Brain-derived Neurotrophin Factor Research Articles

Stimulating myelin restoration with BDNF: a promising therapeutic approach for Alzheimer's disease.

Alzheimer's Disease (AD) is a chronic neurodegenerative disorder constituting the most common form of dementia (60%-70% of cases). Although AD presents majorly a neurodegenerative pathology, recent clinical evidence highlights myelin impairment as a key factor in disease pathogenesis. The lack of preventive or restorative treatment is emphasizing the need to develop novel therapeutic approaches targeting to the causes of the disease. Recent studies in animals and patients have highlighted the loss of myelination of the neuronal axons as an extremely aggravating factor in AD, in addition to the formation of amyloid plaques and neurofibrillary tangles that are to date the main pathological hallmarks of the disease. Myelin breakdown represents an early stage event in AD. However, it is still unclear whether myelin loss is attributed only to exogenous factors like inflammatory processes of the tissue or to impaired oligodendrogenesis as well. Neurotrophic factors are well established protective molecules under many pathological conditions of the neural tissue, contributing also to proper myelination. Due to their inability to be used as drugs, many research efforts are focused on substituting neurotrophic activity with small molecules. Our research team has recently developed novel micromolecular synthetic neurotrophin mimetics (MNTs), selectively acting on neurotrophin receptors, and thus offering a unique opportunity for innovative therapies against neurodegenerative diseases. These small sized, lipophilic molecules address the underlying biological effect of these diseases (neuroprotective action), but also they exert significant neurogenic actions inducing neuronal replacement of the disease areas. One of the significant neurotrophin molecules in the Central Nervous System is Brain-Derived-Neurotrophin-Factor (BDNF). BDNF is a neurotrophin that not only supports neuroprotection and adult neurogenesis, but also mediates pro-myelinating effects in the CNS. BDNF binds with high-affinity on the TrkB neurotrophin receptor and enhances myelination by increasing the density of oligodendrocyte progenitor cells (OPCs) and playing an important role in CNS myelination. Conclusively, in the present review, we discuss the myelin pathophysiology in Alzheimer's Diseases, as well as the role of neurotrophins, and specifically BDNF, in myelin maintenance and restoration, revealing its valuable therapeutic potential against AD.

Brain Derived Neurotrophin Factor (BDNF) as a clinical marker of endometriosis

Background: Endometriosis is a chronic, multifactorial disease of unknown etiology that affects approximately 10% of all women of childbearing age. It is characterized by dysmenorrhea and chronic pelvic pain, often associated with other symptoms (dyspareunia, dyschezia, rectal bleeding, dysuria, among others) and in 30-40% of cases it is associated with infertility. The presence of pelvic pain is related to the process of neuroangiogenesis, with the presence of BDNF being a key piece in its development. Several recent studies have shown that BDNF levels are elevated in the serum of patients with endometriosis compared to patients without endometriosis. The objective of this study is to demonstrate if BDNF levels are higher in patients with endometriosis and if there is am correlation with the level of pain. Material and methods: The study included 59 patients diagnosed with ovarian endometriosis in the Gynecology service of the Garcia Orcoyen Hospital during the period from November 2021 to August 2022. A blood sample was taken before surgery and their BDNF blood levels were determined. The levels of BDNF were analyzed compared to the control group in 10 patients undergoing laparoscopic tubal ligation to establish if the levels were higher in the endometriosis group and if there was a correlation with the intensity of pain.

Electroacupuncture improves learning and memory impairment and enhances hippocampal synaptic plasticity through BDNF/TRKB/CREB signaling pathway in cerebral ischemia-reperfusion injury rats

