. These findings suggest that BDNF is probably involved in the effects of prenatal priming on the development of species-specific behavior. [ABSTRACT FROM AUTHOR]

Abstract Faulty bony repair causes dysrepair of injured growth plate cartilage and bone growth defects in children; however, the underlying mechanisms are unclear. Recently, we observed the prominent induction of neurotrophin‑3 (NT-3) and its important roles as an osteogenic and angiogenic factor promoting the bony repair. The current study investigated its roles in regulating injury site remodelling. In a rat tibial growth plate drill-hole injury repair model, NT-3 was expressed prominently in osteoblasts at the injury site. Recombinant NT-3 (rhNT-3) systemic treatment enhanced, but NT-3 immunoneutralization attenuated, expression of cartilage-removal proteases (MMP-9 and MMP-13), presence of bone-resorbing osteoclasts and expression of osteoclast protease cathepsin K, and remodelling at the injury site. NT-3 was also highly induced in cultured mineralizing rat bone marrow stromal cells, and the conditioned medium augmented osteoclast formation and resorptive activity, an ability that was blocked by presence of anti-NT-3 antibody. Moreover, NT-3 and receptor TrkC were induced during osteoclastogenesis, and rhNT-3 treatment activated TrkC downstream kinase Erk1/2 in differentiating osteoclasts although rhNT-3 alone did not affect activation of osteoclastogenic transcription factors NF-κB or NFAT in RAW 264.7 osteoclast precursor cells. Furthermore, rhNT-3 treatment increased, but NT-3 neutralization reduced, expression of osteoclastogenic cytokines (RANKL, TNF-α, and IL-1) in mineralizing osteoblasts and in growth plate injury site, and rhNT-3 augmented the induction of these cytokines caused by RANKL treatment in RAW 264.7 cells. Thus, injury site osteoblast-derived NT-3 is important in promoting growth plate injury site remodelling, as it induces cartilage proteases for cartilage removal and augments osteoclastogenesis and resorption both directly (involving activing Erk1/2 and substantiating RANKL-induced increased expression of osteoclastogenic signals in differentiating osteoclasts) and indirectly (inducing osteoclastogenic signals in osteoblasts). Graphical abstract Unlabelled Image Highlights • Injury site osteoblast-derived NT-3 has both direct and indirect roles in promoting growth plate injury site remodeling. • NT-3 enhances expression of MMP-9 and MMP-13 and osteoclast recruitment and function at the growth plate injury site. • NT-3 was induced in mineralizing BMSCs, and the conditioned medium augmented osteoclastogenesis and resorptive activity. • NT-3 can induce osteoclastogenic cytokines and RANKL in osteoblasts. • NT-3 and TrkC were induced, and rhNT-3 treatment activated TrkC downstream kinase Erk1/2 in differentiating osteoclasts. [ABSTRACT FROM AUTHOR]

Abstract: Background: Diabetes can result in pathological changes to enteric nervous system. Our aim was to test the dynamic changes of enteric neurons and identify the role of enteric glial cells (EGCs) in regulating enteric neuron expression in diabetic rats. Methods: A single injection of streptozotocin (STZ) was used to establish diabetic rats. Animals were randomly distributed into diabetic 1‐, 4‐, 8‐, and 16‐week groups, as well as age‐matched control groups. The PGP9.5‐ and glial fibrillary acidic protein (GFAP)‐immunopositive cells were quantified by immunohistochemistry. The protein levels of PGP9.5, ChAT, nNOS, S‐100β, and c‐fos were determined by western blotting. The levels of nerve growth factor (NGF), neurotrophin 3 (NT‐3), and glial cell‐derived neurotrophic factor (GDNF) were tested by ELISA. Key Results: An increase in blood glucose and a decrease in body weight were observed following STZ administration. PGP9.5 expression did not change in the diabetic ileum. However, ChAT increased after 16 weeks, and nNOS decreased after 8 and 16 weeks in the ilea of diabetic rats. The absence of degeneration of enteric neurons during the acute stage of the disease could be the consequence of the up‐regulation of GFAP, S‐100β, and c‐fos. Moreover, the content of NGF, NT‐3, and GDNF in the ileum increased by varying degrees after 1 and/or 4 weeks of diabetes. Using 2 co‐culture models of EGCs and SH‐SY5Y cells in a high glucose condition, the supportive role of EGCs was further confirmed. Conclusions & Inferences: Enteric glial cell activation can protect enteric neurons from damage due to diabetes in the acute stage of the disease, in part via the promotion of neurotrophin release. [ABSTRACT FROM AUTHOR]

Background: Previous studies found that visceral sensitivity is increased in bowel obstruction (BO). We hypothesized that mechanical stress‐induced expression of BDNF in smooth muscle cells (SMC) of the distended bowel plays a critical role in visceral hypersensitivity in BO by altering voltage‐gated K+ channel (Kv) activity in sensory neurons. Methods: Partial colon obstruction was maintained in rats for 7 days. Colon‐projecting neurons in the dorsal root ganglia (DRG, T13 to L2) were isolated for electrophysiological and gene expression studies. Key Results: Compared to controls, membrane excitability of colon‐projecting DRG neurons was markedly enhanced in BO. The densities of total Kv and transient A‐type (IA) K+ currents, but not sustained delayed IK current, were significantly reduced in the neurons in BO. The mRNA expression of IA subtype Kv1.4 in colon neurons was down‐regulated in BO. Expression of BDNF mRNA and protein was dramatically increased in colonic smooth muscle of the distended segment, but not in the non‐distended aboral segment. Mechanical stretch of colon SMC in vitro increased BDNF expression. Treatment with anti‐BDNF antibody restored total Kv and IA currents of neurons from BO rats. Administration of Trk B inhibitor ANA‐12 blocked BO‐associated changes of neuronal excitability, Kv activity and gene expression in obstruction. Conclusions and Inferences: Mechanical stress‐induced expression of BDNF in colon SMC plays a critical role in visceral hypersensitivity in BO by suppressing A‐type K+ currents and gene expression in sensory nerve. These findings help to identify therapeutic targets for distention‐associated abdominal pain in the gut. [ABSTRACT FROM AUTHOR]

Nerve growth factor, the prototype of a family of neurotrophins, elicits differentiation and survival of peripheral and central neuronal cells. Although its neural mechanisms have been studied extensively, relatively little is known about the transcriptional regulation governing its effects. We have previously observed that in primary cultures of rat hippocampal neurons treatment with nerve growth factor for 72 hr increases neurite outgrowth and cell survival. To obtain a comprehensive view of the underlying transcriptional program, we performed whole‐genome expression analysis by microarray technology. We identified 541 differentially expressed genes and characterized dysregulated pathways related to innate immunity: the complement system and neuro‐inflammatory signaling. The exploitation of such genes and pathways may help interfering with the intracellular mechanisms involved in neuronal survival and guide novel therapeutic strategies for neurodegenerative diseases. [ABSTRACT FROM AUTHOR]

