Early protein restriction in rats induces anhedonia in adult offspring: A key role of BDNF-TrkB signaling in the nucleus accumbens shell.

Clinical evidence suggests that early malnutrition promotes symptoms related to psychiatric disorders later in life. Nevertheless, the molecular mechanisms underpinning nutritional injury induce depression remains unknown. The purpose of the present study was to evaluate whether perinatal protein restriction increases vulnerability to developing depressive-like behavior in adulthood by focusing on anhedonia, a core symptom of depression. To this, male adult Wistar rats submitted to a protein restriction schedule at perinatal age (PR-rats), were subjected to the sucrose preference test (SPT), the novel object recognition test (NORT), the forced swim test (FST), and the elevated plus maze (EPM), and compared to animals fed with a normoprotein diet. To investigate neurobiological substrates linked to early protein undernutrition-facilitated depressive-like behavior, we assessed the levels of brain-derived neurotrophic factor (BDNF) and its receptor TrkB in the nucleus accumbens (NAc), and evaluated the reversal of anhedonic-like behavior by infusing ANA-12. We found that early malnutrition decreased sucrose preference, impaired performance in the NORT and increased immobility time in the FST. Furthermore, perinatal protein-restriction-induced anhedonia correlated with increased BDNF and p-TrkB protein levels in the NAc, a core structure in the reward circuit linked with anhedonia. Finally, bilateral infusion of the TrkB antagonist ANA-12 into the NAc shell ameliorated a reduced sucrose preference in the PR-rats. Altogether, these findings revealed that protein restriction during pregnancy and lactation facilitates depressive-like behavior later in life and may increase the risk of developing anhedonia by altering BDNF-TrkB in the NAc shell.

Pharmacological Evidence of Eugenia Brasiliensis Leaves in a Reserpine-Induced Fibromyalgia Model: Antinociceptive, Emotional, Anti-Inflammatory, and Neurotrophic Effects.

Fibromyalgia (FM) is a painful chronic condition that significantly impacts the quality of life, posing challenges for clinical management. Given the difficulty of understanding the pathophysiology and finding new therapeutics, this study explored the effects of a medicinal plant, E. brasiliensis, in an FM model induced by reserpine in Swiss mice. Animals were treated with saline 0.9% (vehicle), duloxetine 10 mg/kg (positive control), or hydroalcoholic extract of E. brasiliensis leaves 300 mg/kg (HEEb). Nociceptive parameters, as well as locomotion, motor coordination, strength, anxiety, and depressive-like behaviors, were evaluated for 10 days. After that, the brain and blood were collected for further analysis of cytokines (interleukin 1? and interleukin 6), brain-derived neurotrophic factor (BDNF), and the immunocontents of total and phosphorylated Tropomyosin receptor kinase B (TrkB). The results demonstrated that the acute and prolonged treatment with HEEb was able to reduce both mechanical and thermal nociception. It was also possible to observe an increase in the strength, without changing locomotion and motor coordination parameters. Interestingly, treatment with HEEb reduces anxious and depressive-like behaviors. Finally, we observed a reduction in inflammatory cytokines in the hippocampus of animals treated with HEEb, while an increase in BDNF was observed in the prefrontal cortex (PFC). However, no alterations related to total and phosphorylated TrkB receptor expression were found. Our study demonstrated the antinociceptive and emotional effects of HEEb in mice, possibly acting on neuroinflammatory and neurotrophic mechanisms. These data provide initial evidence about the E. brasiliensis potential for treating chronic pain.

From gains to gaps? How Selective Androgen Receptor Modulator (SARM) YK11 impact hippocampal function: In silico, in vivo, and ex vivo perspectives.

