Brain-derived neurotrophic factor (BDNF) is an important member of the neurotrophic factors, which are critical regulators of the formation and plasticity of neuronal networks. BDNF is abundant in the brain and periphery and it is found in both human serum and plasma. Stressed animals and depressed patients show reduced BDNF expression in the hippocampus and this reduction can be prevented by antidepressant drug treatment. Recent several clinical studies have indicated the decreases of serum or plasma BDNF levels in untreated patients with major depression. These decreases of BDNF can recover after antidepressant treatment. Increasing BDNF after antidepressant treatment could result from improving depressive symptoms, not just from antidepressant treatment. BDNF can play a critical role in the action mechanism of antidepressant treatment. Taken together, major depression may be considered a dysfunction of critical neuronal networks, and the gradual network recovery may induce antidepressant effect. Serum or plasma BDNF levels could indirectly show the above processes of major depression.
Animals ; Brain ; Brain-Derived Neurotrophic Factor ; Depression ; Hippocampus ; Humans ; Nerve Growth Factors ; Neurons ; Plasma ; Plastics

OBJECTIVE: The individual cascades of the insulin-like growth factor-1 (IGF-1) signaling pathway and the molecular mechanism of aging have not been fully clarified. In the current study, we explored the effect of DNA polymerase delta 1 (POLD1) on the IGF-1 signaling pathway in cell aging. METHODS: First, we analyzed the relationship between IGF-1 and POLD1 expression in aging. To investigate the effect of IGF-1 on POLD1 expression and aging, the 2BS cells were incubated with young-age or old-age human serum, IGF-1 protein, or linsitinib. Next, the effect of IGF-1 on aging was examined in the 2BS cells with increased or decreased POLD1 expression to clarify the molecular mechanism. RESULTS: In this study, we found that IGF-1 expression increased and POLD1 expression decreased with aging in human serum and hippocampal tissues of SAMP8 mice, and a negative relationship between IGF-1 and POLD1 expression was observed. Furthermore, the cells cultured with old-age human serum or IGF-1 showed lower POLD1 expression and more pronounced senescence characteristics, and the effect could be reversed by treatment with linsitinib or overexpression of POLD1, while the effect of linsitinib on cell aging could be reversed with the knockdown of POLD1. CONCLUSION Taken collectively, our findings demonstrate that IGF-1 promotes aging by binding to IGF-1R and inhibiting the expression of POLD1. These findings offer a new target for anti-aging strategies.
Humans ; Animals ; Mice ; Insulin-Like Growth Factor I/pharmacology* ; Cellular Senescence ; Aging ; Hippocampus ; DNA Polymerase III

Objective: To explore the effects of exposure of pregnant rats to radio frequency electromagnetic field on the ultrastructure of hippocampus and the levels of obesity related protein (FTO) and nerve growth factor (NGF) in offspring rats. Methods: In September 2019, 36 healthy 7-week-old Wistar rats were selected, including 24 female rats (150-200 g) and 12 male rats (200-250 g) . The male and female mice were mated in the cage at 2: 1 ratio at 18: 00 every night. The smear results showed that the sperm was positive and the mating was successful. The day was regarded as the 0 day of pregnancy. Pregnant rats were randomly divided into 3 experimental groups and 3 control groups, with 4 rats in each group. The experimental group was exposed to 1 800 MHz, Wi-Fi and 1 800 MHz+Wi-Fi respectively, and the three control groups were exposed to virtual exposure. 12 hours a day for 21 days in three batches. After the end of exposure, the offspring of each group were raised for 7 weeks. The ultrastructural changes of the hippocampus were observed by transmission electron microscopy, the FTO level in the hippocampus was determined by Western blot, and the NGF level in the brain tissue was determined by ELISA. Results: Transmission electron microscopy showed that the nuclei of hippocampal tissue of female and male rats in the 1800 MHz group were slightly contracted, the cytoplasm was slightly edema, and the nuclei of male rats were obviously irregular. In the offspring of male and female rats in the Wi-Fi group, the nucleus of hippocampal tissue contracted seriously, the cell membrane was irregular, and the cytoplasm appeared obvious edema. In the 1800 MHz+Wi-Fi group, the nuclei of hippocampal tissue of both male and female offspring rats were severely contracted, the nuclear membrane was irregular, and the cytoplasm was severely edema. there was no significant difference in FTO level among the groups (P>0.05) . Compared with other groups, NGF content in hippocampus of offspring rats in the 1800 MHz+Wi-Fi group was significantly higher (P<0.05) . Conclusion: Exposure to radio frequency electromagnetic fields will damage the morphological structure of hippocampal tissue of offspring and stimulate the increase of NGF expression in the hippocampus.
Animals ; Electromagnetic Fields ; Female ; Hippocampus ; Male ; Mice ; Nerve Growth Factor ; Pregnancy ; Rats ; Rats, Wistar ; Semen

OBJECTIVETo investigate the expression of vascular endothelial growth factor (VEGF) and microvessel density (MVD) in hippocampus of rats with aging.