To observe the effect of electroacupuncture on brain-derived neurotrophin factor (BDNF) / tyrosine kinase receptor B (TRKB) / cyclic adenosine monophosphate response element binding protein (CREB) pathway, synaptic plasticity marker protein and synaptic ultrastructure in the hippocampus of rats with learning and memory impairment induced by cerebral ischemia reperfusion (IR), so as to explore its mechanisms underlying improvement of cognitive impairment after stroke. SD rats were randomly divided into blank, sham operation, model, and EA groups, with 12 rats in each group. The model of IR was established by occlusion of the middle cerebral artery. EA (2 Hz/10 Hz, 1-3 mA) was applied to "Shenting" (GV24) and "Baihui" (GV20) for 30 min, once daily for 14 days. The neurological function was evaluated according to the Zea Longa's score criteria. Morris water maze test was used to detect the learning and memory function of the rats. Nissl staining was used to observe the pathological morphology of the hippocampus. Transmission electron microscopy was used to observe the ultrastructure of the syna-pse in the hippocampus, the synaptic gap width and postsynaptic dense substance (PSD) thickness were measured. Immunofluorescence staining was used to observe the positive expression levels of BDNF, PSD-95 and synaptophysin (SYN) in hippocampal CA1 region. The protein expression levels of BDNF, TRKB, CREB, PSD-95, and SYN in hippocampal tissue were detected by Western blot. Compared with the sham operation group, the neurological function score and escape latency (EL) were significantly increased (P<0.01), the times of crossing the original platform were decreased (P<0.01), the number of neurons in the CA1 area of the hippocampus was reduced, with incomplete morphology, widened synaptic gaps and significantly decreased PSD thickness (P<0.01), the positive expressions of BDNF, PSD-95, SYN and the protein expression levels of BDNF, TRKB, CREB, PSD-95, SYN were significantly decreased (P<0.01) in the model group. Compared with the model group, the neurological function scores and EL on the 12th and 13th day were decreased (P<0.01, P<0.05), the times of crossing the original platform were increased (P<0.01), the morphology of hippocampal CA1 neurons improved, the synaptic gaps was decreased (P<0.01), the PSD thickness was significantly increased (P<0.01), the positive expressions of BDNF, PSD-95, SYN, and the protein expression levels of BDNF, TRKB, CREB, PSD-95, SYN were increased (P<0.05, P<0.01) in the EA group. EA can alleviate cognitive impairment in IR rats, which may be related to its function in up-regulating the proteins of BDNF/TRKB/CREB pathway, promoting the expressions of synaptic plasticity marker proteins PSD-95 and SYN, thus improving the synaptic plasticity.

Correlation of Brain-Derived Neurotrophin Factor Levels in Epilepsy Patients Treated with Valproic Acid and Phenytoin with Cognitive Function

BACKGROUND: Epilepsy cases requiring OAE multitherapy are found in 40% of total epilepsy cases. Many epilepsy patients are referred to Dr. Kariadi Hospital Semarang because of the occurrence of intractable epilepsy. Valproic acid is one of the OAEs that are widely used in the BPJS era in Indonesia as a combination of phenytoin. Seizures increase the expression of BDNF mRNA and protein. METHODS: This study is a cross-sectional study that took place from January to May 2022. The subjects of this study were epilepsy patients who used a combination of phenytoin-valproic acid who met the inclusion criteria. Patient data were obtained from medical records and filling out questionnaires. Patients were asked to fast for ± 8−10 h. Furthermore, blood sampling (±5 ml) of BDNF was carried out at 08.00−10.00 WIB. Cognitive function assessments were performed using MoCA-Ina and the Hamilton depression rating scale at the same time. Data were analyzed by Spearman correlation test and partial correlation test. The results are said to be meaningful if p &lt; 0.05. RESULTS: Thirty-two study subjects used a combination of phenytoin-valproic acid. The Spearman correlation test between the relationship between BDNF levels and cognitive function in epilepsy patients treated with valproic acid and phenytoin showed a significant relationship with the direction and strength of which was strongly positive (r = 0.676 and p ≤ 0.001). The partial correlation test between the relationship between BDNF levels and cognitive function after controlling for age (r = 0.692), seizure frequency (r = 0.641), duration of combination therapy (r = 0.700), and age of seizure onset (r = 0.693) remained the same, while after controlling for the level of education (r = 0.812) and the type of seizure (r = 0.747) increased. CONCLUSION: There is a strong correlation between BDNF levels and cognitive function in epilepsy patients treated with valproic acid and phenytoin. The relationship between BDNF levels and cognitive function remained the same after controlling for age, frequency of seizures, duration of combination therapy, and age of onset of epilepsy.

