Effects of carbamazepine on BDNF expression in trigeminal ganglia and serum in rats with trigeminal neuralgia. / å¡é©¬è¥¿å¹³å¯¹ä¸‰å‰ç¥žç»ç—›å¤§é¼ ä¸‰å‰ç¥žç»èŠ‚åŠè¡€æ¸ ä¸­BDNF表达变化的影响.

OBJECTIVES: Trigeminal neuralgia (TN) is a severe chronic neuropathic pain that mainly affects the distribution area of the trigeminal nerve with limited treating efficacy. There are numerous treatments for TN, but currently the main clinical approach is to suppress pain by carbamazepine (CBZ). Brain-derived neurotrophic factor (BDNF) is closely related to chronic pain. This study aims to determine the effects of CBZ treatment on BDNF expression in both the trigeminal ganglion (TG) and serum of TN via a chronic constriction injury of the infraorbital nerve (ION-CCI) rat model. METHODS: The ION-CCI models were established in male Sprague-Dawley rats and were randomly divided into a sham group, a TN group, a TN+low-dose CBZ treatment group (TN+20 mg/kg CBZ group), a TN+medium-dose CBZ treatment group (TN+40 mg/kg CBZ group), and a TN+high-dose CBZ treatment group (TN+80 mg/kg CBZ group). The mechanical pain threshold in each group of rats was measured regularly before and after surgery. The expressions of BDNF and tyrosine kinase receptor B (TrkB) mRNA in TGs of rats in different groups were determined by real-time PCR, and the expression of BDNF protein on neurons in TGs was observed by immunofluorescence. Western Blotting was used to detect the protein expression of BDNF, TrkB, extracellular regulated protein kinases (ERK), and phospho-extracellular regulated protein kinases (p-ERK) in TGs of rats in different groups. The expression of BDNF in the serum of rats in different groups was detected by enzyme-linked immunosorbent assay (ELISA). RESULTS: The results of mechanical pain sensitivity showed that there was no significant difference in the mechanical pain threshold in the right facial sensory area of the experimental rats in each group before surgery (all P>0.05). From the 3rd day after operation, the mechanical pain threshold of rats in the TN group was significantly lower than that in the sham group (all P<0.01), and the mechanical pain threshold of rats in the TN+80 mg/kg CBZ group, the TN+40 mg/kg CBZ group, and the TN+20 CBZ mg/kg group was higher than that in the TN group (all P<0.05). The BDNF and TrkB mRNA and protein expressions in TGs of rats in the TN group were higher than those in the sham group (all P<0.05), and those in the TN+80 mg/kg CBZ group, the TN+40 mg/kg CBZ group, and the TN+20 mg/kg CBZ group were lower than the TN group (all P<0.05). The p-ERK levels in TG of rats in the TN+80 mg/kg CBZ group, the TN+40 mg/kg CBZ group, and the TN+20 mg/kg CBZ group were significantly decreased compared with the TN group (all P<0.05). The BDNF and neuron-specific nuclear protein (NeuN) were mainly co-expressed in neuron of TGs in the TN group and they were significantly higher than those in the sham group (all P<0.05). The co-labeled expressions of BDNF and NeuN in TGs of the TN+ 80 mg/kg CBZ group, the TN+40 mg/kg CBZ group, and the TN+20 mg/kg CBZ group were lower than those in the TN group (all P<0.05). The results of ELISA showed that the level of BDNF in the serum of the TN group was significantly higher than that in the sham group (P<0.05). The levels of BDNF in the TN+80 mg/kg CBZ group, the TN+40 mg/kg CBZ group, and the TN+20 mg/kg CBZ group were lower than those in the TN group (all P<0.05). Spearman correlation analysis showed that the BDNF level in serum was negatively correlated with mechanical pain threshold (r=-0.650, P<0.01). CONCLUSIONS: CBZ treatment can inhibit the expression of BDNF and TrkB in the TGs of TN rats, reduce the level of BDNF in serum of TN rats and the phosphorylation of ERK signaling pathway, so as to inhibit TN. The serum level of BDNF can be considered as an indicator for the diagnosis and prognosis of TN.

