Brain-derived Neurotrophic Factor In Rats Research Articles

Effect of Hesperidin on Chronic Unpredictable Mild Stress-Related Depression in Rats through Gut-Brain Axis Pathway.

To determine the pharmacological impact of hesperidin, the main component of Citri Reticulatae Pericarpium, on depressive behavior and elucidate the mechanism by which hesperidin treats depression, focusing on the gut-brain axis. Fifty-four Sprague Dawley male rats were randomly allocated to 6 groups using a random number table, including control, model, hesperidin, probiotics, fluoxetine, and Citri Reticulatae Pericarpium groups. Except for the control group, rats in the remaining 5 groups were challenged with chronic unpredictable mild stress (CUMS) for 21 days and housed in single cages. The sucrose preference test (SPT), immobility time in the forced swim test (FST), and number in the open field test (OFT) were performed to measure the behavioral changes in the rats. Enzyme-linked immunosorbent assay was used to determine the levels of 5-hydroxytryptamine (5-HT) and brain-derived neurotrophic factor (BDNF) in brain tissue, and the histopathology was performed to evaluate the changes of colon tissue, together with sequencing of the V3-V4 regions of 16S rRNA gene on feces to explore the changes of intestinal flora in the rats. Compared to the control group, the rats in the model group showed notable reductions in body weight, SPF, and number in OFT (P<0.01). Hesperidin was found to ameliorate depression induced by CUMS, as seen by improvements in body weight, SPT, immobility time in FST, and number in OFT (P<0.05 or P<0.01). Regarding neurotransmitters, it was found that at a dose of 50 mg/kg hesperidin treatment upregulated the levels of 5-HT and BDNF in depressed rats (P<0.05). Compared to the control group, the colon tissue of the model group exhibited greater inflammatory cell infiltration, with markedly reduced numbers of goblet cells and crypts and were significantly improved following treatment with hesperidin. Simultaneously, the administration of hesperidin demonstrated a positive impact on the gut microbiome of rats treated with CUMS, such as Shannon index increased and Simpson index decreased (P<0.01), while the abundance of Pseudomonadota and Bacteroidota increased in the hesperidin-treated group (P<0.05). The mechanism responsible for the beneficial effects of hesperidin on depressive behavior in rats may be related to inhibition of the expressions of BDNF and 5-HT and preservation of the gut microbiota.

Inhibition of 5-HT alleviates PTSD-like behaviors and promotes hippocampal neuroplasticity by modulating hippocampal autophagy in rats.

5-Hydroxytryptamine (5-HT) plays a substantial role in mitigating depression and anxiety. However, the potential effects of 5-HT against posttraumatic stress disorder (PTSD) and its underlying mechanisms remain unclear. Elevated plus maze test evaluates anxiety-related behaviors, and the open field test is used to assess overall activity levels and anxiety. Inflammatory cytokine levels were determined using ELISA. The levels of 5-HT and dopamine were measured using HPLC. mRNA and protein levels were examined by PCR and Western blot, respectively. Rats exposed to single prolonged stress (SPS) exhibited typical PTSD-like phenotypes, with decreased levels of 5-HT in the hippocampus and significant reductions in its downstream targets, brain-derived neurotrophic factor (BDNF) and TrkB. In addition, it was discovered that the autophagy signaling pathway might be involved in regulating hippocampal BDNF in rats exposed to SPS. Subsequent treatment with an intracerebral injection of sh-SERT significantly inhibited anxiety and cognitive dysfunction in rats. Moreover, sh-SERT treatment was observed to substantially reverse the increase in autophagy signaling protein expression and consequently improve the expression of BDNF and TrkB proteins, which had been reduced. The current study demonstrates that sh-SERT exhibits significant anti-PTSD effects, potentially mediated in part through the reduction of cellular autophagy to enhance hippocampal synaptic plasticity.NEW & NOTEWORTHY The study demonstrated that sh-SERT exhibits significant anti-posttraumatic stress disorder (PTSD) effects, potentially mediated in part through the reduction of cellular autophagy to enhance hippocampal synaptic plasticity.

Mild exercise plus levothyroxine ameliorate deficits of spatial navigation, anxiety profile, and hippocampal BDNF in hypothyroid male offspring rats.