The Role of β-Estradiol in Expression of Protective Neuronal Factors of TGFbeta1, TGFbeta2 and Brain Derived Neurotrophin Factor in Cultured Astrocytes

Background: Astrocytes are an important source for the production and release of different cytokines, and their role in the development of neurodegenerative diseases is evident. In the neurodegenerative diseases there are significant changes in these cytokines. For this purpose, the effects of β-estradiol on neuronal protective factors: TGFβ1, TGFβ2 and BDNF were investigated. Methods: In this study, astrocytes from cortex of four newborn rats were isolated and cultivated in cell culture medium. Then their identity confirmed by microscopy and immunocytochemistry. The effect of three different concentrations of β-estradiol (2, 5 and 10 nM) on the expression of selected genes was investigated by Real Time-PCR, also MTT assay was used to evaluate cell viability. Results: In proportion to the increase of β-estradiol concentration, the expression of selective genes changed from 3 to 8 times in comparison to control cells. In addition, by increasing the concentration of β-estradiol, cells exhibited more cellular viability than control cells which was proportional to drug concentration. During neurodegenerative diseases the level of different neuroprotective factors, including the factors selected in this study decreases dramatically. Conclusion: Therefore, increasing the expression of these neuroprotective agents by β-estradiol or other substances may reduce some of the damage associated with astrocytes and prevent disease progression.

Randomized trial of exercise on depressive symptomatology and brain derived neurotrophic factor (BDNF) in ovarian cancer survivors: The Women's Activity and Lifestyle Study in Connecticut (WALC)

ObjectivesDepression is one of the most prevalent mental disorders, and rates are higher among cancer survivors than the general population, and higher in ovarian cancer patients compared to cohorts of other cancer survivors. Physical activity has been associated with lower depressive symptoms in cancer survivors, yet no trial has examined this association in women with ovarian cancer. We examined the effect of exercise on depression symptomatology and serum brain derived neurotrophin factor (BDNF) which has been associated with depression, in women with ovarian cancer. MethodsWe conducted a 6-month home-based randomized trial of exercise vs. attention-control (AC) in 144 ovarian cancer survivors. Depressive symptomatology was measured via the Center for Epidemiologic Studies Depression Scale (CES-D). Serum total and free BDNF was measured at baseline and 6-months. Student's t-statistic and mixed-model repeated measures analysis was used to evaluate six-month change between arms in CES-D scores and BDNF. ResultsWomen were 57.3 ± 8.6 (mean ± SD) years old, 1.7 ± 1.0 years post-diagnosis with a baseline CES-D score of 11.79 ± 10.21. The majority (55%) were diagnosed with stage III/IV ovarian cancer. CES-D scores decreased in the exercise arm by 2.7 points (95% CI: −4.4, −0.9) or a 21% decrease compared to a 0.3 point decrease (−2.2, 1.5) (3% decrease) in the AC arm (P = 0.05). There was no difference in change in total or free BDNF between the exercise and AC arms. ConclusionsOvarian cancer survivors are able to exercise at recommended levels, and exercise was associated with a significant reduction in depressive symptomatology.

Exploring the role and mechanisms of diallyl trisulfide and diallyl disulfide in chronic constriction-induced neuropathic pain in rats.

BackgroundGarlic oil is a rich source of organosulfur compounds including diallyl disulfide and diallyl trisulfide. There have been studies showing the neuroprotective actions of these organosulfur compounds. However, the potential of these organosulfur compounds in neuropathic pain has not been explored. The present study was aimed at investigating the pain attenuating potential of diallyl disulfide and diallyl trisulfide in chronic constriction injury (CCI)-induced neuropathic pain in rats. The study also explored their pain-attenuating mechanisms through modulation of H2S, brain-derived neurotrophin factor (BDNF) and nuclear factor erythroid 2-related factor 2 (Nrf2).MethodsThe rats were subjected to CCI injury by ligating the sciatic nerve in four places. The development of neuropathic pain was measured by assessing mechanical hyperalgesia (Randall–Selittotest), mechanical allodynia (Von Frey test), and cold allodynia (acetone drop test) on 14th day after surgery.ResultsAdministration of diallyl disulfide (25 and 50 mg/kg) and diallyl trisulfide (20 and 40 mg/kg) for 14 days led to a significant reduction in pain in CCI-subjected rats. Moreover, treatment with these organosulfur compounds led to the restoration of H2S, BDNF and Nrf2 levels in the sciatic nerve and dorsal root ganglia. Co-administration of ANA-12 (BDNF blocker) abolished pain attenuating actions as well as BDNF and the Nrf2 restorative actions of diallyl disulfide and diallyl trisulfide, without modulating H2S levels.ConclusionsDiallyl disulfide and diallyl trisulfide have the potential to attenuate neuropathic pain in CCI-subjected rats possibly through activation of H2S-BDNF-Nrf2 signaling pathway.