Metformin Induces MeCP2 in the Hippocampus of Male Mice with Sex-Specific and Brain-Region-Dependent Molecular Impact.

Rett Syndrome (RTT) is a progressive X-linked neurodevelopmental disorder with no cure. RTT patients show disease-associated symptoms within 18 months of age that include developmental regression, progressive loss of useful hand movements, and breathing difficulties, along with neurological impairments, seizures, tremor, and mental disability. Rett Syndrome is also associated with metabolic abnormalities, and the anti-diabetic drug metformin is suggested to be a potential drug of choice with low or no side-effects. Previously, we showed that in vitro exposure of metformin in a human brain cell line induces MECP2E1 transcripts, the dominant isoform of the MECP2 gene in the brain, mutations in which causes RTT. Here, we report the molecular impact of metformin in mice. Protein analysis of specific brain regions in the male and female mice by immunoblotting indicated that metformin induces MeCP2 in the hippocampus, in a sex-dependent manner. Additional experiments confirm that the regulatory role of metformin on the MeCP2 target "BDNF" is brain region-dependent and sex-specific. Measurement of the ribosomal protein S6 (in both phosphorylated and unphosphorylated forms) confirms the sex-dependent role of metformin in the liver. Our results can help foster a better understanding of the molecular impact of metformin in different brain regions of male and female adult mice, while providing some insight towards its potential in therapeutic strategies for the treatment of Rett Syndrome.

Medicinal cannabis oil improves anxiety-like and depressive-like behaviors in CCS mice via the BDNF/TRPC6 signaling pathway.

BACKGROUND: Post-traumatic stress disorder (PTSD) refers to a chronic impairing psychiatric disorder occurring after exposure to the severe traumatic event. Studies have demonstrated that medicinal cannabis oil plays an important role in neuroprotection, but the mechanism by which it exerts anti-PTSD effects remains unclear. METHODS: The chronic complex stress (CCS) simulating the conditions of long voyage stress for 4 weeks was used to establish the PTSD mice model. After that, behavioral tests were used to evaluate PTSD-like behaviors in mice. Mouse brain tissue index was detected and hematoxylin-eosin staining was used to assess pathological changes in the hippocampus. The indicators of cell apoptosis and the BDNF/TRPC6 signaling activation in the mice hippocampus were detected by western blotting or real-time quantitative reverse transcription PCR experiments. RESULTS: We established the PTSD mice model induced by CCS, which exhibited significant PTSD-like phenotypes, including increased anxiety-like and depression-like behaviors. Medicinal cannabis oil treatment significantly ameliorated PTSD-like behaviors and improved brain histomorphological abnormalities in CCS mice. Mechanistically, medicinal cannabis oil reduced CCS-induced cell apoptosis and enhanced the activation of BDNF/TRPC6 signaling pathway. CONCLUSIONS: We constructed a PTSD model with CCS and medicinal cannabis oil that significantly improved anxiety-like and depressive-like behaviors in CCS mice, which may play an anti-PTSD role by stimulating the BDNF/TRPC6 signaling pathway.

Metabolomics-Based Effects of a Natural Product on Remyelination After Cerebral Ischemia Injury Via GABABR-pCREB-BDNF Pathway.