Levothyroxine (LEV) monotherapy cannot completely improve cognitive and behavioral impairments induced by hypothyroidism, whereas a combination therapy of exercise and LEV may ameliorate these deficits. This study aimed to determine the effects of mild-intensity forced exercise and LEV treatment on the anxiety profile and cognitive functions in male offspring of hypothyroid dams. Twenty-four female rats (mothers) were randomly divided into sham (healthy) and hypothyroidism groups and then placed with male rats to mate. The presence of vaginal plaque confirmed pregnancy (gestational day, GD 0). 6-propyl-2-thiouracil (PTU, 100ppm) was added to the drinking water of the hypothyroidism group from GD 6 to the 21st postnatal day (PND). The sham group received tap water. On PND 21, serum T4 levels of mothers, and 10 pups were measured to confirm hypothyroidism. Sixty-four male pups were left undisturbed for 30 days and then were divided into eight groups that received saline or LEV (50μg/kg, i.p.) with or without forced mild-intensity exercise. After 14 days of interventions, anxiety-like behaviors, spatial learning and memory, and hippocampal brain-derived neurotrophic factor (BDNF) levels were evaluated. A pre and postnatal PTU-induced model of hypothyroidism increased anxiety-like behaviors, impaired spatial learning and memory, and decreased hippocampal BDNF levels in male offspring rats. LEV alone increased BDNF levels and improved spatial learning. Exercise alone increased BDNF levels, improved spatial learning and memory, and decreased anxiety-like behaviors. Exercise plus LEV more effectively improved anxiety-like behaviors and spatial learning than exercise or LEV alone. Practically, these pre-clinical findings highlight the importance of the combination of exercise and LEV regimen in treating patients with hyperthyroidism.

Influence of short-term hypoxic exposure on spatial learning and memory function and brain-derived neurotrophic factor in rats-A practical implication to human's lost way.

The present study aimed to investigate the effects of a short period of normobaric hypoxic exposure on spatial learning and memory, and brain-derived neurotrophic factor (BDNF) levels in the rat hippocampus. Hypoxic conditions were set at 12.5% O2. We compared all variables between normoxic trials (Norm), after 24 h (Hypo-24 h), and after 72 h of hypoxic exposure (Hypo-72 h). Spatial learning and memory were evaluated by using a water-finding task in an open field. Time to find water drinking fountains was significantly extended in Hypo 24 h (36.2 ± 21.9 s) compared to those in Norm (17.9 ± 12.8 s; P < 0.05), whereas no statistical differences between Norm and Hypo-72 h (22.7 ± 12.3 s). Moreover, hippocampal BDNF level in Hypo-24 h was significantly lower compared to Norm (189.4 ± 28.4 vs. 224.9 ± 47.7 ng/g wet tissue, P < 0.05), whereas no statistically differences in those between Norm and Hypo-72 h (228.1 ± 39.8 ng/g wet tissue). No significant differences in the changes in corticosterone and adrenocorticotropic hormone levels were observed across the three conditions. When data from Hypo-24 h and Hypo-72 h of hypoxia were pooled, there was a marginal negative relationship between the time to find drinking fountains and BDNF (P < 0.1), and was a significant negative relationship between the locomotor activities and BDNF (P < 0.05). These results suggest that acute hypoxic exposure (24 h) may impair spatial learning and memory; however, it recovered after 72 h of hypoxic exposure. These changes in spatial learning and memory may be associated with changes in the hippocampal BDNF levels in rats.

Korean red ginseng water extract produces antidepressant-like effects through involving monoamines and brain-derived neurotrophic factor in rats

BackgroundGinseng Radix (Panax ginseng Meyer, Araliaceae) has been used medicinally to treat the brain and nervous system problems worldwide. Recent studies have revealed physiological effects that could potentially benefit cognitive performance or mood. The present study aimed to investigate the antidepressant effects of Korean red ginseng water extract (KGE) and its active component in an unpredictable chronic mild stress (UCMS)-induced animal model and elucidate the underlying mechanisms. MethodsThe antidepressant potential of the UCMS model was evaluated using the sucrose preference test and open field tests. The behavioral findings were further corroborated by the assessment of neurotransmitters and their metabolites from the prefrontal cortex and hippocampus of rats. Three doses of KGE (50, 100, and 200 mg/kg) were orally administered during the experiment. Furthermore, the mechanism underlying the antidepressant-like action of KGE was examined by measuring the levels of brain-derived neurotrophic factor (BDNF)/CREB, nuclear factor erythroid 2-related factor 2 (Nrf2), and Kelch-like ECH-associated protein 1 (Keap1) proteins in the prefrontal cortex of UCMS-exposed rats. ResultsKGE treatment normalized UCMS-induced depression-related behaviors. Neurotransmitter studies conducted after completing behavioral experiments demonstrated that KGE caused a reduction in the ratio of serotonin and dopamine, indicating a decrease in serotonin and dopamine turnover. Moreover, the expression of BDNF, Nrf2, Keap1 and AKT were markedly increased by KGE in the prefrontal cortex of depressed rats. ConclusionOur results provide evidence that KGE and its constituents exert antidepressant effects that mediate the dopaminergic and serotonergic systems and expression of BDNF protein in an animal model.

