OBJECTIVES: The neurotoxicity of carbon monoxide (CO) to the central nervous system is a key pathogenesis of delayed encephalopathy after acute carbon monoxide poisoning (DEACMP). Our previous study found that retinoic acid (RA) can suppress the neurotoxic effects of CO. This study further explores, in vivo and in vitro, the molecular mechanisms by which RA alleviates CO-induced central nervous system damage. METHODS: A cytotoxic model was established using the mouse hippocampal neuronal cell line HT22 and primary oligodendrocytes exposed to CO, and a DEACMP animal model was established in adult Kunming mice. Cell viability and apoptosis of hippocampal neurons and oligodendrocytes were assessed using the 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay and Annexin V/propidium iodide (PI) double staining. The transcriptional and protein expression of each gene was detected using real-time fluorescence quantitative PCR (RT-qPCR) and Western blotting. Long noncoding RNA (lncRNA) SNHG15 and LINGO-1 were knocked down or overexpressed to observe changes in neurons and oligodendrocytes. In DEACMP mice, SNHG15 or LINGO-1 were knocked down to assess changes in central nervous tissue and downstream protein expression. RESULTS: RA at 10 and 20 μmol/L significantly reversed CO-induced apoptosis of hippocampal neurons and oligodendrocytes, downregulation of SNHG15 and LINGO-1, and upregulation of brain-derived neurotrophic factor (BDNF) and tyrosine kinase receptor B (TrkB) (all P<0.05). Overexpression of SNHG15 or LINGO-1 weakened the protective effect of RA against CO-induced cytotoxicity (all P<0.05). Knockdown of SNHG15 or LINGO-1 alleviated CO-induced apoptosis of hippocampal neurons and oligodendrocytes and upregulated BDNF and TrkB expression levels (all P<0.05). Experiments in DEACMP model mice showed that knockdown of SNHG15 or LINGO-1 mitigated central nervous system injury in DEACMP (all P<0.05). CONCLUSIONS RA alleviates CO-induced apoptosis of hippocampal neurons and oligodendrocytes, thereby reducing central nervous system injury and exerting neuroprotective effects. LncRNA SNHG15 and LINGO-1 are key molecules mediating RA-induced inhibition of neuronal apoptosis and are associated with the BDNF/TrkB pathway. These findings provide a theoretical framework for optimizing the clinical treatment of DEACMP and lay an experimental foundation for elucidating its molecular mechanisms.
Animals ; RNA, Long Noncoding/physiology* ; Brain-Derived Neurotrophic Factor/genetics* ; Carbon Monoxide Poisoning/complications* ; Mice ; Tretinoin/pharmacology* ; Nerve Tissue Proteins/metabolism* ; Membrane Proteins/metabolism* ; Apoptosis/drug effects* ; Hippocampus/cytology* ; Receptor, trkB/metabolism* ; Neurons/drug effects* ; Male ; Brain Diseases/etiology* ; Oligodendroglia/drug effects* ; Signal Transduction ; Cell Line

OBJECTIVES: To exple the mechanism of Qixiong Zuogui Granules (QXZG) for enhancing synaptic plasticity in aging rats. METHODS: Forty SD rats were randomized into control group, aging model group, donepezil treatment group, and QXZG treatment group (n=10). Except for the control rats, all the rats were subjected to daily intraperitoneal injection of D-galactose for 8 consecutive weeks to induce brain aging, and donepezil hydrochloride and QXZG suspension were administered by gavage during modeling. After the interventions, the rats were evaluated for general conditions, behavioral changes, oxidative stress indicators, hippocampal pathologies, and expressions of the brain-derived neurotrophic factor (BDNF)/tyrosine kinase receptor B (TrkB) pathway, p16, and synaptic plasticity-associated proteins. RESULTS: The rats in the model group exhibited obvious aging phenotypes such as yellowing of the teeth and hair, body weight loss, and impaired learning and memory abilities, with decreased serum SOD and GSH-Px activities and increased serum MDA level. The rat models also showed obvious pathological changes, reduced Nissl bodies, and elevated p16 protein expression in the hippocampal CA1 region, with significantly decreased expression levels of BDNF, TrkB, CREB and synaptic plasticity proteins SYN, GAP43, and PSD95. Treatment with QXZG alleviated the aging phenotypes in the rat models, improved their learning and memory abilities and pathological changes in the hippocampal CA1 region, reduced oxidative stress and p16 protein expression, and promoted the expressions of the BDNF/TrkB pathway proteins and synaptic plasticity proteins. CONCLUSIONS QXZG enhances synaptic plasticity and reduces oxidative stress in aging rats possibly by upregulating the BDNF/TrkB signaling pathway proteins, thereby delaying brain aging and improving learning and memory abilities of the rats.
Animals ; Brain-Derived Neurotrophic Factor/metabolism* ; Neuronal Plasticity/drug effects* ; Signal Transduction/drug effects* ; Rats, Sprague-Dawley ; Receptor, trkB/metabolism* ; Rats ; Aging ; Drugs, Chinese Herbal/pharmacology* ; Male ; Oxidative Stress ; Hippocampus/metabolism*