BACKGROUND: Yi-Qi-Tong-Luo Granules (YQTLs) is a natural compound of Traditional Chinese Medicine authorized by China Food and Drug Administration (CFDA). These granules are employed in the convalescent stage of cerebral infarction and render notable clinical efficacy. This study aims to uncover the underlying mechanisms of YQTLs on remyelination after cerebral ischemia injury. MATERIALS AND METHODS: We established cerebral ischemia model in rats using microsphere-induced multiple cerebral infarction (MCI). We evaluated the pharmacological effects of YQTLs on MCI rats, through Morri's water maze test, open field test, hematoxylin and eosin staining, and glycine silver immersion. We employed liquid chromatography mass spectrometry metabolomics to identify differential metabolites. Enzyme-linked immunosorbent assay was utilized to measure the release of neurotrophins, while immunofluorescence staining was used to assess oligodendrocyte precursor cells differences and myelin regeneration. We used Western blotting to validate the protein expression of remyelination-associated signaling pathways. RESULTS: YQTLs significantly improves cognitive function following cerebral ischemia injury. Pathological tissue staining revealed that YQTLs administration inhibits neuronal denaturation and neurofibrillary tangles. We identified 141 differential metabolites among the sham, MCI, and YQTLs-treated MCI groups. Among these metabolites, neurotransmitters were identified, and notably, gamma-aminobutyric acid (GABA) showed marked improvement in the YQTLs group. The induction of neurotrophins, such as brain-derived neurotrophic factor (BDNF) and PDGFAA, upregulation of olig2 and MBP expression, and promotion of remyelination were evident in YQTLs-treated MCI groups. Gamma-aminobutyric acid B receptors (GABABR), pERK/extracellular regulated MAP kinase, pAKT/protein kinase B, and pCREB/cAMP response element-binding were upregulated following YQTLs treatment. CONCLUSION: YQTLs enhance the binding of GABA to GABABR, thereby activating the pCREB/BDNF signaling pathway, which in turn increases the expression of downstream myelin-associated proteins and promotes remyelination and cognitive function.

The effect of psychedelics on the level of brain-derived neurotrophic factor: A systematic review and meta-analysis.

BACKGROUND: Recent interest in the potential therapeutic effects of psychedelics has led to investigations into their influence on molecular signaling pathways within the brain. AIMS: Integrated review and analysis of different studies in this field. METHODS: A systematic search was conducted across international databases including Embase, Scopus, Web of Science, and PubMed from inception to 9 July 2023. Eligibility criteria encompassed published and peer-reviewed studies evaluating changes in brain-derived neurotrophic factor (BDNF) levels after psychedelic consumption. OUTCOMES: A total of nine studies were included in our study. The meta-analysis demonstrated significantly higher BDNF levels in psychedelic consumers compared to healthy controls, with a pooled standardized mean difference of 0.26 (95% CI: 0.10-0.42, I2 = 38.51%, p < 0.001). Leave-one-out analysis indicated robustness in results upon removal of individual psychedelics. No significant publication bias was observed. The results highlight the potential influence of psychedelics on neuroplasticity by altering BDNF levels. CONCLUSIONS: More precisely, the documented rise in BDNF levels indicates a neurobiological mechanism by which psychedelics could enhance synaptic plasticity and foster the growth of neurons. Given the limited data available on this topic, the conclusions remain uncertain. Consequently, we highly recommend additional research with more extensive sample sizes to yield more reliable evidence in this field.

Engeletin alleviates depression-like phenotype by increasing synaptic plasticity via the BDNF-TrkB-mTORC1 signalling pathway.

Major depressive disorder (MDD) is a severe mental disorder associated with high rates of morbidity and mortality. Current first-line pharmacotherapies for MDD are based on enhancement of monoaminergic neurotransmission, but these antidepressants are still insufficient and produce significant side-effects. Consequently, the development of novel antidepressants and therapeutic targets is desired. Engeletin, a natural Smilax glabra rhizomilax derivative, is a compound with proven efficacy in treating ischemic stroke, yet its therapeutic effects and mechanisms for depression remain unexplored. The effects of engeletin were assessed in the forced swimming test (FST) and tail suspension test (TST) in mice. Engeletin was also investigated in the chronic restraint stress (CRS) mouse model of depression with fluoxetine (FLX) as the positive control. Changes in prefrontal cortex (PFC) spine density, synaptic plasticity-linked protein expressions and the brain-derived neurotrophic factor (BDNF)-tyrosine kinase B (TrkB)- mammalian target of rapamycin complex 1 (mTORC1) signalling pathway after chronic stress and engeletin treatment were then investigated. The TrkB and mTORC1 selective inhibitors, ANA-12 and rapamycin, respectively, were utilized to assess the engeletin's antidepressive mechanisms. Our data shows that engeletin exhibited antidepressant-like activity in the FST and TST in mice without affecting locomotor activity. Furthermore, it exhibited efficiency against the depression of CRS model. Moreover, it enhanced the BDNF-TrkB-mTORC1 pathway in the PFC during CRS and altered the reduction in dendritic spine density and levels of synaptic plasticity-linked protein induced by CRS. In conclusion, engeletin has antidepressant activity via activation of the BDNF-TrkB-mTORC1 signalling pathway and upregulation of PFC synaptic plasticity.