Naringin Prevents Cognitive Dysfunction in Aging Rats by Inhibiting Toll-Like Receptor 4 (TLR4)/NF-κB Pathway and Endoplasmic Reticulum Stress.

Naringin is a flavonoid derived from Chinese herbs. According to earlier studies, naringin may have the potential to alleviate aging-induced cognitive dysfunction. Therefore, this study attempted to explore the protective effect and underlying mechanism of naringin on aging rats with cognitive dysfunction. After the construction of a model of aging rats with cognitive dysfunction through subcutaneous injection of D-galactose (D-gal; 150 mg/kg), intragastric administration of naringin (100 mg/kg) was performed for treatment. Behavioral tests, including Morris water maze test (MWM), novel object recognition test (NORT), and fear conditioning test, were used to measure the cognitive function; ELISA and biochemical tests were used to determine the levels of interleukin (IL)-1β, IL-6, monocyte chemoattractant protein-1 (MCP-1), brain-derived neurotrophic factor (BDNF), nerve growth factor (NGF), malondialdehyde (MDA), and glutathione peroxidase (GSH-Px) in the hippocampus of rats in each group, respectively; H&E staining was used to observe the pathological changes in the hippocampus; Western blot was used to examine the expression of toll-like receptor 4 (TLR4)/NF-κB pathway-related proteins and endoplasmic reticulum (ER) stress-related proteins in the hippocampus. The model was successfully constructed by subcutaneous injection of D-gal (150 mg/kg). The behavioral test results showed that naringin could ameliorate the cognitive dysfunction and alleviate the histopathological damage of hippocampus. Moreover, naringin significantly improve the inflammatory response (the levels of IL-1β, IL-6, and MCP-1 were decreased), oxidative stress response (MDA level was increased while GSH-Px activity was decreased), and ER stress (the expression of glucose-regulated protein 78 (GRP78), C/-EBP homologous protein (CHOP), and transcription factor 6 (ATF6) expression was downregulated), and increased the levels of neurotrophic factors BDNF and NGF in D-gal rats. Besides, further mechanistic studies revealed the downregulation of naringin on TLR4/NF-κB pathway activity. Naringin may inhibit inflammatory response, oxidative stress, and ER stress by downregulating TLR4/NF-κB pathway activity, thereby improving cognitive dysfunction and alleviating histopathological damage of hippocampus in aging rats. Briefly, naringin is an effective drug for the treatment of cognitive dysfunction.

Effect of Hesperetin on the Antidepressant Activity of Electroconvulsive Therapy in an Enforced Reserpine Model of Depression in Male Rats

Background: Depression is a common and debilitating disorder of the brain. Many pharmacological therapies, including many plant components (such as flavonoids), are used to treat depression. Electroconvulsive therapy (ECT) is a useful method for depressed patients who do not respond to medication. However, this method has some side effects. Hence, investigators have tried to improve ECT’s positive points by diminishing its side effects. Objectives: We investigated the effect of hesperetin (a flavonoid component) on the antidepressant activity of ECT in an enforced reserpine model of depression in male rats. Methods: Eighty male rats (230 - 250 g) were randomly divided into control, ECT + reserpine (Res), Res + hesperetin (Hes; 10 or 20 mg/kg), Res + ECT, and Res + ECT + Hes (10 or 20 mg/kg) groups. The effects of hesperetin were evaluated by the forced swimming test (FST), sucrose preference test (SPT), open field test (OFT), elevated plus maze test (EPMT), as well as by measurement of the brain-derived neurotrophic factor (BDNF) and oxidative stress biomarkers [ie, malondialdehyde (MDA), superoxide dismutase (SOD), and glutathione (GSH)] in the prefrontal cortex area. Results: The outcomes of the behavioral experiments showed that Hes + ECT treatment could raise the percentage of open arm entrance in EPMT, anhedonia in SPT, and decrease immobilization time in FST compared to the groups treated with ECT (P &lt; 0.05) or hesperetin alone. Our biochemical research also illustrated a significant reduction in MDA in the groups treated with ECT + Hes (10 or 20 mg/kg; P &lt; 0.01 and P &lt; 0.001) and ECT or hesperetin, as well as a significant increase in GSH, SOD, and BDNF in the ECT + Hes (20 mg/kg) animal group (P &lt; 0.001). Conclusions: In depressed rats, the ECT linked to the application of hesperetin could significantly elevate BDNF, GSH, and SOD reduction in depressed male rats.