Selective Androgen Receptor Modulators (SARMs), particularly (17α,20E)-17,20-[(1-methoxyethylidene)bis(oxy)]-3-oxo-19-norpregna-4,20-diene-21-carboxylic-acid-methyl-ester (YK11), are increasingly popular among athletes seeking enhanced performance. Serving as an Androgen Receptor (AR) agonist, YK11 stimulates muscle growth while inhibiting myostatin. Our study delved into the impact of YK11 on the rat hippocampus, analyzing potential alterations in neurochemical mechanisms and investigating its synergistic effects with exercise (EXE), based on the strong relationship between SARM users and regular exercise. Utilizing Physiologically Based Pharmacokinetic (PBPK) modeling, we demonstrated YK11 remarkable brain permeability, with molecular docking analysis revealing YK11 inhibitory effects on 5-alpha-reductase type II (5αR2), suggesting high cell bioavailability. Throughout a 5-week experiment, we divided the animals into the following groups: Control, YK11 (0.35 g/kg), EXE (swimming exercise), and EXE + YK11. Our findings showed that YK11 displayed a high binding affinity with AR in the hippocampus, influencing neurochemical function and modulating aversive memory consolidation, including the downregulation of the BDNF/TrkB/CREB signaling, irrespective of EXE combination. In the hippocampus, YK11 increased pro-inflammatory IL-1ß and IL-6 cytokines, while reducing anti-inflammatory IL-10 levels. However, the EXE + YK11 group counteracted IL-6 effects and elevated IL-10. Analysis of apoptotic proteins revealed heightened p38 MAPK activity in response to YK11-induced inflammation, initiating the apoptotic cascade involving Bax/Bcl-2/cleaved caspase-3. Notably, the EXE + YK11 group mitigated alterations in Bcl-2 and cleaved caspase-3 proteins. In conclusion, our findings suggest that YK11, at anabolic doses, significantly alters hippocampal neurochemistry, leading to impairments in memory consolidation. This underscore concerns about the misuse risks of SARMs among athletes and challenges common perceptions of their minimal side effects.

Environmental enrichment changes the effects of prenatal and postnatal undernutrition on memory, anxiety traits, Bdnf and TrkB expression in the hippocampus of male adult rats.

Environmental factors such as undernutrition and environmental enrichment can promote changes in the molecular and behavioural mechanisms related to cognition. Herein, we investigated the effect of enriched environment stimulation in rats that were malnourished in the pre- and postnatal periods on changes in the gene expression of brain-derived neurotrophic factor and its receptor in the hippocampus, as well as on anxiety traits and memory. Early undernutrition promoted weight reduction, increased the risk analysis, reduced permanence in the open arm of the elevated plus-maze and induced a reduction in the gene expression of brain-derived neurotrophic factor and tropomyosin receptor kinase B. However, exposure to an enriched environment from 30 to 90 days' old maintained the malnourished phenotype, leading to weight reduction in the control group. In addition, the enriched environment did not alter the risk assessment in the undernourished group, but it did increase the frequency of labyrinth entries. Sixty-day exposure to the enriched environment resulted in a reversal in the gene expression of brain-derived neurotrophic factor and tropomyosin receptor kinase B in the hippocampus of malnourished rats and favoured of long-term memory in the object recognition test in the open-field. These results suggest that an enriched environment may have a protective effect in adult life by inducing changes in long-term memory and anxiety traits in animals that were undernourished in early life. Furthermore, reversing these effects of undernutrition involves mechanisms linked to the molecular signalling of brain-derived neurotrophic factor and tropomyosin receptor kinase B in the hippocampus.

Beta-caryophyllene mitigates the cognitive impairment caused by repeated exposure to aspartame in rats: Putative role of BDNF-TrKB signaling pathway and acetylcholinesterase activity.

Aspartame (ASP) is a common sweetener, but studies show it can harm the nervous system, causing learning and memory deficits. ß-caryophyllene (BCP), a natural compound found in foods, including bread, coffee, alcoholic beverages, and spices, has already described as a neuroprotector agent. Remarkably, ASP and BCP are commonly consumed, including in the same meal. Therefore, considering that (a) the BCP displays plenty of beneficial effects; (b) the ASP toxicity; and (c) that they can be consumed in the same meal, this study sought to investigate if the BCP would mitigate the memory impairment induced by ASP in rats and investigate the involvement of the brain-derived neurotrophic factor (BDNF)/ tropomyosin receptor kinase B (TrKB) signaling pathway and acetylcholinesterase (AChE) activity. Young male Wistar rats received ASP (75 mg/kg; i.g.) and/or BCP (100 mg/kg; i.p.) once daily, for 14 days. At the end of the treatment, the animals were evaluated in the open field and object recognition tests. The cerebral cortex and hippocampus samples were collected for biochemical and molecular analyses. Results showed that the BCP effectively protected against the cognitive damage caused by ASP in short and long-term memories. In addition, BCP mitigated the increase in AChE activity caused by ASP. Molecular insights revealed augmented BDNF and TrKB levels in the hippocampus of rats treated with BCP, indicating greater activation of this pathway. In conclusion, BCP protected against ASP-induced memory impairment. AChE activity and the BDNF/TrkB signaling pathway seem to be potential targets of BCP modulatory role in this study.