In vitro study of ochratoxin A in the expression of genes associated with neuron survival and viability.

Ochratoxin A (OTA) is a common mycotoxin and known contaminant of crops, foods and drinks. As OTA crosses the blood-brain barrier, this study investigated the role of OTA, as an environmental hazard, on neuronal survival and viability. The impact of a range of OTA concentrations on the expression of MAPT, BAX, P53, BDNF and TPPP genes was investigated using human neuroblastoma (SH-SY5Y) cells. The absence of altered gene expression determined using reverse transcription quantitative PCR demonstrated that exposure to a typical daily dose of OTA delivered to the brain (2 fM), may not trigger neuronal dysfunction. However, a dose of OTA (2 pM) decreased BDNF expression. BDNF and TPPP expression were significantly reduced after 1 day and significantly increased after 2 days of exposure to 1 µM OTA. The expression of P53, MAPT, and BAX was reduced at both days. Thus, despite OTA cytotoxicity, SH-SY5Y cells entered a survival state following a strong toxic insult. A typical daily environmental OTA exposure does not appear to carry an increased risk of neurodegenerative disease. However, BDNF dysfunction may occur through prolonged exposure to a dose one thousand times higher than the typical daily consumed OTA dose potentially causing adverse effects on neuronal health.

Acetoacetate Improves Memory in Alzheimer's Mice via Promoting Brain-Derived Neurotrophic Factor and Inhibiting Inflammation.

The ketone bodies, especially the ß-hydroxybutyrate, had been shown to modulate the function of the central nervous system and prevent the pathological progression of Alzheimer's disease (AD). However, little is known about the role of acetoacetate in the AD brain. Thus, we intraventricularly injected acetoacetate into familial AD mice (APPSWE) for 14 days and monitored their memory and biochemical changes. During the behavior test, acetoacetate at 100 mg/kg led to significant improvement in both Y-maze and novel object recognition tests (NORTs) (both P < .05), indicating ameliorating spatial and recognition memory, respectively. Biomedical tests revealed two mechanisms were involved. Firstly, acetoacetate inhibited the GPR43-pERK pathway, which led to apparent inhibition in tumor necrosis factor-α and Interleukin-6 expression in the hippocampus in a concentration-dependent manner. Secondarily, acetoacetate stimulated the expression of hippocampal brain-derived neurotrophic factor (BDNF). We concluded that acetoacetate could ameliorate AD symptoms and exhibited promising features as a therapeutic for AD.

Motor, memory, and anxiety-like behavioral impairments associated with brain-derived neurotrophic factor and dopaminergic imbalance after inhalational exposure to deltamethrin.