The effect of modafinil on passive avoidance memory, brain level of BDNF and oxidative stress markers in sepsis survivor rats

Propose/aim of study: Modafinil (MD) is a psychostimulant drug used off-label and cognitive dysfunction may be a significant emerging treatment target for this drug. The objective of this study was to evaluate the effect of MD on the neurochemical parameters and memory impairment of rats submitted to sepsis by cecal ligation and perforation (CLP). Material and method: Male Wistar rats (250–350g) were submitted to CLP, or sham as control, and divided into the sham + water, sham + MD (300 mg/kg), CLP + water, and CLP + MD (300 mg/kg) groups. Ten days after the administration of MD and CLP, the rats were submitted to a memory test by passive avoidance apparatus being sacrificed. The nitrite and nitrate (N/N) concentration, myeloperoxidase (MPO) and catalase (CAT) activity, lipid and protein oxidative damage, and brain-derived neurotrophic factor (BDNF) levels were measured in the prefrontal cortex and hippocampus. Results: The passive avoidance test verified an increase in the latency time compared training and test section in the groups sham + water and CLP + MD. Decreased N/N concentration and MPO activity were verified in the prefrontal cortex of rats submitted to CLP and MD treatment, as well as reduced protein and lipid oxidative damage in the hippocampus, which was accompanied by increased CAT activity and BDNF levels.Conclusion: Our data indicate the role of MD in attenuating oxidative stress parameters, the alteration of BDNF, and an improvement in memory impairment in rats ten days after induction of sepsis.

Cranial electrotherapy stimulation alleviates depression-like behavior of post-stroke depression rats by upregulating GPX4-mediated BDNF expression

To elucidate whether cranial electrotherapy stimulation (CES) improves depression-like behavior of post-stroke depression (PSD) via regulation of glutathione peroxidase 4 (GPX4)-mediated brain-derived neurotrophic factor (BDNF) expression. Middle cerebral artery occlusion (MCAO) and chronic unpredictable mild stress (CUMS) were used to develop a rat PSD model. CES was applied, and RAS-selective lethal 3 (RSL3) was injected into the hippocampus to inhibit GPX4 in PSD rats. The depression behavior was detected by sucrose preference and forced swimming tests. The structure and morphology of the hippocampus were observed and analyzed by histopathological hematoxylin-eosin (HE) staining. The mRNA and protein expressions of GPX4 and BDNF in the hippocampus were detected by qRT-PCR, western blot and immunohistochemical analysis.The degeneration and necrosis of hippocampal neurons, the depression-like behavior were severer and the expression of BDNF in the hippocampus were decreased in PSD rats than those in MCAO and control groups. CES promoted the hippocampal neuron repair, alleviated the depression-like behavior and increased the expression of BDNF in PSD rats. The inhibition of GPX4 by RSL3 exacerbated the depression-like behavior and decreased the expression of BDNF in PSD rats. In addition, we found that RSL3 disrupted the positive effects of CES on the PSD rats. Conclusion: CES improves depression-like behavior of PSD rats through upregulation of GPX4-mediated BDNF expression in the hippocampus.

The effects of curcumin in learning and memory impairment associated with hypothyroidism in juvenile rats: the role of nitric oxide, oxidative stress, and brain-derived neurotrophic factor.

The effect of curcumin (Cur) on cognitive impairment and the possible role of brain tissue oxidative stress, nitric oxide (NO) levels, and brain-derived neurotrophic factor (BDNF) were investigated in juvenile hypothyroid rats. The juvenile rats (21 days old) were allocated into the following groups: (1) control; (2) hypothyroid (0.05% propylthiouracil (PTU) in drinking water); (3-5) hypothyroid-Cur 50, 100, and 150, which in these groups 50, 100, or 150 mg/kg, Cur was orally administered by gavage during 6 weeks. In the hypothyroid rats, the time elapsed and the traveled distance to locate the hidden platform in the learning trials of Morris water maze (MWM) increased, and on the probe day, the amount of time spent in the target quadrant and the distance traveled in there was decreased. Hypothyroidism also decreased the latency and increased the time spent in the darkroom of the passive avoidance (PA) test. Compared with the hypothyroid group, Cur enhanced the performance of the rats in both MWM and PA tests. In addition, Cur reduced malondialdehyde concentration and NO metabolites; however, it increased thiol content as well as the activity of catalase (CAT) and superoxide dismutase enzymes in both the cortex and hippocampus. Cur also increased hippocampal synthesis of BDNF in hypothyroid rats. The beneficial effects of Cur cognitive function in juvenile hypothyroid rats might be attributed to its protective effect against oxidative stress and potentiation of BDNF production.