Actions of Brain-Derived Neurotrophin Factor in the Neurogenesis and Neuronal Function, and Its Involvement in the Pathophysiology of Brain Diseases.

It is well known that brain-derived neurotrophic factor, BDNF, has an important role in a variety of neuronal aspects, such as differentiation, maturation, and synaptic function in the central nervous system (CNS). BDNF stimulates mitogen-activated protein kinase/extracellular signal-regulated kinase (MAPK/ERK), phosphoinositide-3kinase (PI3K), and phospholipase C (PLC)-gamma pathways via activation of tropomyosin receptor kinase B (TrkB), a high affinity receptor for BDNF. Evidence has shown significant contributions of these signaling pathways in neurogenesis and synaptic plasticity in in vivo and in vitro experiments. Importantly, it has been demonstrated that dysfunction of the BDNF/TrkB system is involved in the onset of brain diseases, including neurodegenerative and psychiatric disorders. In this review, we discuss actions of BDNF and related signaling molecules on CNS neurons, and their contributions to the pathophysiology of brain diseases.

MicroRNA-107 regulates anesthesia-induced neural injury in embryonic stem cell derived neurons.

SummaryKetamine, though widely used in pediatric anesthesia, may induce cortical neurotoxicity in young patients. This study focused on an in vitro model of rat brain embryonic stem cell (ESC)‐derived neurons to investigate the effects of microRNA‐107 (miR‐107) on ketamine‐induced neural injury. Rat brain ESCs were proliferated in vitro and differentiated toward neuronal fate. Ketamine induced neural injury in ESC‐derived neurons was inspected by TUNEL and neurite growth assays. Ketamine‐induce aberrant miR‐107 expression was examined by qRT‐PCR. MiR‐107 was downregulated in ESCs through lentiviral transduction. Its effect on ketamine‐induced neural injury in ESC‐derived neurons was then examined. Potential downstream target of miR‐107, brain derived neurotrophin factor (BDNF), was inspected by dual‐luciferase reporter assay and qRT‐PCR. BDNF was knocked down, through siRNA transfection, in NSCs to investigate its functional involvement in miR‐107 mediated neural protection in ketamine‐injured NSC‐derived neurons. Ketamine induced apoptosis, neurite degeneration, and upregulated miR‐107 in NSC‐derived neurons. Lentivirus‐mediated miR‐107 downregulation attenuated ketamine‐induced neural injury. BDNF was proven to be directly and inversely regulated by miR‐107 in NSC‐derived neurons. SiRNA‐mediated BDNF inhibition reversed the protective effect of miR‐107 downregulation on ketamine injury in NSC‐derived neurons. MiR‐107 / BDNF was demonstrated to be an important epigenetic signaling pathway in regulating ketamine‐induced neural injury in cortical neurons. © 2018 The Authors. IUBMB Life published by Wiley Periodicals,Inc. on behalf of International Union of Biochemistry and Molecular Biology., 71(1):20–27, 2019

Cell type-specific effects of BDNF in modulating dendritic architecture of hippocampal neurons.

Brain-derived neurotrophin factor (BDNF) has been implicated in neuronal survival, differentiation and activity-dependent synaptic plasticity in the central nervous system. It was suggested that during postnatal development BDNF regulates neuronal architecture and spine morphology of neurons within certain brain areas but not others. Particularly striking are the differences between striatum, cortex and hippocampus. Whether this is due to region- or cell type-specific effects is so far not known. We address this question using conditional bdnf knock-out mice to analyze neuronal architecture and spine morphology of pyramidal cortical and hippocampal neurons as well as inhibitory neurons from these brain areas and excitatory granule neurons from the dentate gyrus. While hippocampal and cortical inhibitory neurons and granule cells of the dentate gyrus are strongly impaired in their architecture, pyramidal neurons within the same brain regions only show a mild phenotype. We found a reduced TrkB phosphorylation within hippocampal interneurons and granule cells of the dentate gyrus, accompanied by a significant decrease in dendritic complexity. In contrast, in pyramidal neurons both TrkB phosphorylation and neuronal architecture are not altered. The results suggest diverse levels of responsiveness to BDNF for different hippocampal and cortical neuronal populations within the same brain area. Among the possible mechanisms mediating these differences in BDNF function, we tested whether zinc might be involved in TrkB transactivation specifically in pyramidal neurons. We propose that a BDNF-independent transactivation of TrkB receptor may be able to compensate the lack of BDNF signaling to modulate neuronal morphology in a cell type-specific manner.