Believed to cause damage to the nervous system and possibly being associated with neurodegenerative diseases, deltamethrin (DM) is a type II pyrethroid used in pest control, public health, home environment, and vector control. The objective of this study was to evaluate the motor, cognitive and emotional changes associated with dopaminergic and BDNF imbalance after DM exposure in rats. Sixty Wistar rats (9-10 months-old) were used, under Ethics Committee on Animal Research license (ID 19/2017). The animals were randomly divided into four groups: control (CTL, 0.9% saline), DM2 (2 mg DM in 1.6 mL 0.9% saline), DM4 (4 mg of DM in 1.6 mL of 0.9% saline), and DM8 (8 mg of DM in 1.6 mL of 0.9% saline). DM groups were submitted to 9 or 15 inhalations, one every 48 h. Half of the animals from each group were randomly selected and perfused 24 h after the 9th or 15th inhalation. Throughout the experiment, the animal's behavior were evaluated using catalepsy test, open field, hole-board test, Modified Elevated Plus Maze, and social interaction. At the end of the experiments, the rats were perfused transcardially and their brains were processed for Tyrosine Hydroxylase (TH) and Brain derived neurotrophic factor (BDNF) immunohistochemistries. The animals submitted to 9 inhalations of DM showed a reduction in immunoreactivity for TH in the Substantia nigra pars compacta (SNpc), ventral tegmental area (VTA), and dorsal striatum (DS) areas, and an increase in BDNF in the DS and CA1, CA3 and dentate gyrus (DG) hippocampal areas. Conversely, the animals submitted to 15 inhalations of DM showed immunoreactivity reduced for TH in the SNpc and VTA, and an increase in BDNF in the hippocampal areas (CA3 and DG). Our results indicate that the DM inhalation at different periods induce motor and cognitive impairments in rats. Such alterations were accompanied by dopaminergic system damage and a possible dysfunction on synaptic plasticity.

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.

The Toll-like receptor 4 antagonist TAK-242 induces antidepressant-like effects in a rat learned helplessness model of depression through BDNF-TrkB signaling and AMPA receptor activation.

Finding from animal models of depression indicated that Toll-like receptor 4 (TLR4) is associated with the pathophysiology of depression. Herein, the TLR4 antagonists TAK-242 and baicalin induced antidepressant-like effects in a rat learned helplessness model of depression. The antidepressant-like effects of both TLR4 antagonists were blocked by the TrkB inhibitor ANA-12. Also, the antidepressant-like effects of TAK-242 were blocked by the treatment with AMPA receptor antagonist NBQX. The antidepressant-like effects of the TLR4 antagonist TAK-242 involves BDNF-TrkB signaling and AMPA receptor activation.

7,8-Dihydroxyflavone protects retinal ganglion cells against chronic intermittent hypoxia-induced oxidative stress damage via activation of the BDNF/TrkB signaling pathway.

PURPOSE: Chronic intermittent hypoxia (CIH) plays a key role in the complications of obstructive sleep apnea (OSA), which is strongly associated with retinal and optic nerve diseases. Additionally, the brain-derived neurotrophic factor (BDNF)/tropomyosin receptor kinase B (TrkB) signaling pathway plays an important protective role in neuronal injury. In the present study, we investigated the role of 7,8-dihydroxyflavone (7,8-DHF) in regulating CIH-induced injury in mice retinas and rat primary retinal ganglion cells (RGCs). METHODS: C57BL/6 mice and in vitro primary RGCs were exposed to CIH or normoxia and treated with or without 7,8-DHF. The mice eyeballs or cultured cells were then taken for histochemistry, immunofluorescence or biochemistry, and the protein expression of the BDNF/TrkB signaling pathway analysis. RESULTS: Our results showed that CIH induced oxidative stress (OS) in in vivo and in vitro models and inhibited the conversion of BDNF precursor (pro-BDNF) to a mature form of BDNF, which increased neuronal cell apoptosis. 7,8-DHF reduced the production of reactive oxygen species (ROS) caused by CIH and effectively activated TrkB signals and downstream protein kinase B (Akt) and extracellular signal-regulated kinase (Erk) survival signaling pathways, which upregulated the expression of mature BDNF. ANA-12 (a TrkB specific inhibitor) blocked the protective effect of 7,8-DHF. CONCLUSION: In short, the activation of the BDNF/TrkB signaling pathway alleviated CIH-induced oxidative stress damage of the optic nerve and retinal ganglion cells. 7,8-DHF may serve as a promising agent for OSA related neuropathy.