Sciatic nerve block downregulates the BDNF pathway to alleviate the neonatal incision-induced exaggeration of incisional pain via decreasing microglial activation

Sciatic nerve block is under investigation as a possible therapeutic strategy for neonatal injury-induced exaggeration of pain responses to reinjury. Spinal microglial priming, brain-derived neurotrophic factor (BDNF) and Src homology-2 domain-containing protein tyrosine phosphatase-2 (SHP2) participate in exaggerated incisional pain induced by neonatal incision. However, effects of sciatic nerve block on exacerbated incisional pain and underlying mechanisms remain unclear. Here, we demonstrated that sciatic nerve block alleviates pain hypersensitivity and microglial activation in rats subjected to neonatal incision and adult incision (nIN-IN). Chemogenetic activation or inhibition of spinal microglia attenuates or mimics effects of sciatic nerve block on pain hypersensitivity, respectively. Moreover, α-amino-3-hydroxy- 5-methy- 4-isoxazole propionate (AMPA) receptor subunit GluA1 contributes to the exaggeration of incisional pain. The inhibition of BDNF or SHP2 blocks upregulations of downstream molecules in nIN-IN rats. Knockdown of SHP2 attenuates the increase of GluA1 induced by injection of BDNF in adult rats with only neonatal incision. The inhibition of microglia or ablation of microglial BDNF attenuates upregulations of SHP2 and GluA1. Additionally, sciatic nerve block downregulates the expression of these three molecules. Upregulation of BDNF, SHP2 or AMPA receptor attenuates sciatic nerve block-induced reductions of downstream molecules and pain hypersensitivity. Microglial activation abrogates reductions of these three molecules induced by sciatic nerve block. These results suggest that decreased activation of spinal microglia contributes to beneficial effects of sciatic nerve block on the neonatal incision-induced exaggeration of incisional pain via downregulating BDNF/SHP2/GluA1-containing AMPA receptor signaling. Thus, sciatic nerve block may be a promising therapy.

Neuroprotective Effects of Estrogen Through BDNF-Transient Receptor Potential Channels 6 Signaling Pathway in the Hippocampus in a Rat Model of Perimenopausal Depression.

Estradiol (E2) has been proven to be effective in treating perimenopausal depression (PD); however, the downstream signaling pathways have not been fully elucidated. Transient receptor potential channels 6 (TRPC6) plays a vital role in promoting neuronal development and the formation of excitatory synapses. At present, we found that the serum levels of E2 and brain-derived neurotrophic factor (BDNF) declined significantly in the women with PD compared to perimenopausal women, which was accompanied by a clear reduction in TRPC6 levels. To further reveal the effects of TRPC6 on neuronal survival and excitability, the PD-like rat model was established by the total removal of left ovary and 80% removal of right ovary followed by 21 days of the chronic unpredictable mild stress. Intragastric administration of E2 (2 mg/kg), intraperitoneal injection of BDNF/TrB signaling pathway inhibitor (K252a, 100 μg/kg) and TRPC6 agonist (OAG, 0.6 mg/kg), and intracerebroventricular infusion of anti-BDNF antibody for blocking BDNF (0.5 μg/24 μl/rat) daily for 21 days were conducted. The levels of BDNF and TRPC6 in rat serum were lower in PD rats compared to the control rats; the depression-like behavior was induced, the neuronal death rate in the hippocampus increased, and the thickness of postsynaptic density (PSD) and the number of asymmetric synapses decreased significantly in the PD group. E2 treatment greatly upregulated the serum levels of BDNF and TRPC6, the neuronal excitability indicated by an elevation in the PSD thickness and the numbers of asymmetric synapses, and these actions were reversed by K252a; co-administration of TRPC6 agonist and K252a improved neuronal degeneration and increased the neuronal excitability induced in the E2-treated PD rats. K252a or anti-BDNF antibody inhibited the increased neuronal BDNF and TRPC6 expression in E2-treated PD rats; co-treatment of TRPC6 agonist and anti-BDNF antibody reduced neuronal death and increased the BDNF and TRPC6 expression in the hippocampal CA1 neurons in the E2-treated PD rats. These results suggest that the neuroprotective role of E2 in PD is closely related to enhance the activity of BDNF/TRPC6 pathway and is helpful to provide new prevention and strategies.

Prenatal Isoflurane Exposure Induces Developmental Neurotoxicity in Rats: the Role of Gut Microbiota.

