Possible therapeutic effect of royal jelly on endometriotic lesion size, pain sensitivity, and neurotrophic factors in a rat model of endometriosis.

Endometriosis is the abnormal growth of endometrial tissue. The goals of the study are: (1) Is any correlation between endometriosis pain and neurotrophins in the serum, dorsal root ganglion (DRG), and peritoneal fluid (PF) in rat models of experimental endometriosis?, (2) Possible therapeutic effects of royal jelly (RJ) on pain scores, size of endometriotic lesion, and neurotrophic factors. Forty-eight Sprague Dawley female rats weighing 205.023 ± 21.54 g were maintained in a standard condition. The rats were randomly divided into one of the six groups: Control (no intervention), Sham-1 (remove of uterine horn), RJ (administration of 200 mg/kg/day RJ for 21 days), Endometriosis (induction of endometriosis), Treatment (induction of endometriosis+administration of 200 mg/kg/day RJ for 21 days), and Sham-2 (induction of endometriosis+administration of water). Formalin test performed for pain evaluation. The levels of Brain-derived neurotrophic factor (BDNF), nerve growth factor (NGF), substance P, and calcitonin gene-related peptide (CGRP) were measured by enzyme-linked immunosorbent assay. The mean pain scores in all three phases of the formalin test were significantly increased by endometriosis induction (p < 0.05). The concentrations of BDNF, NGF, and CGRP in DRG of the endometriosis group were significantly higher than these factors in the Control, Sham-1, and RJ groups (p < 0.05). RJ could significantly (p < 0.001) decrease the mean lesion size and the mean pain score in the late phase (p < 0.05). The present results determine that endometriosis pain may be related to nervous system neurotrophic factors. Treatment with RJ could decrease the size of endometriosis lesions as well as pain scores. The findings may shed light on other complementary and alternative remedies for endometriosis.

CCL01, a novel formulation composed of Cuscuta seeds and Lactobacillus paracasei NK112, enhances memory function via nerve growth factor-mediated neurogenesis.

Memory decline occurs due to various factors, including stress, depression, and aging, and lowers the quality of life. Several nutritional supplements and probiotics have been used to enhance memory function, and efforts have been made to develop mixed supplements with maximized efficacy. In this study, we aimed to examine whether a novel formulation composed of Cuscuta seeds and Lactobacillus paracasei NK112, CCL01, enhances memory function and induces neurogenesis via nerve growth factor (NGF) induction. Firstly, we orally administered CCL01 to normal mice and assessed their memory function 4 weeks after the first administration by performing a step-through passive avoidance test. We found that CCL01 at 100 mg kg-1 treatment enhanced the fear-based memory function. By analyzing the expression of Ki-67 and doublecortin, which are the markers of proliferating cells and immature neurons, respectively, we observed that CCL01 induced neuronal proliferation and differentiation in the hippocampus of the mice. Additionally, we found that the expression of synaptic markers increased in the hippocampus of CCL01-treated mice. We measured the NGF expression in the supernatant of C6 cells after CCL01 treatment and found that CCL01 increased NGF release. Furthermore, treatment of CCL01-conditioned glial media on N2a cells increased neuronal differentiation via the TrkA/ERK/CREB signaling pathway and neurotrophic factor expression. Moreover, when CCL01 was administered and scopolamine was injected, CCL01 ameliorated memory decline. These results suggest that CCL01 is an effective enhancer of memory function and can be applied to various age groups requiring memory improvement.

Effect of Water and Ethanol Extracts from Hericium erinaceus Solid-State Fermented Wheat Product on the Protection and Repair of Brain Cells in Zebrafish Embryos.

Extracts from Hericium erinaceus can cause neural cells to produce nerve growth factor (NGF) and protect against neuron death. The objective of this study was to evaluate the effects of ethanol and hot water extracts from H. erinaceus solid-state fermented wheat product on the brain cells of zebrafish embryos in both pre-dosing protection mode and post-dosing repair mode. The results showed that 1% ethanol could effectively promote zebrafish embryo brain cell death. Both 200 ppm of ethanol and water extracts from H. erinaceus solid-state fermented wheat product protected brain cells and significantly reduced the death of brain cells caused by 1% ethanol treatment in zebrafish. Moreover, the zebrafish embryos were immersed in 1% ethanol for 4 h to cause brain cell damage and were then transferred and soaked in the 200 ppm of ethanol and water extracts from H. erinaceus solid-state fermented wheat product to restore the brain cells damaged by the 1% ethanol. However, the 200 ppm extracts from the unfermented wheat medium had no protective and repairing effects. Moreover, 200 ppm of ethanol and water extracts from H. erinaceus fruiting body had less significant protective and restorative effects on the brain cells of zebrafish embryos. Both the ethanol and hot water extracts from H. erinaceus solid-state fermented wheat product could protect and repair the brain cells of zebrafish embryos damaged by 1% ethanol. Therefore, it has great potential as a raw material for neuroprotective health product.