Objective: To evaluate the effects of Hypericum perforatum (hypericum) on cognitive behavior and neurotrophic factor levels in the brain of male and female rats. Methods: Male and female Wistar rats were treated with hypericum or water during 28 days by gavage. The animals were then subjected to the open-field test, novel object recognition and stepdown inhibitory avoidance test. Nerve growth factor (NGF), brain-derived neurotrophic factor (BDNF), and glial cell-line derived neurotrophic factor (GDNF) levels were evaluated in the hippocampus and frontal cortex. Results: Hypericum impaired the acquisition of short- and long-term aversive memory in male rats, evaluated in the inhibitory avoidance test. Female rats had no immediate memory acquisition and decreased short-term memory acquisition in the inhibitory avoidance test. Hypericum also decreased the recognition index of male rats in the object recognition test. Female rats did not recognize the new object in either the short-term or the long-term memory tasks. Hypericum decreased BDNF in the hippocampus of male and female rats. Hypericum also decreased NGF in the hippocampus of female rats. Conclusions: The long-term administration of hypericum appears to cause significant cognitive impairment in rats, possibly through a reduction in the levels of neurotrophic factors. This effect was more expressive in females than in males. [ABSTRACT FROM AUTHOR]

Neurotrophin dysregulation has been implicated in a large number of neurodegenerative and neuropsychiatric diseases. Unfortunately, neurotrophins cannot cross the blood brain barrier thus, novel means of up regulating their expression are greatly needed. It has been demonstrated previously that neurotrophins are up regulated in response to increases in brain activity. Therefore, molecules that act as cognitive enhancers may provide a clinical means of up regulating neurotrophin expression. Ampakines are a class of molecules that act as positive allosteric modulators of AMPA-type glutamate receptors. Currently, they are being developed to prevent opioid-induced respiratory depression without sacrificing the analgesic properties of the opioids. In addition, these molecules increase neuronal activity and have been shown to restore age-related deficits in LTP in aged rats. In the current study, we examined whether two different ampakines could increase levels of BDNF and NGF at doses that are active in behavioral measures of cognition. Results demonstrate that ampakines CX516 and CX691 induce differential increases in neurotrophins across several brain regions. Notable increases in NGF were observed in the dentate gyrus and piriform cortex while notable BDNF increases were observed in basolateral and lateral nuclei of the amygdala. Taken together, our data demonstrates that chronic administration of clinically relevant doses of ampakines have the ability to elevate neurotrophin expression in different brain regions, and may have therapeutic benefit in multiple neurodegenerative and/or neuropsychiatric disorders. [ABSTRACT FROM AUTHOR]

Objectives: Traumatic brain injury (TBI) is a leading cause of death and disability worldwide. Neuritin is a neurotrophic factor that regulates neural growth and development. However, the role of neuritin in alleviating TBI has not been investigated. Methods: In this study, Sprague Dawley rats (n = 144) weighing 300 ± 50 g were categorized into control, sham, TBI and TBI + neuritin groups. The neurological scores and the ultrastructure of cortical neurons, apoptotic cells and caspase-3 were measured by using Garcia scoring system, transmission electron microscopy, terminal deoxynucleotidyl transferase-mediated dUTP nick-end labeling, Western blot analysis and real-time RT-PCR at various time points post-TBI. Conclusions: Our findings indicated that neuritin plays a protective role in TBI by improving neurological scores, repairing injured neurons and protecting the cortical neurons against apoptosis through inhibition of caspase-3 expression. Further investigation of the molecular mechanisms underlying caspase-3 inhibition by neuritin will provide a research avenue for potential TBI therapeutics. [ABSTRACT FROM AUTHOR]

A deficiency of maternal folic acid (FA) can compromise the function and development of the brain, and may produce a susceptibility to diseases such as schizophrenia (SZ) in the later life of offspring. The aim of this study was to evaluate the effects of both FA deficient and FA supplemented diets during gestation and lactation on behavioural parameters, the markers of oxidative stress and neurotrophic factors in adult offspring which had been subjected to an animal model of SZ. Female mother rats (Dam's) were separated into experimental maternal groups, which began receiving a special diet (food) consisting of the AIN-93 diet, a control diet, or an FA deficient diet during the periods of pregnancy and lactation. Dam's receiving the control diet were further subdivided into four groups: one group received only control diet, while three groups to receive supplementation with FA at different doses (5, 10 and 50 mg/kg). Adult offspring bred from the Dam's were divided into ten groups for induction of the animal model of SZ through the administration of ketamine (Ket) (25 mg/kg). After the last administration of the drug, the animals were subjected to the behavioural tests and were then euthanized. The frontal cortex (FC) and hippocampus (Hip) were then dissected for later biochemical analysis. Our data demonstrates that Ket induced the model of SZ by altering the behavioural parameters (e.g. hyperlocomotion, social impairment, deficits in the sensory-motor profile and memory damage in the adult animals); and also caused changes in the parameters of oxidative stress (lipid hydroperoxide – LPO; 8-isoprostane – 8-ISO; 4-hydroxynonenal – 4-HNE; protein carbonyl content; superoxide dismutase – SOD and catalase – CAT) as well as in the levels of neurotrophic factors (brain-derived neurotrophic factor – BDNF and nerve growth factor – NGF) particularly within the FC of adult offspring. A deficiency in maternal FA, alone or in combination with ket, was able to induce hyperlocomotion and social impairment in the offspring with increased levels of lipid and protein damage (LPO, 8-ISO, 4-HNE, carbonylation of protein) within the FC, increased activity of antioxidant enzymes (SOD and CAT) in both of the brain structures studied, and also reduced the levels of neurotrophins (BDNF and NGF), particularly within the Hip of the adult offspring. Supplementation of FA (5, 10 and 50 mg/kg) to the Dam's was mostly able to prevent the cognitive damage which was induced by Ket in the adult animals. FA (10 and 50 mg/kg) attenuated the action of Ket in the animals in relation to the biochemical parameters, proving the possible neuroprotective effect of FA in the adulthood of offspring that were subjected to the animal model of SZ. Our study indicates that the intake of maternal FA during pregnancy and lactation plays an important role, particularly in the regulation of markers of oxidative stress and neurotrophins. [ABSTRACT FROM AUTHOR]