BDNF/TrkB signaling endosomes in axons coordinate CREB/mTOR activation and protein synthesis in the cell body to induce dendritic growth in cortical neurons.

Brain-derived neurotrophic factor (BDNF) and its receptors tropomyosin kinase receptor B (TrkB) and the p75 neurotrophin receptor (p75) are the primary regulators of dendritic growth in the CNS. After being bound by BDNF, TrkB and p75 are endocytosed into endosomes and continue signaling within the cell soma, dendrites, and axons. We studied the functional role of BDNF axonal signaling in cortical neurons derived from different transgenic mice using compartmentalized cultures in microfluidic devices. We found that axonal BDNF increased dendritic growth from the neuronal cell body in a cAMP response element-binding protein (CREB)-dependent manner. These effects were dependent on axonal TrkB but not p75 activity. Dynein-dependent BDNF-TrkB-containing endosome transport was required for long-distance induction of dendritic growth. Axonal signaling endosomes increased CREB and mTOR kinase activity in the cell body, and this increase in the activity of both proteins was required for general protein translation and the expression of Arc, a plasticity-associated gene, indicating a role for BDNF-TrkB axonal signaling endosomes in coordinating the transcription and translation of genes whose products contribute to learning and memory regulation.

c-Abl Tyrosine Kinase Is Required for BDNF-Induced Dendritic Branching and Growth.

Brain-derived neurotrophic factor (BDNF) induces activation of the TrkB receptor and several downstream pathways (MAPK, PI3K, PLC-γ), leading to neuronal survival, growth, and plasticity. It has been well established that TrkB signaling regulation is required for neurite formation and dendritic arborization, but the specific mechanism is not fully understood. The non-receptor tyrosine kinase c-Abl is a possible candidate regulator of this process, as it has been implicated in tyrosine kinase receptors' signaling and trafficking, as well as regulation of neuronal morphogenesis. To assess the role of c-Abl in BDNF-induced dendritic arborization, wild-type and c-Abl-KO neurons were stimulated with BDNF, and diverse strategies were employed to probe the function of c-Abl, including the use of pharmacological inhibitors, an allosteric c-Abl activator, and shRNA to downregulates c-Abl expression. Surprisingly, BDNF promoted c-Abl activation and interaction with TrkB receptors. Furthermore, pharmacological c-Abl inhibition and genetic ablation abolished BDNF-induced dendritic arborization and increased the availability of TrkB in the cell membrane. Interestingly, inhibition or genetic ablation of c-Abl had no effect on the classic TrkB downstream pathways. Together, our results suggest that BDNF/TrkB-dependent c-Abl activation is a novel and essential mechanism in TrkB signaling.

Acute intrahippocampal administration of melanin-concentrating hormone impairs memory consolidation and decreases the expression of MCHR-1 and TrkB receptors.