Analysis of Antidepressant-like Effects and Action Mechanisms of GSB-106, a Small Molecule, Affecting the TrkB Signaling.

Induction of BDNF-TrkB signaling is associated with the action mechanisms of conventional and fast-acting antidepressants. GSB-106, developed as a small dimeric dipeptide mimetic of BDNF, was previously shown to produce antidepressant-like effects in the mouse Porsolt test, tail suspension test, Nomura water wheel test, in the chronic social defeat stress model and in the inflammation-induced model of depression. In the present study, we evaluated the effect of chronic per os administration of GSB-106 to Balb/c mice under unpredictable chronic mild stress (UCMS). It was observed for the first time that long term GSB-106 treatment (1 mg/kg, 26 days) during ongoing UCMS procedure ameliorated the depressive-like behaviors in mice as indicated by the Porsolt test. In addition, chronic per os administration of GSB-106 resulted in an increase in BDNF levels, which were found to be decreased in the prefrontal cortex and hippocampus of mice after UCMS. Furthermore, prolonged GSB-106 treatment was accompanied by an increase in the content of pTrkB706/707 in the prefrontal cortex and by a pronounced increase in the level of pTrkB816 in both studied brain structures of mice subjected to UCMS procedure. In summary, the present data show that chronic GSB-106 treatment produces an antidepressant-like effect in the unpredictable chronic mild stress model, which is likely to be associated with the regulation of the BDNF-TrkB signaling.

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

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

Effects of remifentanil on human C20 microglial pro-inflammatory activation.

OBJECTIVE: Remifentanil (RF) is a potent short-acting µ-opioid receptor agonist. Although preferred for its unique pharmacokinetics, the clinical use may be limited by hyperalgesia. Preclinical studies have shown a potential role of microglia on the development of hyperalgesia, with limited and conflicting evidence on RF. Considering the role of microglia in the initiation and maintenance of brain inflammation and their different responses among species, we aimed at characterizing RF effects on human adult microglia in vitro. MATERIALS AND METHODS: RF was tested at clinically relevant concentrations on the human microglial C20 cell line. Expression and release of interleukin-6 (IL-6) and brain derived neurotrophic factor (BDNF) were assessed under basal and inflammatory conditions. RESULTS: The expression and secretion of IL-6 significantly increased in C20 cells in response to pro-inflammatory cytokines. RF did not modify this response neither under basal nor under inflammatory conditions. No toxicity due to RF was detected. The drug displayed a modest stimulatory effect on the production of BDNF. CONCLUSIONS: Although RF does not exert direct pro-inflammatory actions on human adult microglia, its effects on BDNF, a crucial mediator of pain transmission, suggest a possible role on neuroinflammation and pain perception.

Targeting both BDNF/TrkB pathway and delta-secretase for treating Alzheimer's disease.

Alzheimer's disease (AD) is the most common dementia, and no disease-modifying therapeutic agents are currently available. BDNF/TrkB signaling is impaired in AD and is associated with prominent delta-secretase (δ-secretase, also known as asparaginyl endopeptidase or legumain) activation, which simultaneously cleaves both APP and Tau and promotes Aß production and neurofibrillary tangles (NFT) pathologies. Here we show that the optimized δ-secretase inhibitor (#11a) or TrkB receptor agonist (CF3CN) robustly blocks δ-secretase activity separately, and their combination synergistically blunts δ-secretase, exhibiting promising therapeutic efficacy in 3xTg AD mouse model. The optimal δ-secretase inhibitor reveals demonstrable brain exposure and oral bioavailability, suppressing APP N585 and Tau N368 cleavage by δ-secretase. Strikingly, CF3CN treatment evidently escalates BDNF levels. Both #11a and CF3CN display strong in vivo PK/PD properties and ability to suppress δ-secretase activity in the brain. Orally administrated CF3CN strongly activates TrkB that triggers active Akt to phosphorylate δ-secretase T322, preventing its proteolytic activation and mitigating AD pathologies. #11a or CF3CN significantly diminishes AD pathogenesis and improves cognitive functions with the combination exhibiting the maximal effect. Thus, our data support that these derivatives are strong pharmaceutical candidates for the treatment of AD.