METHODSParaffin sections of brain tissue of rats at the age of 3, 18, 24, 30 months were stained by immunohistochemistry, the expression of VEGF and MVD was quantitatively analyzed.

RESULTSInnunohistochemical staining showed that the VEGF-positive cells were mainly pyramidal neuron in hippocampus; the intensity of VEGF-positivity in neuron cells was decreased with the aging (P<0.05). The MVD in hippocampus was also decreased with the aging of rats (P<0.05).

CONCLUSIONIncreasing VEGF contents and improving blood circulation in brain tissue may prevent or treat vascular dementia and cerebrovascular diseases.

Aging ; Animals ; Capillaries ; pathology ; Hippocampus ; blood supply ; metabolism ; Male ; Rats ; Rats, Sprague-Dawley ; Vascular Endothelial Growth Factor A ; genetics ; metabolism

This study aims to elucidate the underlying mechanism of Erxian Decoction(EXD) against neurogenesis impairment in late-onset depression(LOD) rats based on cerebrospinal fluid(CSF) proteomics. A total of 66 20-21-month-old male Wistar rats were randomized into naturally aged(AGED) group, LOD group, and EXD group. All rats received chronic unpredictable mild stress(CUMS) for 6 weeks for LOD modeling except for the AGED group. During the modeling, EXD group was given EXD(ig, twice a day at 4 g·kg~(-1)) and other groups received equivalent amount of normal saline(ig). After modeling, a series of behavioral tests, such as sucrose preference test(SPT), open-field test(OFT), forced swimming test(FST), and Morris water maze test(MWMT) were performed. Immunofluorescence method was used to detect the number of Ki-67/Nesti-positive cells and BrdU/DCX-positive cells in the hippocampal DG area of each group. High-concentration corticosterone(CORT) was combined with D-galactose(D-gal) to simulate the changes of LOD-related stress and aging and the proliferation and differentiation of primary neural stem cells of hippocampus in each group were observed. Data independent acquisition(DIA)-mass spectrometry(MS) was used to analyze the differential proteins in CSF among groups and bioinformatics analysis was performed to explore the biological functions of the proteins. Behavioral tests showed that sucrose consumption in SPT, total traveling distance in OFT, and times of crossing the platform in MWMT were all reduced(P<0.01) and the immobility time in FST was prolonged(P<0.01) in the LOD group compared with those in the AGED group, suggesting that LOD rats had developed depression symptoms such as anhedonia, decreased locomotor activity ability, and cognitive dysfunction. Behavioral abnormalities were alleviated(P<0.01, P<0.05) in the EXD group as compared with those in the LOD group. Immunofluorescence results demonstrated that Ki-67/Nesti-positive cells and BrdU/DCX-positive cells in the hippocampal DG area were fewer(P<0.05) in LOD group than in the AGED group, and the positive cells in the EXD group were more(P<0.05) than those in the LOD group. In vitro experiment showed that the proliferation and differentiation of primary hippocampal neural stem cells under the CORT+D-gal treatment were reduced(P<0.01). The proliferation rate of neural stem cells decreased(P<0.05) in CORT+D-gal+LOD-CSF group but increased(P<0.01) in CORT+D-gal+EXD-CSF group compared with that in the CORT+D-gal group. A total of 2 620 proteins were identified from rat CSF, with 135 differential proteins between the LOD group and AGED group and 176 between EXD group and LOD group. GDF11, NrCAM, NTRK2, and GhR were related to neurogenesis and 39 differential proteins were regulated by both LOD and EXD. EXD demonstrated obvious anti-LOD effect, as it improved the locomotor activity ability and cognitive function of LOD rats and protected the proliferation and differentiation of hippocampal neural stem cells. EXD exerts anti-LOD effect by regulating the proteins related to neurogenesis in CSF, such as GDF11, NrCAM, NTRK2, and GhR and maintaining hippocampal neurogenesis.
Animals ; Depression/drug therapy* ; Drugs, Chinese Herbal ; Growth Differentiation Factors ; Hippocampus ; Male ; Neurogenesis ; Proteomics ; Rats ; Rats, Wistar