Interest in the role of melanin-concentrating hormone (MCH) in memory processes has increased in recent years, with some studies reporting memory-enhancing effects, while others report deleterious effects. Due to these discrepancies, this study seeks to provide new evidence about the role of MCH in memory consolidation and its relation with BDNF/TrkB system. To this end, in the first experiment, increased doses of MCH were acutely administered in both hippocampi to groups of male rats (25, 50, 200, and 500 ng). Microinjections were carried out immediately after finishing the sample trial of two hippocampal-dependent behavioral tasks: the Novel Object Recognition Test (NORT) and the modified Elevated Plus Maze (mEPM) test. Results indicated that a dose of 200 ng of MCH or higher impaired memory consolidation in both tasks. A second experiment was performed in which a dose of 200 ng of MCH was administered alone or co-administered with the MCHR-1 antagonist ATC-0175 at the end of the sample trial in the NORT. Results showed that MCH impaired memory consolidation, while the co-administration with ATC-0175 reverted this detrimental effect. Moreover, MCH induced a significant decrease in hippocampal MCHR-1 and TrkB expression with no modification in the expression of BDNF and NMDA receptor subunits NR1, NR2A, and NR2B. These results suggest that MCH in vivo elicits pro-amnesic effects in the rat hippocampus by decreasing the availability of its receptor and TrkB receptors, thus linking both endogenous systems to memory processes.

The antidepressant-like effect elicited by vitamin D3 is associated with BDNF/TrkB-related synaptic protein synthesis.

Vitamin D3 (cholecalciferol) has been shown to exert antidepressant-like responses, but the role BDNF/TrkB-related synaptic plasticity in this effect remains to be established. Thus, this study investigated the time-course antidepressant-like response of vitamin D3 in female and male mice and the possible role of BDNF/TrkB signaling in this response. The repeated (7 and 21 days), but not acute (60 min), administration of vitamin D3 (2.5 µg/kg, p.o.) exerted an antidepressant-like effect in female and male mice subjected to the tail suspension test, without altering the basal locomotor activity in the open-field test. Notably, vitamin D3 caused a similar time-dependent antidepressant-like effect in male and female mice, suggesting that this behavioral response in the tail suspension test might not be affected by sex differences. Vitamin D3 administration for 21 days, but not for 7 days or 1 h, augmented BDNF levels in the hippocampus and prefrontal cortex of mice. No effects on phospho-CREB/CREB levels were detected in the hippocampus and prefrontal cortex after chronic vitamin D3 administration. Additionally, vitamin D3 increased TrkB, GluA1, and PSD-95 levels in the prefrontal cortex, but not in the hippocampus. Furthermore, an upregulation of synapsin level was observed in both brain regions after vitamin D3 administration. These findings reinforce and extend the notion that vitamin D3 is effective to produce antidepressant-like responses in male and female mice and provide novel evidence that this effect could be associated with BDNF/TrkB-related synaptic protein synthesis. Finally, vitamin D3 could be a feasible nutritional strategy for the management of depression.

Daily oscillation of cognitive factors is modified in the temporal cortex of an amyloid ß(1-42)-induced rat model of Alzheimer's disease.

Alzheimer's disease (AD) is a devastating disease characterized by loss of synapses and neurons in the elderly. Accumulation of the ß-amyloid peptide (Aß) in the brain is thought to be central to the pathogenesis of AD. ApoE plays a key role in normal and physiological clearance of Aß, since it facilitates the peptide intra- and extracellular proteolytic degradation. Besides the cognitive deficit, AD patients also show alterations in their circadian rhythms. The objective of this study was to investigate the effects of an i.c.v. injection of Aß (1-42) peptide on the 24 h rhythms of Apo E, BMAL1, RORα, Bdnf and trkB mRNA and Aß levels in the rat temporal cortex. We found that an i.c.v. injection of Aß aggregates phase shifts daily Bdnf expression as well as Apo E, BMAL1, RORα, Aß and decreased the mesor of TrkB rhythms. Thus, elevated Aß peptide levels might modify the temporal patterns of cognition-related factors, probably; by affecting the clock factors rhythms as well as in the 24 h rhythms of Apo E.

Modulation of DNA Methylation and Gene Expression in Rodent Cortical Neuroplasticity Pathways Exerts Rapid Antidepressant-Like Effects.