Decreased spasticity of Baishaoluoshi Decoction through the BDNF/TrKB-KCC2 pathway on poststroke spasticity rats.

OBJECTIVE: K+-Cl- cotransporter-2 (KCC2), which primarily extrudes chloride in mature neurons, triggers hemiplegia limb spasticity after ischemic stroke by affecting neuronal excitability. Our previous study revealed that the Chinese herb Baishaoluoshi Decoction decreases hemiplegia limb spasticity in poststroke spasticity (PSS) patients. This study aimed at elucidating on the effects of Baishaoluoshi Decoction on the BDNF/TrKB-KCC2 pathway in PSS rat models. METHODS: Middle cerebral artery occlusion (MCAO) was adopted for the establishment of PSS rat models. Muscle tension was evaluated by Modified Ashworth Scale. Nissl staining and transmission electron microscopy were used to measure the protective effects of Baishaoluoshi Decoction on ischemic injury-induced neuronal damage due to MCAO. Expression levels of BDNF, TrKB, and KCC2 in brain tissues around the infarct and brainstem were detected by immunohistochemical staining. RESULTS: It was found that Baishaoluoshi Decoction suppressed hemiplegia limb spasticity and alleviated the damage in neurons and synapses in PSS rat models. Importantly, the expression of BDNF, TrKB, and KCC2 in brain tissues around the infarct and brainstem were significantly upregulated after treatment with low-dose and high-dose Baishaoluoshi Decoction. CONCLUSION: Suppression of spasticity by Baishaoluoshi Decoction in PSS rat models may be correlated with upregulated BDNF/TrKB-KCC2 pathway, which may be a complementary therapeutic strategy for PSS.

Recovery of post-stroke cognitive and motor deficiencies by Shuxuening injection via regulating hippocampal BDNF-mediated Neurotrophin/Trk Signaling.

A mild ischemic stroke may cause both debilitating locomotor and cognitive decline, for which the mechanism is not fully understood, and no therapies are currently available. In this study, a nonfatal stroke model was constructed in mice by a modified middle cerebral artery occlusion (MCAO) procedure, allowing an extended recovery period up to 28 days. The extended MCAO model successfully mimicked phenotypes of a recovery phase post-stroke, including locomotor motor and cognitive deficiencies, which were effectively improved after Shuxuening injection (SXNI) treatment. Tissue slices staining showed that SXNI repaired brain injury and reduced neuronal apoptosis, especially in the hippocampus CA3 region. Transcriptomics sequencing study revealed 565 differentially expressed genes (DEGs) in the ischemic brain after SXNI treatment. Integrated network pharmacological analysis identified Neurotrophin/Trk Signaling was the most relevant pathway, which involves 15 key genes. Related DEGs were further validated by RT-PCR. Western-blot analysis showed that SXNI reversed the abnormal expression of BDNF, TrkB, Mek3 and Jnk1after stroke. ELISA found that SXNI increased brain level of p-Erk and Creb. At sub-brain level, the expression of BDNF and TrkB was decreased and GFAP was increased on the hippocampal CA3 region in the post-stroke recovery phase and this abnormality was improved by SXNI. In vitro experiments also found that oxygen glucose deprivation reduced the expression of BDNF and TrkB, which was reversed by SXNI. In summary, we conclude that SXNI facilitates the recovery of cognitive and locomotor dysfunction by modulating Neurotrophin/Trk Signaling in a mouse model for the recovery phase of post-ischemic stroke.