Fetal exposure to inhaled anesthetics, such as isoflurane, may lead to neurodevelopmental impairment in offspring. Yet, the mechanisms of prenatal isoflurane-induced developmental neurotoxicity have not been fully elucidated. Gut microbiota is a pivotal modulator of brain development and functions. While the antibiotic effect of isoflurane has been previously investigated, the relationship between prenatal isoflurane exposure and postnatal gut microbiota, brain biology, and behavior remains unknown. In the present study, we treated pregnant rats with 2% isoflurane for 4h on gestational day 14. Their offspring were tested with novel object recognition task on postnatal day 28 (P28) to assess cognition. Fecal microbiome was assessed using 16S RNA sequencing. We also analyzed hippocampal expression of brain-derived neurotrophic factor (BDNF) in P28 rat brains. To further explore the role of gut microbiota on prenatal isoflurane-induced developmental neurotoxicity, we treated rats with mixed probiotics on P14 for 14days and evaluated novel object recognition and hippocampal expression of BDNF on P28. Results indicate that prenatal exposure to isoflurane significantly decreased novel object recognition (novel object preference ratio: mean difference (MD) - 0.157; 95% confidence interval (CI) - 0.234 to - 0.080, P < 0.001) paralleled by diminished expression of hippocampal BDNF in juvenile rats. Prenatal exposure to isoflurane also significantly altered the diversity and composition of gut microbiota. Treatment with probiotics mitigated these changes in cognition (novel object preference ratio: isoflurane group vs. control group: MD - 0.177; 95% CI - 0.307 to - 0.047, P = 0.006; probiotic group vs. isoflurane group: MD 0.140; 95% CI 0.004 to 0.275, P = 0.042) and BDNF expression. Taken together, our findings suggest that gut dysbiosis may be involved in the pathogenesis of maternal isoflurane exposure-induced postnatal cognitive impairment. To determine the causal relationship between gut microbiota and cognition in prenatal anesthetic-induced developmental neurotoxicity, further studies are needed.

Calcitriol supplementation attenuates cisplatin-induced behavioral and cognitive impairments through up-regulation of BDNF in male rats

Chemotherapy-induced cognitive impairment such as memory impairment and concentration problems are now extensively recognized as side effects of chemotherapy. These problems reduce the quality of life in patients. Therefore, the present study aims to examine the effects of calcitriol supplementation (100 ng/kg /day for five weeks) on cognitive impairment, behavioral deficits, and hippocampal brain-derived neurotrophic factor (BDNF) changes following cisplatin treatment (5 mg/kg/ once a week for five weeks). We also determined the impact of cisplatin and calcitriol administration on reaction time against the thermal stimulus and muscle strength. Our findings showed that cisplatin administration resulted in a significant increase in anxiety-like behaviors. Treatment of rats with cisplatin also impaired performance in the passive avoidance and novel object recognition tasks which are indicating cognitive deficits. Co-administration of calcitriol prevented the cisplatin-induced behavioral and cognitive impairments. Cisplatin exposure also resulted in enhanced reaction time to the thermal stimulus and decreased muscle ability. Besides, hippocampal BDNF levels were reduced in cisplatin-treated rats; however, calcitriol alleviated these effects of cisplatin and up-regulated BDNF mRNA in the hippocampus. In addition, calcitriol alone indicated a significant change in BDNF level compared to the control group. We conclude that increased hippocampal BDNF mediates the beneficial effects of calcitriol against neurotoxicity in cisplatin-exposed rats. However, further studies are required to explore the other mechanisms that mediate the beneficial effect of calcitriol

Effects of Ozone on Hippocampus BDNF and Fos Expressions in Rats with Chronic Compression of Dorsal Root Ganglia.

The effects of ozone on hippocampal expression levels of brain-derived neurotrophic factor (BDNF) and c-fos protein (Fos) were evaluated in rats with chronic compression of dorsal root ganglia (CCD). Forty-eight adult female Sprague-Dawley rats were randomly divided into the following 4 groups (n = 12): sham operation (sham group), CCD group, CCD with 20 μg/ml of ozone (CCD + AO3 group), and CCD with 40 μg/ml of ozone (CCD + BO3 group). Except the sham group, unilateral L5 dorsal root ganglion (DRG) compression was performed on all other groups. On days 1, 2, and 4 after the operation, the CCD + AO3 and CCD + BO3 groups were injected with 100 μl of ozone with concentrations of 20 and 40 μg/ml, respectively. Thermal withdrawal latencies (TWLs) and mechanical withdrawal thresholds (MWTs) were measured at various time points before and after the operation. BDNF and Fos expressions were examined in the extracted hippocampi using immunohistochemistry. The TWLs and MWTs of CCD model rats that received ozone were lower with decreased BDNF and increased Fos expression levels, on day 21 after the operation, compared to those of the sham group (P < 0.05). The TWLs and MWTs of the CCD + AO3 and CCD + BO3 groups were higher with increased BDNF and decreased Fos expression levels, on day 21 after the operation, compared to those of the CCD group (P < 0.05). The TWLs were longer and the MWTs were higher in the CCD + BO3 group at each time point with increased BDNF and decreased Fos expression levels, on day 21 after the operation, compared to those of the CCD + AO3 group (P < 0.05). Our results revealed that ozone can relieve the neuropathic pain caused by the pathological neuralgia resulting from DRG compression in rats. The mechanism of action for ozone is likely associated with changes in BDNF and Fos expression levels in the hippocampus.