BACKGROUND: Stress increases DNA methylation, primarily a suppressive epigenetic mechanism catalyzed by DNA methyltransferases (DNMT), and decreases the expression of genes involved in neuronal plasticity and mood regulation. Despite chronic antidepressant treatment decreases stress-induced DNA methylation, it is not known whether inhibition of DNMT would convey rapid antidepressant-like effects. AIM: This work tested such a hypothesis and evaluated whether a behavioral effect induced by DNMT inhibitors (DNMTi) corresponds with changes in DNA methylation and transcript levels in genes consistently associated with the neurobiology of depression and synaptic plasticity (BDNF, TrkB, 5-HT1A, NMDA, and AMPA). METHODS: Male Wistar rats received intraperitoneal (i.p.) injection of two pharmacologically different DNMTi (5-AzaD 0.2 and 0.6 mg/kg or RG108 0.6 mg/kg) or vehicle (1 ml/kg), 1 h or 7 days before the learned helplessness test (LH). DNA methylation in target genes and the correspondent transcript levels were measured in the hippocampus (HPC) and prefrontal cortex (PFC) using meDIP-qPCR. In parallel separate groups, the antidepressant-like effect of 5-AzaD and RG108 was investigated in the forced swimming test (FST). The involvement of cortical BDNF-TrkB-mTOR pathways was assessed by intra-ventral medial PFC (vmPFC) injections of rapamycin (mTOR inhibitor), K252a (TrkB receptor antagonist), or vehicle (0.2 µl/side). RESULTS: We found that both 5-AzaD and RG108 acutely and 7 days before the test decreased escape failures in the LH. LH stress increased DNA methylation and decreased transcript levels of BDNF IV and TrkB in the PFC, effects that were not significantly attenuated by RG108 treatment. The systemic administration of 5-AzaD (0.2 mg/kg) and RG108 (0.2 mg/kg) induced an antidepressant-like effect in FST, which was, however, attenuated by TrkB and mTOR inhibition into the vmPFC. CONCLUSION: These findings suggest that acute inhibition of stress-induced DNA methylation promotes rapid and sustained antidepressant effects associated with increased BDNF-TrkB-mTOR signaling in the PFC.

Immunoexpression of BDNF, TrkB, and p75NTR receptors in peripheral neural lesions of the head and neck.

BACKGROUND: Brain-derived neurotrophic factor (BDNF) and neurotrophin receptors have been recognized as fundamental regulators of normal brain development, homeostasis, and plasticity. They have also been studied in the behavior of central nervous system tumors. Here, we studied the pattern of BDNF, TrkB and p75NTR immunoexpression in peripheral benign and malignant neural lesions in head and neck. METHODS: This cross-sectional analytical study included 79 cases of head and neck neural lesions. Nineteen cases of traumatic neuromas (TN), 20 cases of granular cell tumors (GCT), 16 cases of neurofibromas (NF), 20 cases of schwannomas (SC), and 4 malignant peripheral nerve sheath tumor (MPNST) were submitted to immunohistochemistry with BDNF, TrkB, and p75NTR antibodies. A semi-quantitative analysis was performed. RESULTS: The analysis of BDNF demonstrated a high percentage of positive cells in TN, GCT and SC with a decrease in cases of NF and MPNST. TrkB presented a lower significant immunoexpression in GCT in relation to the TN, NF, SC, and MPNST (P < .0001); and TN showed less percentage of positive cell compared to SC (P = .0017). Regarding p75NTR, the percentage of positive cell was significantly reduced in MPNST compared GCT (P = .009), NF (P = .0138) and SC (P = .0069). Also, a decrease in TN compared to GCT (P = .007) was observed. CONCLUSIONS: Our results showed the immunoreactivity of BDNF, TrkB, and p75NTR in head and neck peripheral neural lesions. Reduction of BDNF and p75NTR in MPNST might suggest down-regulation during the acquisition of malignant phenotype.

Role of Tropomyosin-related kinase B receptor and brain-derived neurotrophic factor in cancer.