Dimethyl fumarate abridged tauo-/amyloidopathy in a D-Galactose/ovariectomy-induced Alzheimer's-like disease: Modulation of AMPK/SIRT-1, AKT/CREB/BDNF, AKT/GSK-3ß, adiponectin/Adipo1R, and NF-κB/IL-1ß/ROS trajectories.

Since the role of estrogen in postmenauposal-associated dementia is still debatable, this issue urges the search for other medications. Dimethyl fumarate (DMF) is a drug used for the treatment of multiple sclerosis and has shown a neuroprotective effect against other neurodegenerative diseases. Accordingly, the present study aimed to evaluate the effect of DMF on an experimental model of Alzheimer disease (AD) using D-galactose (D-Gal) administered to ovariectomized (OVX) rats, resembling a postmenopausal dementia paradigm. Adult 18-month old female Wistar rats were allocated into sham-operated and OVX/D-Gal groups that were either left untreated or treated with DMF for 56 days starting three weeks after sham-operation or ovariectomy. DMF succeeded to ameliorate cognitive (learning/short- and long-term memory) deficits and to enhance the dampened overall activity (NOR, Barnes-/Y-maze tests). These behavioral upturns were associated with increased intact neurons (Nissl stain) and a reduction in OVX/D-Gal-mediated hippocampal CA1 neurodegeneration and astrocyte activation assessed as GFAP immunoreactivity. Mechanistically, DMF suppressed the hippocampal contents of AD-surrogate markers; viz., apolipoprotein (APO)-E1, BACE1, Aß42, and hyperphosphorylated Tau. Additionally, DMF has augmented the neuroprotective parameters p-AKT, its downstream target CREB and BDNF. Besides, it activated AMPK, and enhanced SIRT-1, as well as antioxidant defenses (SOD, GSH). On the other hand, DMF inhibited the transcription factor NF-κB, IL-1ß, adiponectin/adiponectin receptor type (AdipoR)1, GSK-3ß, and MDA. Accordingly, in this postmenopausal AD model, DMF treatment by pursuing the adiponectin/AdipoR1, AMPK/SIRT-1, AKT/CREB/BDNF, AKT/GSK-3ß, and APO-E1 quartet hampered the associated tauo-/amyloidopathy and NF-κB-mediated oxidative/inflammatory responses to advance insights into its anti-amnesic effect.

Sigma 1 receptor agonist cutamesine promotes plasticity of serotonergic boutons in lumbar enlargement in spinal cord injured rats.

Cutamesine, a sigma-1 receptor agonist, functions in both neuroprotection and neurite outgrowth. We assessed the therapeutic effects of cutamesine in a rodent spinal cord injury (SCI) model to demonstrate pre-clinical proof-of-concept. First of all, in order to determine optimal cutamesine dose, cutamesine was administered to normal rats and BDNF protein levels in the lumbar spinal cord were assessed by Western blot. Next, for the SCI model, spinal cords of adult female Sprague-Dawley rats were contused using an Infinite Horizon Impactor. Two weeks post-injury, rats were randomly assigned to receive daily subcutaneous injections of either cutamesine (3.0 mg/kg/day) or saline (as a control) for another two weeks. Immunohistochemistry for BDNF and 5-HT was assessed at four and twelve weeks post-injury in the lumbar spinal cord. Locomotor function was assessed weekly using the BBB locomotor scale until twelve weeks after SCI and CatWalk XT 10.5 gait analysis was conducted at twelve weeks after SCI. In normal rats, cutamesine treatment (3.0 mg/kg/day) significantly up-regulated BDNF expression in the lumbar spinal cord. In SCI rats, cutamesine treatment (3.0 mg/kg/day) significantly increased the fluorescence intensity of neuronal BDNF and serotonin boutons in the injured spinal cord compared to saline. However, cutamesine treatment did not promote significant locomotor recovery. Recent work indicates that cutamesine treatment alone did not promote locomotor recovery in spite of immunohistological changes. Future work will explore the influence of combining cutamesine with other treatment promoting plasticity (e.g. rehabilitative training) in SCI rats.