Salivary glands produce various neurotrophins that are thought to regulate salivary function during normal and pathological conditions. Prosaposin (PSAP) is a potent neurotrophin found in several tissues and various biological fluids and may play roles in the regulation of salivary function. However, little is known about PSAP in salivary glands. As the functions of salivary glands are diverse based on age and sex, this study examines whether PSAP and its receptors, G protein-coupled receptor 37 (GPR37) and GPR37L1, are expressed in the salivary glands of rats and whether sex and aging affect their expression. Immunohistochemical analysis revealed that PSAP and its receptors were expressed in the major salivary glands of rats, although their expression varied considerably based on the type of gland, acinar cells, age and sex. In fact, PSAP, GPR37 and GPR37L1 were predominantly expressed in granular convoluted tubule cells of the submandibular gland and the intensity of their immunoreactivity was higher in young adult female rats than age-matched male rats, which was more prominent at older ages (mature adult to menopause). On the other hand, weak PSAP, GPR37 and GPR37L1 immunoreactivity was observed mainly in the basal layer of mucous cells of the sublingual gland. Triple label immunofluorescence analysis revealed that PSAP, GPR37 and GPR37L1 were co-localized in the basal layer of acinar and ductal cells in the major salivary glands. The present findings indicate that PSAP and its receptors, GPR37 and GPR37L1, are expressed in the major salivary glands of rats and their immunoreactivities differ considerably with age and sex. [ABSTRACT FROM AUTHOR]

Neural stem cells (NSCs) are characterized by the ability of self‑renewal and capacity to proliferate and produce new nervous tissue. NSCs are capable of differentiating to three lineages of neural cells, including neurons, oligodendrocytes and astrocytes. Furthermore, hippocampal NSCs transplantation can improve the neurological deficits associated with expression of cytokines. Therefore, to compare the properties of NSCs of tree shrews and rats in vitro, NSCs from tree shrews (tsNSCs) and rats f(rNSCs) were isolated. Nestin was used as a marker to identify the cultured NSCs. Neuronal nuclei protein and glial fibrillary acidic protein (GFAP) were utilized to demonstrate the differentiation of NSCs towards neurons and astrocytes, respectively, in vitro. Furthermore, the expression of neurotrophin 3 (NT3), brain‑derived neurotrophic factor (BDNF), glial cell‑derived neurotrophic factor (GDNF) and transforming growth factor (TGF)β1 was also investigated in tsNSCs and rNSCs. The expression of all of the aforementioned proteins was detected using immunofluorescence methods. The results demonstrated that, after 5 days of culture, the average number of neurospheres in the cultured tsNSCs was significantly lower compared with rNSCs (P=0.0031). Additionally, compared with the rNSCs, tsNSCs exhibited an enhanced differentiation ability towards neurons. Furthermore, the expression of NT3 in the tsNSCs was higher compared with rNSCs (P<0.01), while the expression of BDNF was lower (P=0.045). However, no significant differences were observed in the expression level of GDNF and TGFβ1 between rNSCs and tsNSCs. Therefore, these results indicate that tsNSCs exhibit specific characteristics that are different from rNSCs, which provides novel information for the understanding of NSCs obtained from tree shrews. Overall, the results of the current study provide evidence to support the increased application of tree shrews as models for diseases of the central nervous system. [ABSTRACT FROM AUTHOR]

Objective: To investigate the effect of H2O2 on the migration and antioxidant defense of mesenchymal stem cells (MSCs) and the neurotrophic effects of H2O2-treated MSCs on spinal cord injury (SCI).Results: Sublethal concentrations of H2O2 decreased cell migration and expression of CXCR4 and CCR2 as well as Nrf2 expression in MSCs. In the second phase, transplantation of treated and untreated MSCs to SCI caused minor changes in locomotor dysfunction. There was a significantly difference between cell-treated and spinal cord injury groups in expression of BDNF (brain-derived neurotrophic factor). Transplantation of H2O2-treated cells caused an increase in BDNF expression compared to non-treated cells.Conclusion: Transplantation of H2O2-treated stem cells may have protective effects against SCI through by increasing neurotrophic factors. [ABSTRACT FROM AUTHOR]

Neurotrophins are present in the gastrointestinal tract where they participate in the survival and growth of enteric neurons, augmentation of enteric circuits, elevation of colonic myoelectrical activity and also in different aspects of colitis. Previous studies largely focused on the role of neural and mucosal neurotrophins in gut inflammation. The expression of neurotrophins in colonic smooth muscle cells (SMCs) and the interactions of this potential source with colitis has not been studied in the gut. The expression of NGF, BDNF, NT-3 and NT-4 in SMCs from longitudinal and circular muscle layers of rat colon from normal and dextran sodium sulphate (DSS)-induced colitis rats was measured by ELISA. NGF, BDNF, NT-3 and NT-4 are differentially expressed in both longitudinal and circular SMCs, where the expressions of BDNF and NT-4 proteins were greater in SMCs from the longitudinal muscle layer than from the circular muscle layer, while NGF protein expression was greater in circular SMCs and NT-3 expression was equal in cells from both muscle layers. Induction of colitis with DSS significantly alters neurotrophins expression pattern in colonic SMCs. NGF levels upregulated in circular SMCs. BDNF level was increased in DSS-induced colitis in longitudinal SMCs. NGF, NT-3 and NT-4 levels were downregulated in longitudinal SMCs of DSS-induced colitis rats' colon. Disturbances of neurotrophins expression in SMCs resulted from colitis might account for the structural and functional changes in inflammatory bowel disease (IBD) such as loss of innervation and characteristic hypercontractility of longitudinal muscle in IBD. [ABSTRACT FROM AUTHOR]

The present study aimed to investigate the effect of exogenous nerve growth factor (NGF) pretreatment on demyelination in the spinal cord of lidocaine‑treated rats, and explored the potential neuroprotective mechanisms of NGF. A total of 36 rats were randomly assigned to three groups (n=12 per group): Sham group; Lido group, received intrathecal injection of lidocaine; NGF group, received intrathecal injection of NGF followed by intrathecal injection of lidocaine. Tail‑flick tests were used to evaluate neurobehavioral function. Ultrastructural alternations were analyzed by transmission electron microscopy. Immunofluorescence was used to examine the expression of myelin basic protein (MBP) and brain‑derived neurotrophic factor (BDNF). ELISA was used to determine serum levels of MBP and proteolipid protein (PLP). Western blotting was used to detect the expression of phosphorylated mitogen activated protein kinase (MAPK). NGF pretreatment reduced lidocaine‑induced neurobehavioral damage, nerve fiber demyelination, accompanied by a decrease in MBP expression in the spinal cord and an increase in MBP and PLP in serum. In addition, NGF pretreatment increased BDNF expression in the spinal cord of lidocaine‑treated rats. Furthermore, NGF pretreatment reduced p38 MAPK phosphorylation in the spinal cord of lidocaine‑treated rats. NGF treatment reduces lidocaine‑induced neurotoxicity via the upregulation of BDNF and inhibition of p38 MAPK. NGF therapy may improve the clinical use of lidocaine in intravertebral anesthesia. [ABSTRACT FROM AUTHOR]