Long noncoding RNA BDNF-AS is associated with clinical outcomes and has functional role in human prostate cancer

BackgroundThe underlying molecular mechanisms of prostate cancer (CaP) are largely unknown. We investigated the expression, prognostic value and functional role of long non-coding RNA (lncRNA) brain-derived neurotrophin factor antisense (BDNF-AS) in CaP. MethodsClinical tumor samples were excised from patients with CaP. Their endogenous BDNF-AS expression levels were evaluated by qRT-PCR. Correlations between CaP patients’ endogenous BDNF-AS expression and their clinicopathological factors, overall survival were statistically analyzed. BDNF-AS expression levels were also probed in immortal CaP cell lines. In LNCaP and PC-3 cells, BDNF-AS was ectopically overexpressed through lentiviral transduction. The functions of BDNF-AS upregulation on CaP cell development were evaluated both in vitro and in vivo. ResultsBDNF-AS was downregulated in human CaP tumors. Low BDNF-AS expression was correlated with CaP patients’ poor prognosis and shorter overall survival. BDNF-AS was also found to be lowly expressed in CaP cell lines. In LNCaP and PC-3 cells, lentivirus-driven BDNF-AS overexpression exerted significantly tumor-suppressing effects on hindering cancer cell proliferation and invasion in vitro, and explant growth in vivo. ConclusionDownregulated BDNF-AS in CaP patients could be a potential prognostic biomarker for predicating poor prognosis and survival. Upregulating BDNF-AS may be a novel molecular intervening target for CaP treatment.

Brain-derived neurotrophic factor derived from sensory neurons plays a critical role in chronic pain.

Many studies support the pro-nociceptive role of brain-derived neurotrophin factor (BDNF) in pain processes in the peripheral and central nervous system. We have previously shown that nociceptor-derived BDNF is involved in inflammatory pain. Microglial-derived BDNF has also been shown to be involved in neuropathic pain. However, the distinct contribution of primary afferent-derived BNDF to chronic pain processing remains undetermined. In this study, we used Avil-CreERT2 mice to delete Bdnf from all adult peripheral sensory neurons. Conditional BDNF knockouts were healthy with no sensory neuron loss. Behavioural assays and in vivo electrophysiology indicated that spinal excitability was normal. Following formalin inflammation or neuropathy with a modified Chung model, we observed normal development of acute pain behaviour, but a deficit in second phase formalin-induced nocifensive responses and a reversal of neuropathy-induced mechanical hypersensitivity during the later chronic pain phase in conditional BDNF knockout mice. In contrast, we observed normal development of acute and chronic neuropathic pain in the Seltzer model, indicating differences in the contribution of BDNF to distinct models of neuropathy. We further used a model of hyperalgesic priming to examine the contribution of primary afferent-derived BDNF in the transition from acute to chronic pain, and found that primed BDNF knockout mice do not develop prolonged mechanical hypersensitivity to an inflammatory insult. Our data suggest that BDNF derived from sensory neurons plays a critical role in mediating the transition from acute to chronic pain.

Comparison of the influence of two models of mild stress on hippocampal brain-derived neurotrophin factor (BDNF) immunoreactivity in old age rats.

The way hippocampal neurons function during stress in old age (critical times of life) is dependent on brain derived neurotrophin factor (BDNF). This study examined the influence of acute and chronic forced swim (FS) or high-light open field (HL‑OF) stimulation on the density of BDNF immunoreactive (ir) neurons in the hippocampal pyramidal layers of CA1, CA2, CA3 regions and the granular layer of dentate gyrus (DG) in old (postnatal day 720; P720) Wistar Han rats. Our data showed that in comparison with non-stressed rats, acute FS caused a significant increase in the density of BDNF-ir neurons in CA2 and CA3, while acute HL-OF led to an increase in this factor in all hippocampal subfields with the exception of DG. However, the density of BDNF-ir cells remained unchanged after exposure to chronic FS or HL‑OF in the hippocampal regions in relation to the control rats. These results indicate that acute FS or HL-OF proved to be a stressor that induces an increase in the density of BDNF-ir pyramidal neurons, which was probably connected with up-regulation of HPA axis activity and short‑time memory processing of the stressful situation. Moreover, as far as the influence on BDNF-ir cells in hippocampus is concerned, chronic FS or HL-OF was not an aggravating factor for rats in the ontogenetic periods studied.