Depression (Dep) is one of the most common concomitant symptoms of Parkinson's disease (PD), but there is a lack of detailed pathologic evidence for the occurrence of PD-Dep. Currently, the management of symptoms from both conditions using conventional pharmacological interventions remains a formidable task. In this study, we found impaired activation of extracellular signal-related kinase (ERK), reduced levels of transcription and translation, and decreased expression of brain-derived neurotrophic factor (BDNF) in the medial prefrontal cortex (mPFC) of PD-Dep rats. We demonstrated that the abnormal phosphorylation of α-synuclein (pS129) induced tropomyosin-related kinase receptor type B (TrkB) retention at the neuronal cell membrane, leading to BDNF/TrkB signaling dysfunction. We chose SEW2871 as an ameliorator to upregulate ERK phosphorylation. The results showed that PD-Dep rats exhibited improvement in behavioral manifestations of PD and depression. In addition, a reduction in pS129 was accompanied by a restoration of the function of the BDNF/ERK signaling loop in the mPFC of PD-Dep rats.
Animals ; Brain-Derived Neurotrophic Factor/metabolism* ; alpha-Synuclein/metabolism* ; Male ; Prefrontal Cortex/drug effects* ; Rats, Sprague-Dawley ; Depression/metabolism* ; MAP Kinase Signaling System/drug effects* ; Rats ; Parkinson Disease/metabolism* ; Receptor, trkB/metabolism* ; Phosphorylation ; Disease Models, Animal ; Signal Transduction

The neurotrophin-tyrosine receptor kinase B (TrkB) signaling pathway plays an important role in regulating the balance of excitation and inhibition in the primary visual cortex (V1). Previous studies have revealed its mechanism of regulating the level of cortical excitability by increasing the efficiency of excitatory transmission, but it has not been elucidated how TrkB receptors regulate the balance of excitation and inhibition through the inhibitory system, which in turn affects visual cortex function. Therefore, the objective of this study was to investigate how the TrkB signaling pathway specifically regulates the most important inhibitory neuron-PV neurons affects the visual cortex function of mice. The expression of TrkB receptor on PV neurons in the V1 region was specifically reduced by the virus, the functional changes of inhibitory and excitatory neurons in the primary visual cortex were recorded by multi-channel electrophysiological in vivo. The orientation discrimination ability of mice was tested by behavioral experiments, and altered orientation discrimination ability of mice was tested by behavioral experiments. The results showed that reduced expression of TrkB receptors on PV inhibitory neurons in primary visual cortex significantly increased the response intensity of excitatory neurons, reduced the orientation discrimination ability of inhibitory and excitatory neurons, and increased the signal-to-noise ratio, but the orientation discrimination ability at the individual level in mice showed a decrease. These results suggest that the TrkB signaling pathway does not modulate the function of PV neurons solely by increasing excitatory transmission targeting PV neurons, and its effect on neuronal signal-to-noise ratio is not due to enhancement of the inhibitory system.
Mice ; Animals ; Receptor, trkB/metabolism* ; Neurons/metabolism* ; Signal Transduction