Arsenic promotes hippocampal neuronal damage inducing cognitive impairments. However, mechanism arbitrating arsenic-mediated cognitive deficits remains less-known. Here, we identified that chronic exposure to environmentally relevant doses of arsenic increased apoptosis, characterized by caspase-3 activation, poly(ADP-ribose) polymerase cleavage and Terminal deoxynucleotidyl transferase dUTP nick-end labeling of rat hippocampal neurons, marked by NeuN. Investigating apoptotic mechanism through in vivo and in vitro studies revealed that arsenic promoted bone morphogenetic protein-2 (BMP2) expression, supported by increased BMP-receptor2 (BMPR2) and p-Smad1/5 in hippocampal neurons. BMP2-silencing and treatment with BMP antagonist, noggin, attenuated the arsenic-induced apoptosis and loss in hippocampal neurons. We then investigated whether BMP2/Smad signaling stimulated neuronal apoptosis independently or required other intermediate pathways. We hypothesized participation of brain-derived neurotrophic factor (BDNF) that promotes neuronal survival. We identified an arsenic-mediated attenuation of BDNF-dependent TrkB signaling, and observed that co-treatment with recombinant-BDNF reinstated BDNF/TrkB and reduced neuronal apoptosis. To probe whether BMP2/Smad and BDNF/TrkB pathways could be linked, we co-treated arsenic with noggin or recombinant BDNF. We detected a noggin-mediated restored BDNF/TrkB, while recombinant-BDNF failed to affect BMP2/Smad signaling. In addition, we found that TrkB-inhibitor, K252a, nullified noggin-induced protection, proving the necessity of a downstream reduced BDNF/TrKB signaling for BMP2/Smad-mediated apoptosis in arsenic-treated neurons. We further related our observations with cognitive performances, and detected noggin-mediated restoration of transfer latency time and learningmemory ability for passive avoidance and Y-Maze tests respectively in arsenic-treated rats. Overall, our study proves that arsenic promotes hippocampal neuronal apoptosis through an up-regulated BMP2/Smad-dependent attenuation of BDNF/ TrkB pathway, inducing cognitive deficits. [ABSTRACT FROM AUTHOR]

Lithium (Li) is a mood-stabilizing drug used in the treatment of bipolar disorder (BD). Recently, preclinical studies have demonstrated the potential of tamoxifen (TMX) in the treatment of acute episodes of BD. However, the prolonged use of TMX for mood disorders treatment is controversial. In this study, we evaluated the effects of TMX or Li on cognitive behavior, as well as the levels of neurotrophic factors in the brain of male and female rats. Male and female Wistar rats received administrations of water (control group), TMX or Li via gavage for a period of 28 days; the rats were then subjected to the open-field test (to evaluate spontaneous locomotion), and the novel object recognition and step-down inhibitory avoidance tests (to evaluate cognition). The levels of NGF, BDNF and GDNF were evaluated in the hippocampus and frontal cortex of the subject rats. No significant differences were observed in the open-field and inhibitory avoidance tests after drug administration in either the male or female rats. The administration of TMX, but not Li, decreased the recognition index of both the male and female rats in the object recognition test. The chronic administration of TMX decreased, whereas Li increased the levels of BDNF in the hippocampus of both the male and female rats. Tamoxifen decreased the levels of NGF in the hippocampus of female rats. In conclusion, it can be suggested that long-term treatments with TMX can lead to significant cognitive impairments by reducing the levels of neurotrophic factors in the brain of rats. [ABSTRACT FROM AUTHOR]

Tyrosine receptor kinase B (TrkB), a receptor for brain-derived neurotrophic factor and neurotrophin-3, includes the alternatively spliced three isoforms specifically in rats. Each isoform, full length TrkB (TrkB FL), truncated TrkB type-1 (TrkB T1) and type-2 (TrkB T2), seems to mediate diverse cellular function. Some studies suggest that TrkB plays a key role in both neural and non-neural systems. In the present study, we examined mRNA and protein expression profile of three TrkB isoforms in normal adult rat multiple tissues. TrkB FL mRNA and protein were both highly expressed exclusively in brain. While TrkB T1 mRNA was highly expressed exclusively in brain, glycosylated TrkB T1 protein was expressed in brain and heart. TrkB T2 mRNA level in brain was the highest. In brain, TrkB FL mRNA expression was higher in cerebral cortex, but lower in brainstem. TrkB T1 mRNA expression was higher in hypothalamus, but lower in cerebellum. TrkB T2 mRNA expression was higher in cerebral cortex and cerebellum, but lower in brainstem. The present study for the first time clarified diverse distribution of three TrkB isoforms in rat multiple tissues and could serve as a useful resource for understanding the physiology and pathophysiology of mammals including human via comparing the expression pattern of TrkB isoforms. [ABSTRACT FROM AUTHOR]

Memory decline during aging or accompanying neurodegenerative diseases, represents a major health problem. Neurotrophins have long been considered relevant to the mechanisms of aging-associated cognitive decline and neurodegeneration. Mature Brain-Derived Neurotrophic Factor (BDNF) and its precursor (proBDNF) can both be secreted in response to neuronal activity and exert opposing effects on neuronal physiology and plasticity. In this study, biochemical analyses revealed that increased levels of proBDNF are present in the aged mouse hippocampus relative to young and that the level of hippocampal proBDNF inversely correlates with the ability to perform in a spatial memory task, the water radial arm maze (WRAM). To ascertain the role of increased proBDNF levels on hippocampal function and memory we performed infusions of proBDNF into the CA1 region of the dorsal hippocampus in male mice trained in the WRAM paradigm: In well-performing aged mice, intrahippocampal proBDNF infusions resulted in a progressive and significant impairment of memory performance. This impairment was associated with increased p-cofilin levels, an important regulator of dendritic spines and synapse physiology. On the other hand, in poor performers, intra-hippocampal infusions of TAT-Pep5, a peptide which blocks the interaction between the p75 Neurotrophin Receptor (p75NTR) and RhoGDI, significantly improved learning and memory, while saline infusions had no effect. Our results support a role for proBDNF and its receptor p75NTR in aging-related memory impairments. [ABSTRACT FROM AUTHOR]