AB303. SPR-30 Neurotrophin dysregulation after dual injury childbirth model is corrected via electrical stimulation of the pudendal nerve in a rat model

ObjectiveStress urinary incontinence (SUI), the leakage of urine due to an increase in abdominal pressure, affects 30% of women over the age of 40. Childbirth is the primary risk factor for SUI since the child’s head passing through the birth canal can injure the EUS and the nerve that innervates it, the pudendal nerve (PN). Animal models with combined EUS [vaginal distension (VD)] and PN crush (PNC) injuries have shown that the nerve does not recover as well as with PNC alone and the animals have delayed return of function. Typically after a nerve injury, the neuron upregulates neurotrophin factors [i.e., brain derived neurotrophin factor (BDNF)] and their receptors [i.e., tyrosine kinase B (Trk B) and p75], and Schwann cells also upregulate neurotrophin factors [i.e., glial derived neurotrophin factor (GDNF) and NT4] as part of the regeneration process. The impaired nerve regeneration in the dual injury model was shown to be due to a dysregulation of BDNF in the PN motoneuron, so any potential treatment would need to upregulate BDNF. Electrical stimulation (ES) has been shown to upregulate BDNF and Trk B in neurons and GDNF in Schwann cells. Our previous work has shown daily and 4 times per week stimulation for 2 weeks accelerates functional recovery after PNC + VD. The aim of the study was to determine if daily stimulation causes an upregulation of neurotrophin factor and their receptors in motoneurons of the PN after injury. We hypothesize that the accelerated recovery from ES is mediated by an upregulation of BDNF and NT4 and their receptor Trk B, as well as GFRα1, the receptor of GDNF.MethodsAnimals were divided into five groups: Sham PNC, PNC, PNC + VD, PNC + VD with sham stimulation (SS) or PNC + VD + ES. ES (20 Hz, 0.3 mA, 0.1 ms) was conducted daily for 1 or 2 weeks after injury, when the spinal cord was harvested from L4–S3. The spinal cord was sectioned and Onuf’s nucleus, the motoneuron nucleus for the PN, was harvested via laser capture microscopy. RNA was then isolated and preamplified before running PCR and compared to GAPDH expression. A one way Anova was used to determine statistically significant differences between groups.ResultsOne week after PNC + VD, BDNF was not upregulated as previously shown. Neither were p75 or GFRα1, as expected. NT4 was not downregulated after PNC + VD, as expected. P75 was significantly increased in the PNC + VD + ES group compared to the PNC + VD group 2 weeks after injury. BDNF was also upregulated 2 weeks after PNC + VD + ES compared to PNC + VD.ConclusionsP75, NT4 and GFRα1 expression data suggest that PNC + VD causes dysregulation of other regenerative proteins other than BDNF. BDNF was upregulated 2 weeks after PNC + VD with ES. Future research will be designed to investigate the mechanism of this effect.Funding Source(s)VA Merit A1262-R and the RR&D Service of the VA