Effect of Aloe vera on the expression of nerve factors, p75 and TrkA receptors in the hippocampus of diabetic rats / Efecto del Aloe vera sobre la expresión de factores de crecimiento nervioso, Receptores p75 y TrkA en el hipocampo de ratas diabéticas

SUMMARY: Diabetes mellitus can lead to structural disorders in the brain. One of the most common complications of diabetes, diabetic neuropathy is associated with central nervous system disorders. Aloe vera has anti-diabetic, antioxidant, and neuroprotective effects. This study was designed to evaluate the effects of Aloe vera gel on the hippocampus changes as well as the expression of nerve growth factor and receptors TrkA and P75 in the hippocampus of streptozotocin (STZ)-induced diabetic rats. 25 male Wistar rats were randomly divided into 5 groups including: control (normal saline), diabetic (normal saline), Aloe vera gel (400 mg/kg/day; gavage), diabetic + Aloe vera gel (400 mg/kg/day; gavage) and diabetic + insulin NPH (10 IU/kg/day; subcutaneous). Experimental diabetes was induced by streptozotocin injection (60 mg/kg; intraperitoneal). All groups treated for 8 weeks. At the end of treatment course, the rat brains were removed for measuring the expression of nerve growth factor, p75 and TrkA receptors were evaluated in the hippocampus. Diabetes induction after 8 weeks caused NGF and P75 expression levels in the diabetic group than other groups significantly increased (p<0.05). The TrkA receptor expression in the diabetic group compared with the control had a significant reduction (p<0.05). On the other hand in the diabetic group receiving Aloe vera gel expression of NGF and P75 expression levels compared to the diabetic group was significantly reduced (p<0.05) and the TrkA receptor expression compared with the diabetic group had a significant increase (p<0.05). The results showed that oral administration of Aloe vera gel in diabetic rats ameliorates diabetes-induced hyperglycemia. On the other hand, Aloe vera gel cause modulation of the expression of NGF neurotrophic factor via increased expression of TrkA receptor-specific and non-specific receptor down-regulation of P75 in the hippocampus of STZ-induced diabetic rats.

RESUMEN: La diabetes mellitus puede provocar trastornos estructurales en el cerebro. Es una de las complicaciones más comunes de la diabetes y la neuropatía diabética y está relacionada con trastornos del sistema nervioso central. El Aloe vera tiene efectos antidiabéticos, antioxidantes y neuroprotectores. Este estudio fue diseñado para evaluar los efectos del gel de Aloe vera en los cambios del hipocampo, así como la expresión del factor de crecimiento nervioso y los receptores TrkA y P75 en el hipocampo de ratas diabéticas inducidas por estreptozotocina (STZ). Se dividieron al azar 25 ratas Wistar macho en 5 grupos de: control (solución salina normal), diabéticos (solución salina normal), gel de Aloe vera (400 mg / kg / día; sonda), diabéticos + gel de Aloe vera (400 mg / kg / día; sonda) y diabéticos + insulina NPH (10 UI / kg / día; subcutánea). La diabetes experimental fue inducida por inyección de estreptozotocina (60 mg / kg; intraperitoneal). Todos los grupos fueron tratados durante 8 semanas. Al final del tratamiento, se extrajeron los cerebros de las ratas para medir la expresión del factor de crecimiento nervioso y se evaluaron los receptores p75 y TrkA en el hipocampo. La inducción de diabetes después de 8 semanas provocó que los niveles de expresión de NGF y P75 en el grupo de diabéticos aumentaran significativamente en comparación con otros grupos (p <0,05). La expresión del receptor TrkA en el grupo diabético comparado con el control tuvo una reducción significativa (p <0,05). Por otro lado, el grupo de ratas diabéticas que recibieron la expresión en gel de Aloe vera de NGF y los niveles de expresión de P75 en comparación con el grupo de ratas diabéticas se redujo significativamente (p <0,05) y la expresión del receptor de TrkA en comparación con el grupo de ratas diabéticas tuvo un aumento significativo (p <0,05). Los resultados mostraron que la administración oral de gel de Aloe vera en ratas diabéticas mejora la hiperglucemia inducida por la diabetes. Por otro lado, el gel de Aloe vera causa modulación de la expresión del factor neurotrófico NGF a través del aumento de la expresión de receptor TrkA específico y no específico y regulación negativa del receptor de P75 en el hipocampo de ratas diabéticas inducidas por STZ.