OBJECTIVE: To investigate the inhibitory effect of ANA-12 that blocks brain-derived neurotrophic factor (BDNF)/ tropomyosin receptor kinase B (TrkB) signaling on inflammatory pain in rats and explore the underlying mechanism. METHODS: Forty-two adult SD rats were randomized into BDNF-induced acute pain group (n=24) and CFA-induced chronic pain group. The former group were randomly divided into 4 subgroups, including a control group, ANA-12 treatment group, BDNF treatment group, and BDNF+ANA-12 treatment group; the latter group were subgrouped into control group, CFA treatment group (CFA) and CFA + ANA-12 treatment group. The effects of ANA-12 treatment on pain behaviors of the rats with BDNF-induced acute pain and CFA-induced chronic inflammatory pain were observed. Western blotting was used to examine TrkB signaling and expressions of microglia marker protein Iba1 and TNF-α in the spinal cord of the rats. RESULTS: BDNF injection into the subarachnoid space significantly increased the number of spontaneous paw withdrawal of the rats (P < 0.05), which was obviously reduced by ANA-12 treatment (P < 0.05). The rats with intraplantar injection of CFA, showed significantly increased ipsilateral mechanical stimulation sensitivity (P < 0.05), and ANA-12 treatment obviously increased the ipsilateral foot withdrawal threshold (P < 0.05). Treatment with either BDNF or CFA significantly increased the phosphorylation level of TrkB (Y705) in the spinal cord of the rats (P < 0.05), which was significantly lowered by ANA-12 treatment (P < 0.05). Treatment with BDNF and CFA both significantly up-regulated the expressions of Iba1 and TNF-α in the spinal cord (P < 0.05), but ANA-12 significantly reduced their expression levels (P < 0.05). CONCLUSION ANA-12 can reduce spinal cord inflammation and relieve acute and chronic pain in rats by targeted blocking of BDNF/TrkB signaling.
Animals ; Brain-Derived Neurotrophic Factor/metabolism* ; Chronic Pain/drug therapy* ; Inflammation ; Rats ; Rats, Sprague-Dawley ; Receptor, trkB/metabolism*

OBJECTIVE: To explore the effect of electrical stimulation at auricular points (EAS) combined with sound masking on the expression of cAMP-response element binding protein (CREB), brain-derived neurotrophic factor (BDNF) and tyrosine receptor kinase B (TrkB) in the auditory cortex of tinnitus rats. METHODS: A total of 27 adult male SD rats were randomly divided into a control group, a model group and an EAS group. The rats in the model group and the EAS group were intervened with intraperitoneal injection of sodium salicylate to induce tinnitus model, while the rats in the control group were intervened with injection of 0.9% NaCl solution. After the model was successfully established, the rats in the EAS group were treated with electrical stimulation at "Shenmen" (TF) and "Yidan" (CO), combined with sound masking; the treatment was given once a day for 15 days. The gap prepulse inhibition of acoustic startle (GPIAS) and prepulse inhibition (PPI) testing were performed using the acoustic startle reflex starter package for rats. The expression of BDNF, TrkB, CREB and p-CREB in the auditory cortex of each group were measured with Western Blot analysis. RESULTS: ① Compared with the control group, the GPIAS values in 12 kHz, 16 kHz, 20 kHz and 28 kHz were significantly decreased in the model group (all <0.05); compared with the model group, GPIAS values in 12 kHz, 16 kHz, 20 kHz and 28 kHz were significantly increased in the EAS group (all <0.05). ② Compared with the control group, the expression of BDNF and p-CREB in the model group was significantly increased (<0.01), and the expression of TrkB in the model group was significantly increased (<0.05); the differences of expression of BDNF, TrkB, CREB and p-CREB between the model group and the EAS group had no statistics significance (all >0.05). CONCLUSION EAS could improve the GPIAS values of high-frequency background sound in tinnitus rats, which may be related with the upregulation of the BDNF/TrkB/CREB signaling pathway in the auditory cortex, leading to the reversion of the maladaptive plasticity.
Acupuncture Points ; Animals ; Auditory Cortex ; Brain-Derived Neurotrophic Factor ; metabolism ; Cyclic AMP Response Element-Binding Protein ; metabolism ; Electric Stimulation ; Male ; Rats ; Rats, Sprague-Dawley ; Receptor, trkB ; metabolism ; Tinnitus ; metabolism ; therapy

BackgroundGlehnia littoralis has been used for traditional Asian medicine, which has diverse therapeutic activities. However, studies regarding neurogenic effects of G. littoralis have not yet been considered. Therefore, in this study, we examined effects of G. littoralis extract on cell proliferation, neuroblast differentiation, and the maturation of newborn neurons in the hippocampus of adult mice.