Ketamine shows promise as a therapeutic agent for the treatment of depression. The increased expression of brain-derived neurotrophic factor (BDNF) has been associated with the antidepressant-like effects of ketamine, but the mechanism of BDNF induction is not well understood. In the current study, we demonstrate that the treatment of rats with ketamine results in the dose-dependent rapid upregulation of Bdnf promoter IV activity and expression of Bdnf exon IV mRNAs in rat hippocampal neurons. Transfection of histone deacetylase 5 (HDAC5) into rat hippocampal neurons similarly induces Bdnf mRNA expression in response to ketamine, whereas transfection of a HDAC5 phosphorylation-defective mutant (Ser259 and Ser498 replaced by Ala259 and Ala498), results in the suppression of ketamine-mediated BDNF promoter IV transcriptional activity. Viral-mediated hippocampal knockdown of HDAC5 induces Bdnf mRNA and protein expression, and blocks the enhancing effects of ketamine on BDNF expression in both unstressed and stressed rats, and thereby providing evidence for the role of HDAC5 in the regulation of Bdnf expression. Taken together, our findings implicate HDAC5 in the ketamine-induced transcriptional regulation of Bdnf, and suggest that the phosphorylation of HDAC5 regulates the therapeutic actions of ketamine. [ABSTRACT FROM AUTHOR]

At molecular levels, it has been shown that aging is associated with alterations in neuroplastic mechanisms. In this study, it was examined if the altered expression of neurotrophins observed in aged rats could be corrected by a chronic treatment with S 47445 (1–3–10 mg/kg, p.o.), a novel selective positive allosteric modulator of the AMPA receptors. Both the mRNA and the protein levels of the neurotrophins Bdnf, NT-3 and Ngf were specifically measured in the prefrontal cortex and hippocampus (ventral and dorsal) of aged rats. It was found that 2-week-treatment with S 47445 corrected the age-related deficits of these neurotrophins and/or positively modulated their expression in comparison to vehicle aged rats in the range of procognitive and antidepressant active doses in rodents. Collectively, the ability of S 47445 to modulate various neurotrophins demonstrated its neurotrophic properties in two major brain structures involved in cognition and mood regulation suggesting its therapeutic potential for improving several diseases such as Alzheimer’s disease and/or Major Depressive Disorders. [ABSTRACT FROM AUTHOR]

Rationale: Repeated social defeat (RSD) increases the rewarding effects of cocaine in adolescent and adult rodents. Objective: The aim of the present study was to compare the long-term effects of RSD on the conditioned rewarding effects of cocaine and levels of the transcription factors Pitx3 and Nurr1 in the ventral tegmental area (VTA), the dopamine transporter (DAT), the D2 dopamine receptor (D2DR) and precursor of brain-derived neurotrophic factor (proBDNF) signaling pathways, and the tropomyosin-related kinase B (TrkB) receptor in the nucleus accumbens (NAc) in adult and adolescent mice. Methods: Male adolescent and young adult OF1 mice were exposed to four episodes of social defeat and were conditioned 3 weeks later with 1 mg/kg of cocaine. In a second set of mice, the expressions of the abovementioned dopaminergic and proBDNF and TrkB receptor were measured in VTA and NAc, respectively. Results: Adolescent mice experienced social defeats less intensely than their adult counterparts and produced lower levels of corticosterone. However, both adult and adolescent defeated mice developed conditioned place preference for the compartment associated with this low dose of cocaine. Furthermore, only adolescent defeated mice displayed diminished levels of the transcription factors Pitx3 in the VTA, without changes in the expression of DAT and D2DR in the NAc. In addition, stressed adult mice showed a decreased expression of proBDNF and the TrkB receptor, while stressed adolescent mice exhibited increased expression of latter without changes in the former. Conclusion: Our findings suggest that dopaminergic pathways and proBDNF signaling and TrkB receptors play different roles in social defeat-stressed mice exposed to cocaine. [ABSTRACT FROM AUTHOR]

Hypoglycemia is a major adverse effect of insulin therapy for people with type 1 diabetes (T1D). Profound defects in the normal counterregulatory response to hypoglycemia explain the frequency of hypoglycemia occurrence in T1D. Defective counterregulation results to a large extent from prior exposure to hypoglycemia per se, leading to a condition called impaired awareness of hypoglycemia (IAH), the cause of which is unknown. In the current study, we investigate the hypothesis that IAH develops through a special type of adaptive memory referred to as habituation. To test this hypothesis, we used a novel intense stimulus (high-intensity exercise) to demonstrate two classic features of a habituated response, namely dishabituation and response recovery. We demonstrate that after recurrent hypoglycemia the introduction of a novel dishabituating stimulus (a single burst of high-intensity exercise) in male Sprague-Dawley rats restores the defective hypoglycemia counterregulatory response. In addition, the rats showed an enhanced response to the novel stimulus (response recovery). We make the further observation using proteomic analysis of hypothalamic extracts that high-intensity exercise in recurrently hypoglycemic rats increases levels of a number of proteins linked with brain-derived neurotrophic factor signaling. These findings may lead to novel therapeutic approaches for individuals with T1D and IAH. [ABSTRACT FROM AUTHOR]

Chronic intermittent exposure to ethanol (EtOH; CIE) that produces binge-like levels of intoxication has been associated with age-dependent deficits in cognitive functioning. Male Sprague–Dawley rats were exposed to CIE (5 g/kg, 25% EtOH, 13 intragastric gavages) beginning at three ages: early adolescence (postnatal day [PD] 28), mid-adolescence (PD35) and adulthood (PD72). In experiment 1, rats were behaviorally tested following CIE. Spatial memory was not affected by CIE, but adult CIE rats were impaired at acquiring a non-spatial discrimination task and subsequent reversal tasks. Rats exposed to CIE during early or mid-adolescence were impaired on the first reversal, demonstrating transient impairment in behavioral flexibility. Blood EtOH concentrations negatively correlated with performance on reversal tasks. Experiment 2 examined changes in brain-derived neurotrophic factor (BDNF) levels within the frontal cortex (FC) and hippocampus (HPC) at four time points: during intoxication, 24 h after the final EtOH exposure (acute abstinence), 3 weeks following abstinence (recovery) and after behavioral testing. HPC BDNF levels were not affected by CIE at any time point. During intoxication, BDNF was suppressed in the FC, regardless of the age of exposure. However, during acute abstinence, reduced FC BDNF levels persisted in early adolescent CIE rats, whereas adult CIE rats displayed an increase in BDNF levels. Following recovery, neurotrophin levels in all CIE rats recovered. Our results indicate that intermittent binge-like EtOH exposure leads to acute disruptions in FC BDNF levels and long-lasting behavioral deficits. However, the type of cognitive impairment and its duration differ depending on the age of exposure. [ABSTRACT FROM AUTHOR]