Moderate Exercise Combined with Enriched Environment Enhances Learning and Memory through BDNF/TrkB Signaling Pathway in Rats.

This study aimed to investigate the effects and potential mechanisms of exercise combined with an enriched environment on learning and memory in rats. Forty healthy male Wistar rats (7 weeks old) were randomly assigned into 4 groups (N = 10 in each group): control (C) group, treadmill exercise (TE) group, enriched environment (EE) group and the TE + EE group. The Morris water maze (MWM) test was used to evaluate the learning and memory ability in all rats after eight weeks of exposure in the different conditions. Moreover, we employed enzyme-linked immunosorbent assay (ELISA) to determine the expression of brain-derived neurotrophic factor (BDNF) and receptor tyrosine kinase B (TrkB) in the rats. The data showed that the escape latency and the number of platform crossings were significantly better in the TE + EE group compared to the TE, EE or C groups (p < 0.05). In addition, there was upregulation of BDNF and TrkB in rats in the TE + EE group compared to those in the TE, EE or C groups (p < 0.05). Taken together, the data robustly demonstrate that the combination of TE + EE enhances learning and memory ability and upregulates the expression of both BDNF and TrkB in rats. Thus, the BDNF/TrkB signaling pathway might be modulating the effect of exercise and enriched environment in improving learning and memory ability in rats.

Black Bamboo Rhizome Extract Improves Cognitive Dysfunction by Upregulating the Expression of Hippocampal BDNF and CREB in Rats with Cerebral Ischaemia-Reperfusion Injury.

IntroductionThe study aimed to explore the effects of treatment with black bamboo rhizome extracts on learning and memory and determine the underlying mechanisms in rats with cerebral ischaemia-reperfusion injury.MethodsSprague-Dawley rats were randomly divided into the following four groups: control, middle cerebral artery occlusion (MCAO), low-dose drug, and high-dose drug groups. Rats underwent MCAO using a suture method before drug treatment. Then, neurological impairment was assessed using the Longa scoring method, and triphenyl tetrazolium chloride staining was used to analyse the cerebral infarction area. The Elliott formula was used to calculate water content in the brain tissue. A Morris water maze (MWM) was used to assess changes in learning and memory abilities, and Western blotting was used to detect cyclic adenosine phosphate response element-binding protein (CREB) and brain-derived neurotrophic factor (BDNF) expression in the hippocampus of MCAO rats.ResultsAfter treatment with black bamboo rhizome extracts, the neurological dysfunction score was lower in the drug groups than in the MCAO group, and a significant difference was observed between the high-dose drug and MCAO groups (P<0.05). Additionally, the cerebral infarction area was significantly smaller in the drug groups than in the MCAO group (P<0.01), and the effect was more obvious in the high-dose drug group than in the low-dose drug group. There was also a significant difference in water content between the high-dose drug and MCAO groups, and cerebral oedema was significantly reduced in the high-dose drug group (P<0.05). In the MWM, the incubation period was significantly reduced, the number of platform crossings was significantly increased, and the search time was prolonged in the drug groups compared with those in the MCAO group (P<0.05). Moreover, the expression of BDNF and CREB was significantly increased in the drug groups compared to that in the MCAO group, and the increase was more obvious in the high-dose group than in the low-dose group (P<0.05).DiscussionBlack bamboo rhizome extracts significantly improved cognitive dysfunction, reduced cerebral oedema, decreased the cerebral infarction area, and improved the neurological function score and learning and memory abilities in rats with cerebral ischaemia-reperfusion injury.