Intracranial self-stimulation-reward or immobilization-aversion had different effects on neurite extension and the ERK pathway in neurotransmitter-sensitive mutant PC12 cells.

Various actions trigger pleasure (reward) or aversion (punishment) as emotional responses. Emotional factors that negatively affect brain neural control processes for long periods of time might cause various mental diseases by inducing neuronal changes. In the present study, newly developed PC12m12 cells which are　highly sensitivity to neurotransmitters such as acetylcholine (ACh), were used. Exposing the cells to plasma from rats that had been subjected to intracranial self-stimulation (ICSS) markedly upregulated neurite outgrowth. In addition, voluntary running in a wheel or forced on a rotating rod was used to induce behavioral excitation in rats, and examinations of their plasma confirmed that the ICSS-induced neurite outgrowth was not associated with the ICSS behavior itself. Furthermore, immunoblotting and treatment with U0126, an ERK (extracellular signal-regulated kinase) antagonist, showed that the ICSS-induced neurite outgrowth was related to neuronal ERK activity. Exposing the same cells to plasma from rats that had been subjected to immobilization (IMM) also increased neurite outgrowth. Although the degree of enhancement was not as great as that seen after the ICSS rat plasma treatment, it was less than that observed after treatment with ACh as a positive control. These results indicate that ICSS or IMM lead to varying degrees of morphological changes, such as enhanced neurite outgrowth, in PC12m12 cells, but the neuronal signal transduction pathways underlying these effects differ; i.e.,the former morphological change might involve the activation of the ERK pathway, whereas the latter changes might not. Using PC12m12 cells which exhibit sensitivity to neurotransmitters, it might be possible to clarify the pathogeneses of mental diseases at the neuronal level and search for therapeutic drugs.

Effects of Environmental Enrichment on Neurotrophins in an MPTP-Induced Parkinson's Disease Animal Model: A Randomized Trial.

The aim of this study was to investigate the effect of environmental enrichment (EE) on neurotrophin expression in an animal model of Parkinson's disease (PD). PD was induced via intraperitoneal injection of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP). Male mice (N = 42) were randomly divided into 3 groups: control, MPTP + standard condition (SC), and MPTP + EE. The groups were raised separately for 28 days. On Day 21 they received 1 injection (20 mg/kg MPTP or saline for MPTP and control groups, respectively) every 2 hr for a total of 4 injections. Animals were sacrificed 7 days after the final injection and their brains were immediately removed. Neurotrophins and messenger ribonucleic acid (mRNA) expression levels were measured. The BCL-2/Bax ratio significantly increased in the MPTP + EE compared to the MPTP + SC group. Nerve growth factor (NGF) mRNA level was upregulated (but not significantly) in the MPTP + EE compared to the MPTP + SC group. Tyrosine hydroxylase (TH) expression significantly increased in the MPTP + EE compared to the MPTP + SC group. Finally, expressions of proNGF and p75 neurotrophin receptor (p75NTR) were significantly downregulated in the MPTP + EE compared to the MPTP + SC group. Results confirm that EE has neuroprotective effects on dopaminergic neurons via suppression of activation of the p75NTR-mediated signaling pathway through the binding of proNGF and p75NTR. Findings suggest that use of EE as a therapeutic intervention would promote healthy aging by facilitating recovery following brain injury and preventing neurodegenerative diseases.

The Mixture of Gotu Kola, Cnidium Fruit, and Goji Berry Enhances Memory Functions by Inducing Nerve-Growth-Factor-Mediated Actions Both In Vitro and In Vivo.

Nerve growth factor (NGF), a typical neurotrophin, has been characterized by the regulation of neuronal cell differentiation and survival involved in learning and memory functions. NGF has a main role in neurite extension and synapse formation by activating the cyclic adenosine monophosphate-response-element-binding protein (CREB) in the hippocampus. The purpose of this study was to determine whether a mixture of Gotu Kola, Cnidium fruit, and Goji berry (KYJ) enhances memory function by inducing NGF-mediated actions both in vitro and in vivo. The KYJ combination increased NGF concentration and neurite length in C6 glioma and N2a neuronal cells, respectively. Additionally, we discovered memory-enhancing effects of KYJ through increased NGF-mediated synapse maturation, CREB phosphorylation, and cell differentiation in the mouse hippocampus. These findings suggest that this combination may be a potential nootropic cognitive enhancer via the induction of NGF and NGF-dependent activities.

The potential effects of anticonvulsant drugs on neuropeptides and neurotrophins in pentylenetetrazol kindled seizures in the rat.