Neurotrophin 3 (NT-3) is an important factor for promoting prenatal neural development, as well as regeneration, axogenesis and plasticity in postnatal life. Therapy with NT-3 was reported to improve the condition of patients suffering from degenerative diseases and traumatic injuries, however, the disadvantage of NT-3 protein delivery is its short half-life, thus our alternative approach is the use of NT-3 gene therapy. In this study, the bone marrow stromal cells (BMSCs) were isolated from adult rats, cultured for 4 passages and transfected with either pEGFP-N1 or a constructed vector containing murine proNT-3 (pSecTag2/HygroB-murine proNT-3) using Lipofectamine 2000 followed by Hygromycin B (200 mg/kg). The transfection efficiency of the transiently transfected BMSCs was evaluated using the green fluorescence protein containing vector (pEGFP-N1). A quantitative evaluation of the NT-3 expression of mRNA using real time qRT-PCR shows that there was double fold increase in NT-3 gene expression compared with non-transfected BMSCs, also, the culture supernatant yielded double fold increase in NT-3 using ELISA technique, the data were supported by immunoblotting technique. This suggests that the use of this transfection technique can be useful for gene therapy in different neurological disorders with neurodegenerative or traumatic origins. [ABSTRACT FROM AUTHOR]

The neurotrophic factor neuregulin 1 (NRG1) regulates neuronal development, glial differentiation, and excitatory synapse maturation. NRG1 is synthesized as a membrane-anchored precursor and is then liberated by proteolytic processing or exocytosis. Mature NRG1 then binds to its receptors expressed by neighboring neurons or glial cells. However, the molecular mechanisms that govern this process in the nervous system are not defined in detail. Here we prepared neuron-enriched and glia-enriched cultures from embryonic rat neocortex to investigate the role of neurotransmitters that regulate the liberation/release of NRG1 from the membrane of neurons or glial cells. Using a two-site enzyme immunoassay to detect soluble NRG1, we show that, of various neurotransmitters, glutamate was the most potent inducer of NRG1 release in neuron-enriched cultures. NRG1 release in glia-enriched cultures was relatively limited. Furthermore, among glutamate receptor agonists, N-Methyl-D-Aspartate (NMDA) and kainate (KA), but not AMPA or tACPD, mimicked the effects of glutamate. Similar findings were acquired from analysis of the hippocampus of rats with KA-induced seizures. To evaluate the contribution of members of a disintegrin and metalloproteinase (ADAM) families to NRG1 release, we transfected primary cultures of neurons with cDNA vectors encoding NRG1 types I, II, or III precursors, each tagged with the alkaline phosphatase reporter. Analysis of alkaline phosphatase activity revealed that the NRG1 type II precursor was subjected to tumor necrosis factor-α-converting enzyme (TACE) / a Disintegrin And Metalloproteinase 17 (ADAM17) -dependent ectodomain shedding in a protein kinase C-dependent manner. These results suggest that glutamatergic neurotransmission positively regulates the ectodomain shedding of NRG1 type II precursors and liberates the active NRG1 domain in an activity-dependent manner. [ABSTRACT FROM AUTHOR]

Infectious diseases in early postnatal ontogenesis can induce neuroinflammation, disrupt normal central nervous system development, and contribute to pathogenesis of cerebral pathologies in adults. To study long-term consequences of such early stress, we induced neonatal proinflammatory stress (NPS) by injecting bacterial lipopolysaccharide into rat pups on postnatal days 3 and 5 and then assessed the levels of corticosterone, proinflammatory cytokines and their mRNAs, and neurotrophins and their mRNAs in the hippocampus and neocortex of the one-month-old animals. Long-term potentiation (LTP) was studied in hippocampal slices as an index of synaptic plasticity. NPS-induced impairments of LTP were accompanied by the accumulation of corticosterone and IL-6 in the hippocampus. In the neocortex, a decrease in exon IV BDNF mRNA was detected. We suggest that excessive corticosterone delivery to hippocampal receptors and proinflammatory changes persisting during brain maturation are among the principal molecular mechanisms responsible for NPSinduced neuroplasticity impairments. [ABSTRACT FROM AUTHOR]

Alzheimer's disease (AD) is the most common type of age-related dementia. The development of neurodegeneration in AD is closely related to alterations in neurotrophic supplementation of the brain, which may be caused either by disorder of neurotrophin metabolism or by modification of its availability due to changes in the microenvironment of neurons. The underlying mechanisms are not fully understood. In this work, we used senescence-accelerated OXYS rats as a unique model of the sporadic form of AD to examine the relationship of development of AD signs and changes in neurotrophic supplementation of the cortex. Based on comparative analysis of the transcriptome of the frontal cerebral cortex of OXYS and Wistar (control) rats, genes of a neurotrophin signaling pathway with different mRNA levels in the period prior to the development of AD-like pathology in OXYS rats (20 days) and in the period of its active manifestation (5 months) and progression (18 months) were identified. The most significant changes in mRNA levels in the cortex of OXYS rats occurred in the period from 5 to 18 months of age. These genes were associated with neurogenesis, neuronal differentiation, synaptic plasticity, and immune response. The results were compared to changes in the levels of brain-derived neurotrophic factor (BDNF), its receptors TrkB and p75, as well as with patterns of their colocalization, which reveal the balance of proneurotrophins and mature neurotrophins and their receptors. We found that alterations in neurotrophic balance indicating increased apoptosis precede the development of AD-like pathology in OXYS rats. Manifestation of AD-like pathology occurs against a background of activation of compensatory and regenerative processes including increased neurotrophic supplementation. Active progression of AD-like pathology in OXYS rats is accompanied by the suppression of activity of the neurotrophin system. Thus, the results confirm the importance of the neurotrophin system as a potential target for development of new approaches to slow age-related alterations in brain and AD development. [ABSTRACT FROM AUTHOR]

The number of children suffered from autism spectrum disorder (ASD) is increasing dramatically. However, the etiology of ASD is not well known. This study employed mammalian target of rapamycin inhibitor rapamycin to explore its effect on ASD and provided new therapeutic strategies for ASD. ASD rat model was constructed and valproic acid (VPA) was injected intraperitoneally into rats on pregnancy day 12.5. Offspring from VPA group were divided into ASD group and ASD + rapamycin (ASD + RAPA) group. Compared with normal group, the frequency and duration of social behavior and straight times of ASD group were shortened, but the grooming times were extended. Meanwhile, in ASD group, the average escape latency and the frequency of crossing plates were decreased, the apoptotic index (AI) detected by TUNEL assay was increased, and the expression of brain-derived neurotrophic factor (BDNF) and B-cell lymphoma 2 (Bcl-2) analyzed was decreased with great difference compared with normal group (P>0.01). However, rapamycin treatment in ASD rats mitigated the ASD-like social behavior, such as the frequencies of straight and grooming. Furthermore, rapamycin shortened the average escape latency, but increased the frequency of crossing plates of ASD rats. In hippocampus, rapamycin decreased the AI, but increased the levels of BDNF and Bcl-2 (P>0.01) of ASD rats. These findings revealed that rapamycin significantly mitigated the social behavior by enhancing the expression of BDNF and Bcl-2 to suppress the hippocampus apoptosis in VPA-induced ASD rats. [ABSTRACT FROM AUTHOR]