PS 07-01 EFFECT OF EXERCISE TRAINING ON BDNF AND TrkB IN THE HIPPOCAMPUS IN SPONTANEOUSLY HYPERTENSIVE RATS

Objective: Hypertension decreases neuronal plasticity and survival in the hippocampus, contributing to cognitive impairment. Brain-derived neurotrophin factor (BDNF) plays an important role in neuronal plasticity and neurogenesis in the dentate gyrus (DG) of the hippocampus. Exercise training up-regulates BDNF in the hippocampus, and improves neurogenesis and cognitive function. It is unclear whether exercise-induced activation of BDNF in the hippocampus also occurs in hypertensive rats, associated with decrease in blood pressure (BP). Therefore, the effects of exercise training on BDNF and its binding receptor tropomyosin-related kinase B (TrkB) mRNA were assessed in the hippocampus of spontaneously hypertensive rats (SHR). Design and Method: SHR (SHR-ExT, n = 7) and normotensive Wistar-Kyoto (WKY) rats (WKY-ExT, n = 9) were trained using a moderate-intensity exercise treadmill program for 5 weeks. Sedentary SHR (n = 6) and WKY rats (n = 10) were included as controls. At the end, systolic BP (SBP) and diastolic BP (DBP) were measured and the brains were collected. DG and CA regions of the hippocampus were micro-punched separately, and BDNF and TrkB mRNA were assessed by real-time PCR. Results: SHR had significantly higher BP compared to WKY. In SHR, BDNF mRNA was decreased in the DG, but not in the CA regions. In contrast, TrkB mRNA was increased in both the DG and CA regions. Exercise decreased BP of SHR. BDNF mRNA was increased in the DG compared to SHR-Sed, but there are no effects of exercise in CA regions. Exercise had no effect on TrkB mRNA in DG and CA regions. BDNF mRNA in the DG correlated inversely with SBP (r = −0.66, p < 0.01) and DBP (r = −0.71, p < 0.01). Conclusions: Exercise normalizes decreased BDNF mRNA in the DG of SHR, and this improvement may contribute to its beneficial effects on cognitive function.

Exposure to mild stress and brain derived neurotrophin factor (BDNF) immunoreactivity in the hypothalamic paraventricular (PVN) and supraoptic (SON) nuclei: Comparison between aged and adult rats

It seems that age-dependent changes in stress response may be correlated with alterations in the hypothalamic brain derived neurotrophin factor (BDNF). Two hypothalamic nuclei, ie. paraventricular (PVN) and supraoptic (SON) are closely related to the stress response. Therefore, the aim of our study was to explore the influence of acute and chronic high-light open field (HL-OF) or forced swim (FS) stimulation on the density of BDNF immunoreactive (ir) neurons in the PVN and SON in adult (postnatal day 90; P90) and aged (P720) Wistar Han rats. Our data demonstrated that in comparison with non-stressed rats, neither acute nor chronic FS caused significant changes in the density of BDNF-ir neurons of PVN and SON in P90 or P720 rats. However, a significant increase in the density of BDNF-ir neurons in the SON of P90 and a decrease in the PVN of the P720 rats were noted after acute HL-OF. Despite the lack of change in the density of BDNF-ir neurons between P90 and P720 non-stressed and FS stressed rats, there was an age-dependent decrease in the BDNF-ir cells of HL-OF stressed rats, especially in the PVN. We may conclude that in terms of its influence on the BDNF-ir neurons in PVN and SON, acute HL-OF was the factor inducing changes in the density of BDNF-ir neurons in the hypothalamic nuclei of adult or aged rats. Furthermore, ageing involutional processes, which can impair hypothalamic-pituitary-adrenal axis functioning, may have been able to cause an age-related decrease in the BDNF-ir PVN and/or SON neurons in HL-OF stressed rats.

Effect of repetitive transcranial magnetic stimulation on auditory function following acoustic trauma.

Repetitive transcranial magnetic stimulation (rTMS) is one form of non-invasive brain stimulation and increasingly shows neuroprotection in multiple neurological disorders. However, the potential of rTMS for protective action on auditory function following acoustic trauma has not been investigated. Here, we examined effect of TMS on hearing conservation, neurons survival and brain-derived neurotrophin factor (BDNF) expression in the cochlea and auditory cortex following acoustic trauma in rats. Wistar rats were exposed to intense pure tone noise (10kHz, 120dB SPL for 2h) followed by rTMS treatment or sham treatment (handling control) daily for 14days. Auditory brainstem response revealed there was no significant difference in hearing threshold shifts between rTMS- and sham-treated rats, although rTMS-treated rats showed less neuron loss in the auditory cortex in comparison with sham rats. Additionally, acoustic trauma increased BDNF expression in the cochlea and auditory cortex, and this elevation could be attenuated by rTMS treatment. Our results suggest present regiment of rTMS does not protect hearing against acoustic trauma, but maybe have implications for tinnitus treatment.