Purpose: Neuropeptides and neurotrophic factors are thought to be involved in epileptogenesis. This study aims to investigate the potential effects of anticonvulsant drugs on neuropeptides (galanin and neuropeptide Y) and neurotrophic factors (BDNF and NGF) in pentylenetetrazol (PTZ)-kindled seizures in the rat.Methods: Forty-eight adult male Sprague-Dawley rats were included in the study. The animals were divided into 8 groups of six rats. Group 1 was defined as naïve control, and received no medication. Group 2 (PTZ + saline) was treated with sub-convulsive doses of PTZ (35 mg/kg) and saline i.p. for 14 days. For anticonvulsant treatments, Groups 3-8 were treated with 200 mg/kg levetiracetam (PTZ + LEV), 1 mg/kg midazolam (PTZ + MDZ), 80 mg/kg phenytoin (PTZ + PHT), 80 mg/kg topiramate (PTZ + TPR), 40 mg/kg lamotrigine (PTZ + LMT) and 50 mg/kg sodium valproate (PTZ + SV), respectively. All anticonvulsant drugs were injected 30 min prior to PTZ injection throughout 14 days. Following treatment period, behavioral, biochemical and immunohistochemical studies were performed.Results: PTZ + saline group revealed significantly decreased galanin, NPY, BDNF and NGF levels compared to control. PTZ + MDZ group had significantly increased galanin, BDNF and NGF levels compared to saline group. Also, PTZ + LEV group showed increased BDNF levels. PTZ + saline group revealed significantly lower neuron count and higher GFAP (+) cells in hippocampal CA1-CA3 regions. All anticonvulsants significantly reduced hippocampal astrogliosis whereas only midazolam, levetiracetam, sodium valproate and lamotrigine prevented neuronal loss.Conclusion: Our results suggested that anticonvulsant drugs may reduce the severity of seizures, and exert neuroprotective effects by altering the expression of neuropeptides and neurotrophins in the epileptogenic hippocampus.

Effects of lithium and valproate on behavioral parameters and neurotrophic factor levels in an animal model of mania induced by paradoxical sleep deprivation.

The present study aimed to evaluate the effects of treatment with lithium (Li) and valproate (VPA) on behaviors and brain BDNF, NGF, NT-3, NT-4 and GDNF levels in mice submitted to paradoxical sleep deprivation (PSD), which induces an animal model of mania. Male C57BL/6J mice received an intraperitoneal (i.p.) injection of saline solution (NaCl 0.09%, 1 ml/kg), Li (47.3 mg/kg, 1 ml/kg) or VPA (200 mg/kg, 1 ml/kg) once a day for seven days. Animals were randomly distributed into six groups (n = 10 per group): (1) Control + Sal; (2) Control + Li; (3) Control + VPA; (4) PSD + Sal; (5) PSD + Li; or (6) PSD + VPA. Animals were submitted to 36 h of PSD, and then, they were submitted to the open field test. The frontal cortex and hippocampus were dissected from the brain. The manic-like behaviors in the mice were analyzed. Treatment with Li and VPA reversed the behavioral alterations induced by PSD. PSD decreased BDNF, NGF, and GDNF levels in the frontal cortex and hippocampus of mice. The administration of Li and VPA protected the brain against the damage induced by PSD. However, PSD and the administration of Li and VPA did not affect the levels of NT-3 and NT-4 in either brain structure evaluated. In conclusion, the PSD protocol induced manic-like behavior in rats and induced alterations in neurotrophic factor levels. It seems that neurotrophic factors and sleep are essential targets to treat BD.

Role of serotonin 4 receptor in the growth of hippocampal neurons during the embryonic development in mice.

Serotonin (5-HT) homeostasis is critical for the brain development which influences neurogenesis, neuronal migration, and circuit formation. Distinctive distribution patterns of serotonin receptors (5-HTRs) in the brain govern various physiological activities. Amongst the 5-HTRs, serotonin 4 receptor (5-HT4R) is widely expressed in embryonic forebrain and affects neuronal development, synaptogenesis, and behavior, but its specific role in brain development is still not completely understood. Therefore, in the present study, we addressed the roles of 5-HT4R in the growth of hippocampal neurons during the development of mice brain. We cultured hippocampal neurons of the mouse at embryonic day 18 and then treatment of 5-HT4R agonist RS67333 was employed. We found RS67333 significantly increased the axonal length, diameter and branching along with total dendritic length, number of primary dendrites and their branching. In addition, these effects were neutralized by the concomitant treatment of 5-HT4R antagonist GR125487, which confirmed the specific role of the 5-HT4R in the growth of axon and dendrites. Further, the treatment of RS67333 upregulated the mRNA expression of collapsin response mediator protein-2 (CRMP2) and non-phosphorylated CRMP2 (npCRMP2) together with neurotrophic factors (BDNF, NT-3, NGF) and TRK-A. Additionally, the current research findings reveal that the knockdown of CRMP2 inhibited RS67333-induced growth of the axons and dendrites, which indicates that CRMP2 is required for the 5-HT4R-mediated growth of the axons and dendrites. Overall, the findings of the present in vitro study enrich the understanding and provide insight roles of 5-HT4R in embryonic brain development by promoting the growth of hippocampal neurons.