Growth differentiation factor 15 (GDF15) is, a member of the transforming growth factor beta (TGF-beta) superfamily of proteins. Although GDF15 is well established as a potent neurotrophic factor for neurons, little is known about its role in glial cells under neuropathological conditions. We monitored GDF15 expression in astrocyte activation after a kainic acid (KA)-induced neurodegeneration in the ICR mice hippocampus. In control, GDF15 immunoreactivity (IR) was evident in the neuronal layer of the hippocampus; however, GDF15 expression had increased in activated astrocytes throughout the hippocampal region at day 3 after the treatment with KA. LPS treatment in astrocytes dramatically increased GDF15 expression in primary astrocytes. In addition, LPS treatment resulted in the decrease of the IkappaB-alpha degradation and increase of the phosphorylation level of RelA/p65. These results indicate that GDF15 has a potential link to NF-kappaB activation, making GDF15 a valuable target for modulating inflammatory conditions.
Animals ; Astrocytes* ; Growth Differentiation Factor 15* ; Hippocampus* ; Kainic Acid ; Mice* ; Mice, Inbred ICR ; Neuroglia ; Neurons ; NF-kappa B ; Phosphorylation ; Transforming Growth Factor beta

BACKGROUND: It has been recognized that a defect in klotho gene expression accelerates the degeneration of multiple age-sensitive traits. Accumulating evidence indicates that aging is associated with declines in cognitive function and the activity of growth hormone (GH)/insulin-like growth factor-1 (IGF-1). METHODS: In this study, we examined whether a GH-releaser diet could be effective in protecting against cognitive impairment in klotho mutant mice. RESULTS: The GH-releaser diet significantly induced the expression of IGF-1 and IGF-1 receptors in the hippocampus of klotho mutant mice. Klotho mutant mice showed significant memory impairments as compared with wild-type mice. In addition, the klotho mutation significantly decreased the expression of cell survival/antiapoptotic factors, including phospho-Akt (p-Akt)/phospho-glycogen synthase kinase3beta (p-GSK3beta), phospho-extracellular signal-related kinase (p-ERK), and Bcl-2, but significantly increased those of cell death/proapoptotic factors, such as phospho-c-jun N-terminal kinase (p-JNK), Bax, and cleaved caspase-3 in the hippocampus. Treatment with GH-releaser diet significantly attenuated both decreases in the expression of cell survival/antiapoptotic factors and increases in the expression of cell death/proapoptotic factors in the hippocampus of klotho mutant mice. In addition, klotho mutation-induced oxidative stress was significantly attenuated by the GH-releaser diet. Consequently, a GH-releaser diet significantly improved memory function in the klotho mutant mice. GH-releaser diet-mediated actions were significantly reversed by JB-1, an IGF-1 receptor antagonist. CONCLUSION: The results suggest that a GH-releaser diet attenuates oxidative stress, proapoptotic changes and consequent dysfunction in klotho mutant mice by promoting IGF-1 expression and IGF-1 receptor activation.
Aging* ; Animals ; Caspase 3 ; Diet* ; Gene Expression ; Growth Hormone ; Hippocampus ; Insulin-Like Growth Factor I ; Memory ; Mice* ; Oxidative Stress ; Phosphotransferases ; Receptor, IGF Type 1

OBJECTIVE: To investigate the effects of dexmedetomidine (DEX) on hippocampal neuron development process and the expressions of molecules in brain-derived neurotropic factor (BDNF)-tyrosine receptor kinase B (TrkB) signaling pathway in neonatal rats. METHODS: The hippocampal neurons were isolated from neonatal rats and cultured in vitro. The cells were seeded in 96-well plates,which were divided into 4 groups (control group, 1 μmol/L DEX treatment group, 5 μmol/L DEX treatment group, 50 μmol/L DEX treatment group), six wells were set in each group, and different concentrations of dexmedetomidine 1, 5 and 50 μmol/L were administered respectively. Cell viability was detected at 2, 4, 6, 8, and 10 d after treatment, and apoptosis was detected 10 days after treatment. The mRNA expression levels of synaptophysin (SYN) and postsynaptic density protein 95 (PSD95) were detected by q-PCR, and the expressions of BDNF, TrkB and N-methyl-D-aspartate receptor (NMDAR) protein were analyzed. RESULTS: Compared with the control group, there was no significant difference in neuronal cell viability between the different doses of DEX treatment group. There was no significant difference in the expression of SYN and PSD95 mRNA and TrkB protein between the 1 μmol/L and 5 μmol/L DEX treatment groups (P＞0.05). The expression levels of SYN and PSD95 mRNA in the 50 μmol/L DEX group were increased significantly (P＜0.01), and the expression level of BDNF protein was up-regulated significantly (P＜0.01), the expression of the p-N-methyl-D-aspartate receptor was increased (P＜0.01). CONCLUSION 50 μmol/L DEX has a certain effect on rat hippocampal neurons, which may be achieved by up-regulating the expression of BDNF and the phosphorylation level of N-methyl-D-aspartate receptor.
Animals ; Brain-Derived Neurotrophic Factor ; Dexmedetomidine ; pharmacology ; Growth and Development ; Hippocampus ; drug effects ; growth & development ; Hypnotics and Sedatives ; pharmacology ; Neurons ; drug effects ; Rats

OBJECTIVETo observe the expression levels of hippocampal vascular endothelial growth factor (VEGF), fms-like tyrosine kinase-1 (flt-1), basic fibroblast growth factor (bFGF), and basic fibroblast growth factor receptor (bFGF-r) in vascular dementia (VD) rats, thus studying the angiogenesis mechanism of moxibustion in VD.