Aims Nerve growth factor ( NGF) eyedrops (ed- NGF) activate brain neurons, stimulate growth factors, including brain-derived neurotrophic factor ( BDNF), and exert neuroprotection in the forebrain of streptozotocin-induced diabetic rats ( STZ rats). In this study, the effects of ed- NGF on BDNF signaling in the prefrontal cortex ( PFC) were explored in healthy and STZ-diabetic rats, in which cortical neuronal and axonal loss, and altered circulating BDNF associated with depressive phenotype are also described. Methods STZ and healthy ( CTR) adult rats received ed- NGF twice a day for 2 weeks. Depressive phenotype was identified by force swimming test ( FST). Proteins extracted from PFC were processed for ELISA and Western blot analyses to measure the expression of BDNF, pro BDNF, and their receptors and intracellular signals. Results ed- NGF treatment modulates BDNF pathway in PFC and normalizes the STZ-induced BDNF alterations by stimulating TRK-mediated survival mechanism. A decreased latency in FST was also found in STZ rats, while no change was observed comparing CTR + NGF and STZ + NGF with CTR. Conclusion The present data confirm the capacity of ed- NGF treatment to affect brain neurons and lead to brain damage recovery by activating protective and remodeling pathways triggered by BDNF. We suggest that the ed- NGF-induced changes in BDNF signaling might influence the manifestation of depressive phenotype in diabetic rats. [ABSTRACT FROM AUTHOR]

Rationale: In depressive disorders, one of the mechanisms proposed for antidepressant drugs is the enhancement of synaptic plasticity in the hippocampus and cerebral cortex. Previously, we showed that the muscarinic acetylcholine receptor (mAChR) agonist oxotremorine (Oxo) increases neuronal plasticity in hippocampal neurons via FGFR1 transactivation. Objectives: Here, we aimed to explore (a) whether Oxo exerts anxiolytic effect in the rat model of anxiety-depression-like behavior induced by chronic restraint stress (CRS), and (b) if the anxiolytic effect of Oxo is associated with the modulation of neurotrophic factors, brain-derived neurotrophic factor (BDNF) and fibroblast growth factor-2 (FGF2), and phosphorylated Erk1/2 (p-Erk1/2) levels in the dorsal or ventral hippocampus and in the medial prefrontal cortex. Methods: The rats were randomly divided into four groups: control unstressed, CRS group, CRS group treated with 0.2 mg/kg Oxo, and unstressed group treated with Oxo. After 21 days of CRS, the groups were treated for 10 days with Oxo or saline. The anxiolytic role of Oxo was tested by using the following: forced swimming test, novelty suppressed feeding test, elevated plus maze test, and light/dark box test. The hippocampi and prefrontal cortex were used to evaluate BDNF and FGF2 protein levels and p-Erk1/2 levels. Results: Oxo treatment significantly attenuated anxiety induced by CRS. Moreover, Oxo treatment counteracted the CRS-induced reduction of BDNF and FGF2 levels in the ventral hippocampus and medial prefrontal cerebral cortex Conclusions: The present study showed that Oxo treatment ameliorates the stress-induced anxiety-like behavior and rescues FGF2 and BDNF levels in two brain regions involved in CRS-induced anxiety, ventral hippocampal formation, and medial prefrontal cortex. [ABSTRACT FROM AUTHOR]

Proglucagon-derived peptides, especially glucagon-like peptide-1 (GLP-1) and its long-acting mimetics, have exhibited neuroprotective effects in animal models of stroke. Several of these peptides are in clinical trials for stroke. Oxyntomodulin (OXM) is a proglucagon-derived peptide that co-activates the GLP-1 receptor (GLP-1R) and the glucagon receptor (GCGR). The neuroprotective action of OXM, however, has not been thoroughly investigated. In this study, the neuroprotective effect of OXM was first examined in human neuroblastoma (SH-SY5Y) cells and rat primary cortical neurons. GLP-1R and GCGR antagonists, and inhibitors of various signaling pathways were used in cell culture to characterize the mechanisms of action of OXM. To evaluate translation in vivo, OXM-mediated neuroprotection was assessed in a 60-min, transient middle cerebral artery occlusion (MCAo) rat model of stroke. We found that OXM dose- and time-dependently increased cell viability and protected cells from glutamate toxicity and oxidative stress. These neuroprotective actions of OXM were mainly mediated through the GLP-1R. OXM induced intracellular cAMP production and activated cAMP-response element-binding protein (CREB). Furthermore, inhibition of the PKA and MAPK pathways, but not inhibition of the PI3K pathway, significantly attenuated the OXM neuroprotective actions. Intracerebroventricular administration of OXM significantly reduced cerebral infarct size and improved locomotor activities in MCAo stroke rats. Therefore, we conclude that OXM is neuroprotective against ischemic brain injury. The mechanisms of action involve induction of intracellular cAMP, activation of PKA and MAPK pathways and phosphorylation of CREB. [ABSTRACT FROM AUTHOR]

Metabolic diseases such as diabetes mellitus type-II (DM-II) may increase the risk of suffering painful connective tissue disorders and tendon ruptures. The pathomechanisms, however, by which diabetes adversely affects connective tissue matrix metabolism and regeneration, still need better definition. Our aim was to study the effect of DM-II on expressional changes of neuro- and angiotrophic mediators and receptors in intact and healing Achilles tendon. The right Achilles tendon was transected in 5 male DM-II Goto-Kakizaki (GK) and 4 age-matched Wistar control rats. The left Achilles tendons were left intact. At week 2 post-injury, NGF, BDNF, TSP, and receptors TrkA, TrkB and Nk1 gene expression was studied by quantitative RT-PCR (qRT-PCR) and their protein distribution by immunohistochemistry in intact and injured tendons. The expression of tendon-related markers, Scleraxis (SCX) and Tenomodulin (TNMD), was evaluated by qRT-PCR in intact and injured tendons. Injured tendons of diabetic GK rats exhibited significantly down-regulated Ngf and Tsp1 mRNA and corresponding protein levels, and down-regulated Trka gene expression compared to injured Wistar controls. Intact tendons of DM-II GK rats displayed reduced mRNA levels for Ngf, Tsp1 and Trkb compared to corresponding intact non-diabetic tendons. Up-regulated Scx and Tnmd gene expression was observed in injured tendons of normal and diabetic GK rats compared to intact Wistar controls. However, these molecules were not up-regulated in injured DM-II GK rats compared to their corresponding controls. Our results suggest that DM-II has detrimental effects on neuro- and angiotrophic pathways, and such effects may reflect the compromised repair seen in diabetic Achilles tendon. Thus, novel approaches for regeneration of injured, including tendinopathic, and surgically repaired diabetic tendons may include therapeutic molecular modulation of neurotrophic pathways such as NGF and its receptors. [ABSTRACT FROM AUTHOR]