Effects of chronic mild stress on behavioral and neurobiological parameters — Role of glucocorticoid

Major depression is thought to originate from maladaptation to adverse events, particularly when impairments occur in mood-related brain regions. Hypothalamus–pituitary–adrenal (HPA) axis is one of the major systems involved in physiological stress response. HPA axis dysfunction and high glucocorticoid concentrations play an important role in the pathogenesis of depression. In addition, astrocytic disability and dysfunction of neurotrophin brain-derived neurotrophin factor (BDNF) greatly influence the development of depression and anxiety disorders. Therefore, we investigated whether depressive-like and anxiety-like behaviors manifest in the absence of glucocorticoid production and circulation in adrenalectomized (ADX) rats after chronic mild stress (CMS) exposure and its potential molecular mechanisms. The results demonstrate that glucocorticoid-controlled rats showed anxiety-like behaviors but not depression-like behaviors after CMS. Molecular and cellular changes included the decreased BDNF in the hippocampus, astrocytic dysfunction with connexin43 (cx43) decreasing and abnormality in gap junction in prefrontal cortex (PFC). Interestingly, we did not find any changes in glucocorticoid receptor (GR) or its chaperone protein FK506 binding protein 51 (FKBP5) expression in the hippocampus or PFC in ADX rats subjected to CMS. In conclusion, the production and circulation of glucocorticoids are one of the contributing factors in the development of depression-like behaviors in response to CMS. In contrast, the effects of CMS on anxiety-like behaviors are independent of the presence of circulating glucocorticoids. Meanwhile, stress decreased GR expression and enhanced FKBP5 expression via higher glucocorticoid exposure. Gap junction dysfunction and changes in BDNF may be associated with anxiety-like behaviors.

THE EFFECTS OF ETHANOL EXTRACTS OF Centella asiatica LEAF ON SERIAL SERUM BRAIN DERIVED NEUROTROPHIN FACTOR (BDNF) CONCENTRATION OF RATS (SPRAGUE DAWLEY) FOLLOWING CHRONIC STRESS

&lt;p&gt;Centella asiatica is considered herbal plant for increasing memory performance. Brain-derived neurotrophin factor (BDNF) has a significant role in memory formation process, while stress causes memory impairment. Objective: This study aimed to investigate the effects of ethanol extracts of Centella asiatica leaf on serum BDNF concentration of rats that was taken serially before and after chronic electrical stress. Materials and Methods : Twenty male rats (Sprague Dawley) were divided into four groups: control/aquades group and groups treated with different doses (mg/kg) of Centella asiatica :150 (CA150), 300 (CA300) and 600 (CA600). Each rat underwent memory exercise for nine days before and after electrical stress and oral administration of ethanol extracts of Centella asiatica for twenty-eight days. Blood sampling was taken serially from rats’ tail for four times : (1) before memory exercise, (2) after memory exercise (before stress), (3) after chronic stress, and (4) after memory exercise (following chronic stress). Concentration of serum BDNF was assessed using ELISA. Results: There was no significant difference in serum BDNF concentration between groups in first and second serum sampling, which was prior to chronic stress and administration of different treatments. However, there was significant difference in third and fourth serum sampling between groups. Mean concentration of serum BDNF (ng/ml) in third and fourth sampling for control group, CA150, CA300, and CA600, respectively were 1.88+0.21 &amp;amp;1.93+0.24; 2.29+0.13 &amp;amp; 2.01+0.22; 2.29+0.08 &amp;amp;1.86+0.11; 2.71+0.70 and 2.99+0.27 (p&amp;lt;0.05). Conclusion: Ethanol extracts of Centella asiatica leaf increases serum BDNF concentration in rats after chronic stress. &lt;br /&gt;&lt;strong&gt;&lt;/strong&gt;&lt;/p&gt;&lt;p&gt;&lt;strong&gt;Keywords&lt;/strong&gt;: stress, memory, Centella asiatica, BDNF&lt;/p&gt;

Transcriptome response to infraorbital nerve transection in the gonadally intact male rat barrel cortex: RNA-seq.

The effects of infraorbital nerve (ION) transection on gene expression in the adult male rat barrel cortex were investigated using RNA sequencing. After a 24-hour survival duration, 98 genes were differentially regulated by ION transection. Differentially expressed genes suggest changes in neuronal activity, excitability, and morphology. The production of mRNA for neurotrophins, including brain-derived neurotrophin factor (BNDF), was decreased following ION transection. Several potassium channels showed decreased mRNA production, whereas a sodium channel (Na(V)β4) associated with burst firing showed increased mRNA production. The results may have important implications for phantom-limb pain and complex regional pain syndrome. Future experiments should determine the extent to which changes in RNA result in changes in protein expression, in addition to utilizing laser capture microdissection techniques to differentiate between neuronal and glial cells.