FTY720-Mitoxy reduces toxicity associated with MSA-like α-synuclein and oxidative stress by increasing trophic factor expression and myelin protein in OLN-93 oligodendroglia cell cultures.

Multiple system atrophy (MSA) is a fatal demyelinating disorder lacking any disease-modifying therapies. MSA pathology stems from aggregated α-synuclein (aSyn) accumulation in glial cytosolic inclusions of oligodendroglial cell (OLGs), the myelinating cells of brain. In MSA brains and in MSA animal models with aSyn accumulation in OLGs, aberrant expression of brain-derived neurotrophic factor (BDNF) and glial-cell-line-derived neurotrophic factor (GDNF) occur. Nerve growth factor (NGF) expression can also be altered in neurodegenerative diseases. It is unclear if oxidative stress impacts the viability of aSyn-accumulating OLG cells. Here, we show that OLN-93 cells stably expressing human wild type aSyn or the MSA-associated-aSyn-mutants G51D or A53E, are more vulnerable to oxidative stress. In dose response studies we found that OLN-93 cells treated 48 h with 160 nM FTY720 or our new non-immunosuppressive FTY720-C2 or FTY720-Mitoxy derivatives sustained normal viability. Also, FTY720, FTY720-C2, and FTY720-Mitoxy all stimulated NGF expression at 24 h. However only FTY720-Mitoxy also increased BDNF and GDNF mRNA at 24 h, an effect paralleled by increases in histone 3 acetylation and ERK1/2 phosphorylation. Myelin associated glycoprotein (MAG) levels were also increased in OLN-93 cells after 48 h treatment with FTY720-Mitoxy. FTY720, FTY720-C2, and FTY720-Mitoxy all prevented oxidative-stress-associated-cell-death of OLN-93 cells that lack any aSyn expression. However, only FTY720-Mitoxy protected MSA-like aSyn-expressing-OLN-93-cells against oxidative-cell-death. These data identify potent protective effects for FTY720-Mitoxy with regard to trophic factors as well as MAG expression by OLG cells. Testing of FTY720-Mitoxy in mice is thus a judicious next step for neuropharmacological preclinical development.

[Effects of n-hexane on learning and memory and the expressions of nerve growth factor mRNA and nerve growth factor receptor mRNA of brain tissue in mice exposed to N-hexane].

Objective: To Effects of n-hexane on learning and memory and the expressions of nerve growth factor (NGF) mRNA and nerve growth factor receptor (NGFR) mRNA of brain tissue in mice exposed to N-hexane. Methods: 40 Kunming mice were randomly divided into low-dose group, meddle-dose group, high-dose dose group and control group, with 10 mice in each group. All the groups were orally exposed to n-hexane in different doses: low-dose group with 43.5 mg/kg, middle-dose group with 86.5 mg/kg and high-dose group with 173.0 mg/kg, 1 time per day for 20 d. After the poisoning, the Y-arm test and the expressions of NGF mRNA and NGFR mRNA and the concentrations of NGF and NGFR in the brain tissues of each group were measured. Results: In the first Y-arm test, there existed a significant difference in correct reaction rate generally in all groups (P<0.05), and correct reaction rate in the middle-dose group and the high-dose group were low significantly compared with that in the control group(P<0.05). In the second Y-arm test, there existed a significant differences in total electric shock time and correct reaction rate generally in all groups (P<0.01), and the total electric shock time prolonged significantly and the correct response rate decreased significantly in 3 dose groups compared with those of the control group(P<0.05). The expression levels of NGF mRNA in brain tissues of low, meddle and high dose-groups were 0.81±0.66, 0.67±0.37 and 0.69±0.26, and the expression levels of NGFR mRNA were 1.22±0.42, 1.98±0.84 and 2.01±2.01, respectively. Compared with the control group, the expressions of NGF mRNA in the 3 dose groups decreased significantly (P<0.05), and the expression of NGFR mRNA in middle-and high-dose groups increased significantly (P<0.05). The concentrations of NGF in brain tissues of low,meddle and high dose-groups were 39.97±7.24 ng/L, 39.26±7.88 ng/L,31.70±8.21 ng/L,and the concentrations of NGFR were 17.37±6.82 ng/L,21.37±7.16 ng/L, 22.46±7.70 ng/L, respectively. Compared with the control group, the concentrations of NGF in high-dose groups decreased significantly(P<0.05), and the concentrations of NGFR in middle-and high-dose groups increased significantly (P<0.05). Conclusion: N-hexane exposure can result in decrease of learning and memory in mice, which may be related to abnormal expression of NGF mRNA and NGFR mRNA in brain tissue.