METHODSSixty male elderly Wistar rats were selected. The VD rat model was prepared by bilateral carotid artery occlusion and reperfusion of sodium nitroprusside injection. The model rats were divided into 3 groups by the random digit table, i. e., the moxibustion group, the Western medicine group, and the model group. A sham-operation control group was also set up. In the moxibustion group rats was acupunctured at Baihui (GV20), Shenting (GV14), and Dazhui (GV24). Aniracetam was given to rats in the Western medicine group by gastrogavage for 2 therapeutic courses, 15 days as one course. The learning and memory results were observed by the neuroethological score in combination of step-down avoidance test before treatment and by the end of the 2nd course respectively. The expression levels of hippocampal VEGF, flt-1, bFGF, and bFGF-r of all rats were detected using immunohistochemical assay.

RESULTSAfter 2 courses of treatment, statistical difference existed in the latent period, the error times, and the neuroethological score in the moxibustion group and the Western medicine group when compared with the model group (P < 0.01, P < 0.05). Statistical difference existed in the latent period and the neuroethological score between the moxibustion group and the Western medicine group (P < 0.05), which indicated that moxibustion and Western medicine showed significant effects in improving the latent period, decreasing the error times and the neuroethological score. Better results were obtained in the moxibustion group than in the Western medicine group (P < 0.01, P < 0.05). Statistical difference of the average grey level (AGL) of hippocampal VEGF, flt-1, and bFGF existed in the moxibustion group and the Western medicine group when compared with the model group. Statistical difference of the bFGF-r expression existed only between the moxibustion group and the model group. Statistical difference of the VEGF and flt-1 expressions existed between the moxibustion group and the Western medicine group (P < 0.05).

CONCLUSIONSMoxibustion showed confirmative effects in improving the behavioral score and memory performance in VD rats. Its mechanisms might lie in that moxibustion regulated and controlled the expression levels of hippocampal VEGF, flt-1, bFGF, and bFGF-r in VD rats. Particularly it up-regulated the expression levels of key factors VEGF and flt-1, promoted the angiogenesis in the vital parts, and ultimately stimulated the repairing mechanisms of cerebral nerve injury.

Animals ; Dementia, Vascular ; metabolism ; therapy ; Fibroblast Growth Factor 2 ; metabolism ; Hippocampus ; metabolism ; Male ; Moxibustion ; Rats ; Rats, Wistar ; Receptor, Fibroblast Growth Factor, Type 2 ; metabolism ; Vascular Endothelial Growth Factor A ; metabolism ; Vascular Endothelial Growth Factor Receptor-1 ; metabolism

In the adult mammalian brain, neural-lineage cells are continuously generated in the subventricular zone (SVZ) and dentate gyrus of the hippocampus. These cells in vivo arising from the adult SVZ may be regulated by environmental enrichment (EE). EE is a method of raising animals in a huge cage containing novel objects, running wheels and social interaction with a complex combination of physical, cognitive, and social stimulations. EE can affect neural plasticity via overexpression of growth factors such as brain-derived neurotrophic factor (BDNF), vascular endothelial growth factor (VEGF), insulin-like growth factor-1 (IGF-1), fibroblast growth factor-2 (FGF-2), and synaptic activity-regulating genes. EE also have advanced effects on brain functions including the enhancement of motor and cognitive functions in normal and pathological states. Additionally, behavioral changes by EE are related with molecular changes including neurogenesis, gliogenesis, angiogenesis, axonal sprouting, and dendritic branching in the adult brain. In this review, we focus on brain plasticity and neurorestoration associated with molecular changes of neurotrophic growth factors such as BDNF, VEGF, IGF-1, FGF-2 and synaptic activity-regulating genes that occurs in interaction to EE.
Adult ; Animals ; Axons ; Brain* ; Brain-Derived Neurotrophic Factor ; Dentate Gyrus ; Fibroblast Growth Factor 2 ; Hippocampus ; Humans ; Insulin-Like Growth Factor I ; Intercellular Signaling Peptides and Proteins ; Interpersonal Relations ; Neurogenesis ; Plastics* ; Running ; Vascular Endothelial Growth Factor A