MethodsA total of 39 male ICR mice (12 weeks old) were randomly assigned to vehicle-treated and 100 and 200 mg/kg G. littoralis extract-treated groups (n = 13 in each group). Vehicle and G. littoralis extract were orally administrated for 28 days. To examine neurogenic effects of G. littoralis extract, we performed immunohistochemistry for 5-bromo-2-deoxyuridine (BrdU, an indicator for cell proliferation) and doublecortin (DCX, an immature neuronal marker) and double immunofluorescence staining for BrdU and neuronal nuclear antigen (NeuN, a mature neuronal marker). In addition, we examined expressional changes of brain-derived neurotrophic factor (BDNF) and its major receptor tropomyosin-related kinase B (TrkB) using Western blotting analysis.

ResultsTreatment with 200 mg/kg, not 100 mg/kg, significantly increased number of BrdU-immunoreactive () and DCX cells (48.0 ± 3.1 and 72.0 ± 3.8 cells/section, respectively) in the subgranular zone (SGZ) of the dentate gyrus (DG) and BrdU/NeuN cells (17.0 ± 1.5 cells/section) in the granule cell layer as well as in the SGZ. In addition, protein levels of BDNF and TrkB (about 232% and 244% of the vehicle-treated group, respectively) were significantly increased in the DG of the mice treated with 200 mg/kg of G. littoralis extract.

ConclusionG. littoralis extract promots cell proliferation, neuroblast differentiation, and neuronal maturation in the hippocampal DG, and neurogenic effects might be closely related to increases of BDNF and TrkB proteins by G. littoralis extract treatment.

Animals ; Apiaceae ; chemistry ; Blotting, Western ; Brain-Derived Neurotrophic Factor ; metabolism ; Cell Differentiation ; drug effects ; Cell Proliferation ; drug effects ; Dentate Gyrus ; cytology ; drug effects ; Hippocampus ; cytology ; drug effects ; Immunohistochemistry ; Male ; Mice ; Microtubule-Associated Proteins ; metabolism ; Neurogenesis ; drug effects ; Neuropeptides ; metabolism ; Plant Extracts ; pharmacology ; Receptor, trkB ; metabolism

OBJECTIVETo observe the effects of acute immobilization stress on the mRNA expression of tyrosine kinase B (TrkB) in rats' hippocampus.

METHODSEighteen SD rats were randomly divided into three groups, i.e., the normal control group, the model group, and the medication group, 6 in each group. The acute immobilization stress model was prepared in the model group using acute immobilization for 2 h. Ginsenoside Rb1 (40 mg/kg) was peritoneally injected to rats in the medication group 30 min before modeling, with the same procedure as those for rats in the model group. No treatment was performed to rats in the normal control group. The plasma adrenocorticotropic hormone (ACTH) and corticosterone (CORT) contents were detected using ELISA. The mRNA expression of TrkB in the rats' hippocampus was detected using real-time fluorescence quantitative RT-PCR.

RESULTSBefore modeling there was no statistical difference of plasma CORT or ACTH concentrations among three groups (P >0.05). The plasma CORT and ACTH concentrations increased in the model group and the medication group more significantly after modeling than before modeling, showing statistical difference (P <0.05). Besides, they were obviously higher in the model group than in the normal control group (P <0.05). They were obviously higher in the medication group than in the model control group (P <0.05). Compared with the normal control group, the mRNA expression of TrkB significantly decreased in the model group (87.73 +/- 7.62 vs 50.65 +/- 5.19, P < 0.05), showing statistical difference. The mRNA expression of TrkB was significantly higher in the medication group (78.91 +/- 18.07) than in the model group, showing statistical difference (P <0.05).

CONCLUSIONPretreatment by ginsenoside Rb1 could increase the plasma CORT and ACTH concentrations, maintain the mRNA expression of TrkB, thus relieving injury induced by acute immobilization stress.

Adrenocorticotropic Hormone ; blood ; Animals ; Corticosterone ; blood ; Ginsenosides ; pharmacology ; Hippocampus ; metabolism ; Male ; RNA, Messenger ; genetics ; Rats ; Rats, Sprague-Dawley ; Receptor, trkB ; genetics ; metabolism ; Stress, Psychological ; metabolism

OBJECTIVETo observe the effects of Shuyu Ningxin Recipe (SNR) on the praxiology and the expressions of hippocampal brain-derived neurotrophic factor (BDNF) and its receptor tyrosine kinase B (TrkB) of model rats with chronic stress-induced depression, thus exploring its anti-depression mechanisms.