Effect of lurasidone vs olanzapine on neurotrophic biomarkers in unmedicated schizophrenia: A randomized controlled trial.

Neurotrophic factors like Brain-Derived Neurotrophic Factor (BDNF), Neurotrophin 3 (NT3) and Nerve Growth Factor (NGF), play a role in neuroplasticity and neurogenesis contributing to the pathogenesis of schizophrenia. The objective of the present study was to investigate and compare the effect of olanzapine and lurasidone on the change in serum neurotrophins in patients with schizophrenia. The present study was a randomized, open-label, active-controlled, parallel design clinical trial. After randomization baseline evaluations of serum BDNF, NGF, NT3, Positive and Negative Syndrome Scale (PANSS) scoring, Social and Occupational Functioning Assessment Scale (SOFAS) scoring of 101 unmedicated schizophrenia patients were done. Patients were reassessed after 6 weeks of monotherapy with olanzapine or lurasidone. Serum BDNF increased after treatment with both the drug groups but rise with olanzapine was found to be significantly higher (916.22; 95 %CI: 866.07 to 966.37; p < 0.001) in comparison to lurasidone. Increase in levels NGF and NT3 was also observed but there was no significant difference between the groups (NGF: 2.32; CI: 3.54 to -3.53; p = 0.57 and NT3: 0.99; CI: 2.11 to 0.14; p = 0.086). The difference in improvement in PANSS and SOFASS with both the drugs was not statistically significant. Both the drugs alleviate the symptoms of schizophrenia but olanzapine was better tolerated. Our findings suggest that increase in serum BDNF with olanzapine monotherapy is significantly higher than that with lurasidone but there is no significant difference in change in serum NGF and NT3. TRIAL REGISTRATION: ClinicalTrials.gov identifier: (NCT03304457).

The role of neurotrophic factors in manic-, anxious- and depressive-like behaviors induced by amphetamine sensitization: Implications to the animal model of bipolar disorder.

BACKGROUND: Bipolar disorder (BD) and substance use disorders share common symptoms, such as behavioral sensitization. Amphetamine-induced behavioral sensitization can serve as an animal model of BD. Neurotrophic factors have an important role in BD pathophysiology. This study evaluated the effects of amphetamine sensitization on behavior and neurotrophic factor levels in the brains of rats. METHODS: Wistar rats received daily intraperitoneal (i.p) injections of dextroamphetamine (d-AMPH) 2 mg/kg or saline for 14 days. After seven days of withdrawal, the animals were challenged with d-AMPH (0.5 mg/kg, i.p) and locomotor behavior was assessed. In a second protocol, rats were similarly treated with d-AMPH (2 mg/kg, i.p) for 14 days. After withdrawal, without d-AMPH challenge, depressive- and anxiety-like behaviors were evaluated through forced swimming test and elevated plus maze. Levels of brain-derived neurotrophic factor (BDNF), nerve growth factor (NGF), neurotrophin 3 (NT-3), neurotrophin 4/5 (NT-4/5) and glial-derived neurotrophic factor (GDNF) were evaluated in the frontal cortex, hippocampus, and striatum. RESULTS: D-AMPH for 14 days augmented locomotor sensitization to a lower dose of d-AMPH (0.5 mg/kg) after the withdrawal. d-AMPH withdrawal induced depressive- and anxious-like behaviors. BDNF, NGF, and GDNF levels were decreased, while NT-3 and NT-4 levels were increased in brains after d-AMPH sensitization. LIMITATIONS: Although d-AMPH induces manic-like behavior, the mechanisms underlying these effects can also be related to phenotypes of drug abuse. CONCLUSIONS: Together, vulnerability to mania-like behavior following d-AMPH challenge and extensive neurotrophic alterations, suggest amphetamine-induced behavioral sensitization is a good model of BD pathophysiology.

Direct and indirect evidences of BDNF and NGF as key modulators in depression: role of antidepressants treatment.