This study aimed to investigate whether helium preconditioning (He-PC) is able to exert neuroprotective effects via improving focal neurovascular niche in a neonatal rat hypoxia/ischemia (HI) brain injury model. Seven day old rat pups were divided into control group, HI group and He-PC group. HI was induced by exposure to 8% oxygen for 90 min one day after preconditioning with 70% helium—30% oxygen for three 5-min periods. At 3 and 7 days, the brain was collected for the detection of inflammation related factors (tumor necrosis factor α [TNF-α], interleukin-1β [IL-1β], IL-10) and growth/neurotrophic factors (brain-derived neurotrophic factor [BDNF], basic fibroblast growth factor [bFGF] and nerve growth factor [NGF]); at 7 days, neurobehaviors were evaluated, and the brain was collected for the detection of mRNA expression of vascular endothelial growth factor (VEGF) and angiopoietin-1 (Ang-1) by PCR, protein expression of angiogenesis related molecules (VEGF, Ang-1, Tie-2 and Flt-1) by Western blotting and microvessel density (MCD) by immunohistochemistry for vWF. Results showed He-PC was able to reduce TNF-α and IL-1β, further increase IL-10, BDNF, bFGF and NGF, elevate the mRNA expression of VEGF and Ang-1, increase the protein expression of VEGF, Ang-1, Tie-2 and Flt-1, promote angiogenesis and improve neurobehaviors as compared to HI group. These findings suggest that He-PC may improve the post-stroke neurovascular niche to exert neuroprotective effects on neonatal HI brain injury. [ABSTRACT FROM AUTHOR]

Background: Radix Puerariae and hawthorn fruit have been demonstrated to treat diabetes. They offer potential benefits for preventing depression in diabetes. Objective: The aim of this study was to investigate whether the combination of Radix Puerariae and hawthorn fruit (CRPHF) could prevent depression in a diabetic rat model generated by feeding the rats with a high-fat diet and a low-dose streptozotocin (STZ). Methods: The CRPHF was provided by the Shanghai Chinese Traditional Medical University. Twenty-four rats were randomly divided into four groups: normal control, normal-given- CRPHF (NC), diabetic control, and diabetic-given-CRPHF (DC) groups. The type 2 diabetic model was created by feeding the rats with a high-fat diet for 4 weeks followed by injection of 25 mg/kg STZ. CRPHF was given at 2 g/kg/d to the rats of NC and DC groups by intragastric gavage daily for 4 weeks after the type 2 diabetic model was successfully created. Body weight, random blood glucose (RBG), oral glucose tolerance test, total cholesterol (TC), triglyceride (TG), high-density lipoprotein cholesterol (HDL-C), and low-density lipoprotein cholesterol (LDL-C) were measured during the study. Depressive-like behavior was evaluated at the end of the treatment by using the open field test (OFT), the elevated plus-maze test (EPMT), locomotor activity test (LAT), and forced swimming test (FST). Levels of extracellular signal-regulated protein kinase (ERK) and brain-derived neurotrophic factor (BDNF) in the prefrontal cortex were evaluated by using Western blot. Results: 1) CRPHF reduced RBG and improved glucose tolerance in diabetic rats; 2) CRPHF reduced TC and TG but did not significantly change HDL-C or LDL-C in diabetic rats; 3) CRPHF reversed the loss in body weights observed in diabetic rats; 4) CRPHF reduced depressive-like behavior as measured by OFT, EPMT, LAT, and FST; 5) BDNF was upregulated, and ERK was activated in the prefrontal cortex of diabetic rats treated with CRPHF. Conclusion: CRPHF has the potential of preventing depression in patients with diabetes. [ABSTRACT FROM AUTHOR]

Objective: To investigate the permeability of β-NGF through blood-brain-barrier (BBB) in neonatal and adult rats, and the spatial distribution of β-NGF in different brain regions in hypoxic-ischemic (HI) and normal neonatal rats. Methods: To investigate the overall permeability of β-NGF through BBB, β-NGF labeled with I was injected into adult rats, neonatal rats and HI neonatal rats via tail vein. The radioactivity of brain tissue and blood was examined and analyzed 30 min after injection. Also, brain regions including the basal forebrain, frontal cortex, hippocampus, hypothalamus, cerebellum, bulbus olfactorius and hypophysis, of all the rats were dissected and radioactivity was examined to investigate the spatial specificity of NGF permeation through BBB. Results: Statistically significant results were observed in I-β-NGF contents in brain tissues of adult rats group, neonatal rats group and HI neonatal rats group (P < 0.05). Compared to the HI neonatal rats' brain with the highest I-β-NGF contents, normal neonatal rats ranks the second while the adult rats were the lowest. While for the spatial specificity examination part, I-β-NGF in both HI group and control group were widely distributed in basal forebrain, frontal cortex, hippocampus, cerebellum and bulbus olfactorius. But the radioactivity in frontal cortex, hippocampus and cerebellum of HI groups are statistically higher than control groups (P < 0.05). Conclusion: β-NGF can more easily penetrate the BBB of newborn rats than adult rats via peripheral venous administration and this effect can be enhanced by HI insult. Also, this HI-induced permeation of β-NGF through BBB is more obvious in frontal cortex, hippocampus and cerebellum. [ABSTRACT FROM AUTHOR]

Alzheimer’s disease (AD) is an age-related progressive neurodegenerative disease, and early stage AD is characterized by synaptic dysfunction generally ascribed to soluble oligomers of amyloid-beta (Aβ). Neurotrophic factors are promising for AD treatment and are integrally involved in neuronal growth, survival and maintenance. Cerebral dopamine neurotrophic factor (CDNF) was recently discovered to have beneficial effects on long-term memory. The present study explored the synaptoprotective effects of CDNF in Aβ-treated primary hippocampal cells. Immunofluorescent analysis of synaptophysin and postsynaptic density protein 95 (PSD95) puncta densities in the group of pretreatment with CDNF before Aβ exposure revealed significant improvements compared to Aβ group. In addition, pretreatment with CDNF reduced the expression levels of endoplasmic reticulum (ER) stress-related proteins, including Bip (also known as GRP78), phosphorylation of eukaryotic translation initiation factor 2 subunit α (peIF2α), phosphorylation of c-Jun N-terminal kinase (pJNK), and cleaved caspase 3, which are increased by Aβ treatment at early stage. Our results revealed protective effects of CDNF on Aβ-induced synaptotoxicity and ER stress, implying that CDNF may protect against Aβ-induced synaptotoxicity through suppression of ER stress. CDNF could be a potential drug candidate for early AD treatment. [ABSTRACT FROM AUTHOR]