Working memory and hippocampal expression of BDNF, ARC, and P-STAT3 in rats: effects of diet and exercise

ABSTRACT Objectives Mounting evidence suggests diet and exercise influence learning and memory (LM). We compared a high-fat, high-sucrose Western diet (WD) to a plant-based, amylose/amylopectin blend, lower-fat diet known as the Daniel Fast (DF) in rats with and without regular aerobic exercise on a task of spatial working memory (WM). Methods Rats were randomly assigned to the WD or DF at 6 weeks of age. Exercised rats (WD-E, DF-E) ran on a treadmill 3 times/week for 30 min while the sedentary rats did not (WD-S, DF-S). Rats adhered to these assignments for 12 weeks, inclusive of ab libitum food intake, after which mild food restriction was implemented to encourage responding during WM testing. For nine months, WM performance was assessed once daily, six days per week, after which hippocampal sections were collected for subsequent analysis of brain-derived neurotrophic factor (BDNF), activity-regulated cytoskeletal protein (ARC), and signal transducer and activator of transcription 3 (P-STAT3, Tyr705). Results DF-E rats exhibited the best DSA performance. Surprisingly, the WD-S group outperformed the WD-E group, but had significantly lower BDNF and ARC relative to the DF-S group, with a similar trend from the WD-E group. P-STAT3 expression was also significantly elevated in the WD-S group compared to both the DF-S and WD-E groups. Discussion These results support previous research demonstrating negative effects of the WD on spatial LM, demonstrate the plant-based DF regimen combined with chronic aerobic exercise produces measurable WM and neuroprotective benefits, and suggest the need to carefully design exercise prescriptions to avoid over-stressing individuals making concurrent dietary changes.

The Impact of Intermittent Fasting on Brain-Derived Neurotrophic Factor, Neurotrophin 3, and Rat Behavior in a Rat Model of Type 2 Diabetes Mellitus.

Type 2 diabetes mellitus (T2DM) is known to be associated with an increased risk of dementia, specifically Alzheimer’s disease and vascular dementia. Intermittent fasting (IF) has been proposed to produce neuroprotective effects through the activation of several signaling pathways. In this study, we investigated the effect of IF on rat behavior in type 2 diabetic rats. Forty male Wistar Kyoto rats were divided into four groups (n = 10 for each): the ad libitum (Ad) group, the intermittent fasting group (IF), the streptozotocin-induced diabetic 2 group (T2DM) fed a high-fat diet for 4 weeks followed by a single intraperitoneal (i.p.) injection of streptozotocin (STZ) 25 mg kg−1, and the diabetic group with intermittent fasting (T2DM+IF). We evaluated the impact of 3 months of IF (16 h of food deprivation daily) on the levels of brain-derived neurotrophic factor (BDNF), neurotrophin 3 (NT3), serotonin, dopamine, and glutamate in the hippocampus, and rat behavior was assessed by the forced swim test and elevated plus maze. IF for 12 weeks significantly increased (p < 0.05) the levels of NT3 and BDNF in both control and T2DM rats. Additionally, it increased serotonin, dopamine, and glutamic acid in diabetic rats. Moreover, IF modulated glucose homeostasis parameters, with a significant decrease (p < 0.05) in insulin resistance and downregulation of serum corticosterone level. Interestingly, T2DM rats showed a significant increase in anxiety and depression behaviors, which were ameliorated by IF. These findings suggest that IF could produce a potentially protective effect by increasing the levels of BDNF and NT3 in both control and T2DM rats. IF could be considered as an additional therapy for depression, anxiety, and neurodegenerative diseases.

Short communication: Effects of Canarium indicum oil in enhancing brain-derived neurotrophic factor in rats

Abstract. Rahman H, Anggadiredja K, Gusdinar T, Sitompul JP, Tursino. 2020. Short communication: Effects of Canarium indicum oil in enhancing brain-derived neurotrophic factor in rats. Nusantara Bioscience 12: 168-174. The brain-derived neurotrophic factor (BDNF) is one of the neurotrophins family and plays an essential role during the development of neurons called neurogenesis. Since BDNF is critical for the function and survival of neurons, thus it represents the neuroprotective agent which useful in preventing neurodegenerative diseases. Here, we investigated BDNF serum concentrations after feeding the canarium oil (CO) and Canarium oil-based structured triglyceride (COST) in rats. Analysis of the BDNF serum was conducted by sandwich enzyme-linked immunosorbent assay (ELISA). The results demonstrated that the CO and the COST with the main composition of unsaturated fatty acids at the sn-2 position as much as 94.92% mol may enhance BDNF serum concentrations of up to 2.66% and 21.96% compared to the normal group of rats, respectively. This finding proves that the COST has prospects as an inducer of BDNF. However, further studies should be conducted to identify the precise dosage and safety products.