PURPOSE: Depression is one of the most prevalent, recurrent and life-threatening mental illnesses. However, the precise mechanism underlying the disorder is not yet clearly understood. It is therefore, essential to identify the novel biomarkers which may help in the development of effective treatment. METHODS: In this milieu, the profile of the brain-derived neurotrophic factor (BDNF) and nerve growth factor (NGF) were considered as biomarkers in the light of pathophysiology of depression and its treatment. RESULTS: Previously, we have reported that BDNF level in the postmortem brain of suicide victims was significantly lower than those of normal controls. We also found decreased BDNF levels in the specific brain regions of the learned helplessness model of depression in rat, and was found to increase normal level following chronic fluoxetine hydrochloride treatment. NGF is another important member of neurotrophin, which is dysregulated in the pathophysiology of depression in some models of peripheral nerve damage and stress. The results shown evidences of the effect of antidepressants on modulating depression via the NGF in preclinical and clinical models of depression, but conflicted, therefore make it currently difficult to affirm the therapeutic role of antidepressants. CONCLUSIONS: Here, we review some of the preclinical and clinical studies aimed at disclosing the role of BDNF and NGF mediated pathophysiological mechanisms of depression and the new therapeutic approaches targeting those key molecules. In addition, an important link between BDNF, NGF and depression has been discussed in the light of current existing knowledge.

Binding of Zn(II) to Tropomyosin Receptor Kinase A in Complex with Its Cognate Nerve Growth Factor: Insights from Molecular Simulation and in Vitro Essays.

The binding of the human nerve growth factor (NGF) protein to tropomyosin receptor kinase A (TrkA) is associated with Alzhemeir's development. Owing to the large presence of zinc(II) ions in the synaptic compartments, the zinc ions might be bound to the complex in vivo. Here, we have identified a putative zinc binding site using a combination of computations and experiments. First, we have predicted structural features of the NGF/TrkA complex in an aqueous solution by molecular simulation. Metadynamics free energy calculations suggest that these are very similar to those in the X-ray structure. Here, the "crab" structure of the NGF shape binds tightly to two TrkA "pincers". Transient conformations of the complex include both more extended and more closed conformations. Interestingly, the latter features facial histidines (His60 and His61) among the N-terminal D1-D3 domains, each of which is a potential binding region for biometals. This suggests the presence of a four-His Zn binding site connecting the two chains. To address this issue, we investigated the binding of a D1-D3 domains' peptide mimic by stability constant and nuclear magnetic resonance measurements, complemented by density functional theory-based calculations. Taken together, these establish unambiguously a four-His coordination of the metal ion in the model systems, supporting the presence of our postulated binding site in the NGF/TrkA complex.

Lion's Mane Medicinal Mushroom, Hericium erinaceus (Agaricomycetes), Modulates Purinoceptor-Coupled Calcium Signaling and Murine Nociceptive Behavior.

Hericium erinaceus is well known for the neurotrophic effect it confers by promoting nerve growth factor biosynthesis. We discovered a novel bioactivity of H. erinaceus in its ability to suppress adenosine triphosphate (ATP)-induced calcium signaling in neuronal PC12 cells. ATP, known primarily as a neurotransmitter, also acts on purinoceptors (P2 purinergic receptor [P2R]) to generate the cellular calcium signaling and secretion that mediate P2R physiological manifestations, including pain. Chronic pain reduces quality of life. However, constant analgesic administration can cause liver and kidney injury, as well as loss of the analgesic effect because of desensitization. In this study we investigated the analgesic potential of H. erinaceus through measurements of ATP-induced Ca2+ signaling in cell lines and observation of pain behaviors in mice. In P2R-coupled Ca2+ signaling measurements, extracts of H. erinaceus mycelia (HEEs) blocked ATP-induced Ca2+ signaling in both rat PC12 cells and human HOS cells. HEEs completely blocked ATP-induced Ca2+ signaling in human HOS cells, suggesting that this effect of HEEs is exerted through the P2R subtypes present in HOS cells, which include the P2X4, P2X7, P2Y2, and P2Y4 subtypes. In observations of animal behavior during pain, HEEs significantly reduced heat-induced pain, including postponing both the tail-flick response to heat stimulation and the paw-lifting response to a hot plate. This study demonstrates novel characteristics of H. erinaceus in reducing nociceptive behavior and blocking the functional activity of P2R. Further studies are required to verify this linkage and its molecular mechanisms.

Epigenetic Regulation of the Promotor Region of Vascular Endothelial Growth Factor-A and Nerve Growth Factor in Opioid-Maintained Patients.