METHODSSixty adult SD rats were randomly divided into 6 groups, i.e., the normal control group, the model group, the fluoxetine group, the high dose SNR group, the medium dose SNR group, and the low dose SNR group, 10 in each group. All rats were subjected to establish chronic stress-induced depression model for 21 consecutive days. Except those in the normal control group, rats in the rest groups received gastrogavage from the 22nd day. Mice in the model group were administered with normal saline by gastrogavage. SNR at 25.0, 7.5, and 2.5 g/kg was respectively administered to rats in the high dose SNR group, the medium dose SNR group, and the low dose SNR group by gastrogavage. Fluoxetine suspension (12 mg/kg) was given to rats in the fluoxetine group by gastro-gavage. All medication lasted for 3 successive weeks. The weight, open-field test, and the immobility time in forced swimming test were determined before modeling, 3 weeks (after successful modeling), and 6 weeks (by the end of medication). The expressions of hippocampal BDNF and TrkB were measured after the brain tissues were drawn by the end of the experiment.

RESULTSCompared with the normal control group, the body weight grew slowly, the behavior index decreased, the immobility time in forced swimming test was prolonged, and the expressions of BDNF and TrkB were weaken in the model group (P <0.05, P <0.01).The body weight increased, the behavior was improved, the immobility time in forced swimming test was shortened, and the expressions of BDNF and TrkB were enhanced in the high dose SNR group and the fluoxetine group by the and of medication, showing statistical difference when compared with the model group (P <0.05, P <0.01).

CONCLUSIONSNR could exert anti-depression by improving the expression levels of hippocampal BDNF and TrkB.

Animals ; Behavior, Animal ; Brain-Derived Neurotrophic Factor ; metabolism ; Depression ; metabolism ; Drugs, Chinese Herbal ; pharmacology ; Hippocampus ; metabolism ; Male ; Rats ; Rats, Sprague-Dawley ; Receptor, trkB ; metabolism ; Stress, Psychological ; metabolism

The purpose of the present study was to investigate the effects of icariin (ICA) on the content of beta-amyloid (Abeta) and the expression of neurotrophic factors in the brain of mitochondrial deficiency model rats. SD rats were infused subcutaneously with sodium azide, which is an inhibitor of mitochondrial respiratory chain complex IV, via a minipump (0. 5 mg . kg-1 h-1) for 28 days to establish the mitochondrial deficiency animal model. The activity of mitochondrial respiratory chain complex IV (i. e. cytochrome C oxidase, COX) in hippocampus was measured by biochemical methods. ELISA method was used to detect the content of Abeta in the brain. The expression of neurotrophic factors was detected by Western blot and immunohistochemistry methods. Image analysis was performed by Image-pro software. The results showed that chronic infusion of sodium azide by minipump induced a significant decrease in the activity of mitochondrial cytochrome C oxidase, an obvious increase in the content of Abeta, and a marked decline in the expression of nerve growth factor (NGF), brain-derived neurotrophic factor (BDNF) and its receptor TrkB in the brain of rats. Intragastrical administration of ICA (12 or 36 mg . kg-l) significantly ameliorated all these abnormalities in the model rats. In conclusion, ICA can increase mitochondrial activity, inhibit Abeta production, and enhance the expression of neurotrophic factors in the brain of model rats induced by sodium azide. The results suggested that ICA may have beneficial prospect for the treatment of Alzheimer's disease.
Amyloid ; metabolism ; Animals ; Brain ; drug effects ; metabolism ; Brain-Derived Neurotrophic Factor ; metabolism ; Disease Models, Animal ; Enzyme-Linked Immunosorbent Assay ; Flavonoids ; pharmacology ; therapeutic use ; Mitochondria ; drug effects ; metabolism ; pathology ; Mitochondrial Diseases ; drug therapy ; metabolism ; Nerve Growth Factor ; metabolism ; Nerve Growth Factors ; metabolism ; Rats ; Rats, Sprague-Dawley ; Receptor, trkB ; metabolism