AIMS: The nerve growth factor (NGF) and the vascular endothelial growth factor-A (VEGF-A) may be of importance for psychiatric diseases including substance use disorders. The aim of the study was to identify differences in the regulation of both neuropeptides via the DNA-methylation status of the promotor regions of NGF and VEGF-A in different forms of maintenance therapy for opioid dependence and the related stress regulation via the hypothalamic-pituitary-adrenal axis. METHODS: We compared methylation levels of opioid-dependent patients receiving treatment with diamorphine (n = 28) or levomethadone (n = 54) and similar levels in a healthy control group (n = 72). RESULTS: There was a significantly higher methylation of VEGF-A in opioid-maintained patients with levomethadone compared to that in the control group (estimated marginal means [EMM] [SE]): 0.036 [0.003] vs. 0.020 [0.003]; p < 0.001). We performed a cluster analysis for NGF, splitting up the results in 4 clusters. We found significant changes in methylation rates of the opioid-maintained patients compared to the controls in cluster I ([EMM] [SE]: 0.064 [0.005] vs. 0.084 [0.006]; p = 0.03), cluster II ([EMM] [SE]: 0.133 [0.013] vs. 0.187 [0.014]; p < 0.001) and cluster III ([EMM] [SE]: 0.190 [0.014] vs. 0.128 [0.016]; p < 0.001). CONCLUSIONS: The results are of importance, as they indicate that long-term changes in stress regulation regulated by neurotrophines are a crucial part of the symptomatology of opioid dependence, thus influencing drug consumption and the different forms of opioid-maintenance therapies.

Effects of Taurine on Alterations of Neurobehavior and Neurodevelopment Key Proteins Expression in Infant Rats by Exposure to Hexabromocyclododecane.

Hexabromocyclododecanes (HBCDs) is a widely used flame retardant. Studies have found that HBCDs has toxic effects on endocrine and neural development, leading to adverse effects on behavior, learning and memory. This study aimed to investigate the protective effects of taurine on cognitive function, neurotrophic factors expression of infant rats exposured to HBCDs. Sprague-Dawley rats of 10-days old were oral gavaged of different doses (0.3, 3 and 30 mg/kg) of HBCDs and 30 mg/kg HBCDs with 300 mg/kg taurine for 60 consecutive days. Rat cognitive function was detected by the method of Morris water maze test. The protein expressions of brain derived neurotrophic factor (BDNF), nerve growth factor (NGF) and fibroblast growth factor (FGF) were assayed by Western-blotting. Results showed that rats exposed to HBCDs significantly declined rats spatial learning and memory ability by increasing the latency time of seeking the platform (P < 0.05), decreasing the numbers that each rat had crossed the non-exits and the time spent in the target quadrant as compared with those in control rats (P < 0.05). Taurine treatment significantly reversed the effects of HBCDs. Western-blotting results showed that expression of BDNF, NGF and FGF proteins in the low dose group were obviously increased compared with those in control rats (P < 0.01), and middle-dose and high dose groups significantly decreased. Taurine treatment increased BDNF and NGF expression as compared with high dose groups while Taurine seemed to have no effects on FGF. These result suggested that higher doses of HBCDs early exposure in the developing rats could decrease neurotrophic factors including BDNF, NGF, FGF, which have an impact on neural development, damage on learning and memory.

Effect of estradiol on the expression of angiogenic factors in epithelial ovarian cancer.

INTRODUCTION: Ovarian cancer presents a high angiogenesis (formation of new blood vessels) regulated by pro-angiogenic factors, mainly vascular endothelial growth factor (VEGF) and nerve growth factor (NGF). An association between endogenous levels of estrogen and increased risk of developing ovarian cancer has been reported. Estrogen action is mediated by the binding to its specific receptors (ERα and ERß), altered ERα/ERß ratio may constitute a marker of ovarian carcinogenesis progression. OBJECTIVE: To determine the effect of estradiol through ERα on the expression of NGF and VEGF in epithelial ovarian cancer (EOC). METHODOLOGY: Levels of phosphorylated estrogen receptor alpha (pERα) were evaluated in well, moderate and poorly differentiated EOC samples (EOC-I, EOC-II, EOC-III). Additionally, ovarian cancer explants were stimulated with NGF (0, 10 and 100 ng/ml) and ERα, ERß and pERα levels were detected. Finally, human ovarian surface epithelial (HOSE) and epithelial ovarian cancer (A2780) cell lines were stimulated with estradiol, where NGF and VEGF protein levels were evaluated. RESULTS: In tissues, ERs were detected being pERα levels significantly increased in EOC-III samples compared with EOC-I (p<0.05). Additionally, ovarian explants treated with NGF increased pERα levels meanwhile total ERα and ERß levels did not change. Cell lines stimulated with estradiol revealed an increase of NGF and VEGF protein levels (p<0.05). CONCLUSIONS: Estradiol has a positive effect on pro-angiogenic factors such as NGF and VEGF expression in EOC, probably through the activation of ERα; generating a positive loop induced by NGF increasing pERα levels in epithelial ovarian cells.