The tropomyosin-related kinase B (TrkB) receptor is a member of the neurotrophic tyrosine kinase receptors family and, together with the brain-derived neurotrophic factor (BDNF), plays an important role in the development of breast cancer, lung cancer, neuroblastoma, colorectal cancer, leukemia, cervical cancer, gallbladder cancer, gastric cancer, kidney cancer, Ewing's sarcoma, esophageal cancer, and head and neck cancer. Overexpression of these two factors has been associated with increased processes involved in carcinogenesis, such as invasion, migration, epithelial-mesenchymal transition (EMT), angiogenesis, metastasis, cell proliferation, resistance to apoptosis, resistance to cell death due to loss of adhesion (anoikis), activation of cell proliferation pathways, regulation of tumor suppressor genes, and drug resistance, and is related to advanced clinical stage. Inhibition of the TrkB/BDNF axis using drugs in phase 1 studies, approved drugs, and small interfering RNA (siRNA) are promising strategies for the treatment of various malignant tumors in addition to increasing the sensitivity of cells resistant to chemotherapy, improving the effectiveness of drugs without increasing toxicity. Another factor related to poor cancer prognosis is the presence of cancer stem cells, having effects similar to the high expression of the TrkB/BDNF axis, on cancer. This review aimed to show the role of the TrkB/BDNF axis in several types of cancer, its possible use as a prognostic biomarker, the effects of inhibiting this axis, and its role in the cancer stem cells.

Early life exposure to hypercaloric diet impairs eating behavior during weaning: The role of BDNF signaling and astrocyte marks.

Literature shows that gestational and/or lactational exposure to hypercaloric diets induces long term effects on eating behavior and the involvement of neurochemical mechanisms. We hypothesized that the effects of hypercaloric diets in early development phases can precede an overweight or an obesity status. The aim of the present study was to evaluate the impact of gestational and lactational exposure to cafeteria diet on eating behavior and neurochemical parameters, BDNF signaling, epigenetic and astrocyte marks in the hippocampus and olfactory bulb during the weaning phase. Pregnant female rats were randomized between standard and cafeteria diet, the respective diet was maintained through the lactational period. The framework of feeding pattern, meal, and its microstructure, was observed in postnatal day 20. Exposure to cafeteria diet increased the number of meals, associated with a lower first inter-meal interval and higher consumption in both genders, without any changes in body weight. Diet exposure also reduced the number of grooming, a behavior typically found at the end of meals. Hypercaloric diet exposure reduced BDNF levels in the olfactory bulb and hippocampus from rats of both sexes and increased the content of the TrkB receptor in hippocampi. It was observed an increase in HDAC5 levels, an epigenetic mark. Still, early exposure to the hypercaloric diet reduced hippocampal GFAP and PPARγ levels, without any effect on NeuN content, indicating that alterations in astrocytes can precede those neuronal outcomes. Our results showed that changes in interrelated neurochemical signaling, BDNF, and astrocyte marks, induced by hypercaloric diet in early stages of development may be related to impairment in the temporal distribution of eating pattern and consequent amounts of consumed food during the weaning phase.

Orexin A injection into the ventral medial prefrontal cortex induces antidepressant-like effects: Possible involvement of local Orexin-1 and Trk receptors.

RATIONALE: Reduced levels of orexin-A (OXA) in the central nervous system (CNS) have been associated with the pathophysiology of depression and its exogenous administration promotes antidepressant-like effect. The mechanisms associated with these effects are, however, not yet known. Herein, we investigated the hypothesis that OXA effects could be associated with orexin 1 receptor (OX1R) and tyrosine receptor kinase B (TrkB) activation, in the ventromedial prefrontal cortex (vmPFC), a brain region that is central to depression neurobiology. OBJECTIVES: 1. To Investigate the effects induced by OXA administration into the vmPFC; 2. Evaluate the participation of OX1R and TrkB in behavioral responses induced by OXA. METHODS: Male Wistar rats received intra-vmPFC injections of OXA (10, 50 and 100 pmol/0.2 µL) and were exposed to the forced swimming test (FST) or the open field test (OFT). Independent groups received an intra-vmPFC injection of SB334867 (OX1R antagonist, 10 nmol/0.2 µL) or K252a (non-selective Trk antagonist, 10 pmol/0.2 µL), before local injection of OXA, and were exposed to the same tests. RESULTS: OXA injection (100 pmol/0.2 µL) into the vmPFC induced antidepressant-like effect, which was prevented by SB334867 and K252a pretreatments. CONCLUSION: OXA signaling in the vmPFC induces antidepressant-like effect in the FST which is dependent on OX1R and Trk receptors.

Expression and pharmacological inhibition of TrkB and EGFR in glioblastoma.

A member of the Trk family of neurotrophin receptors, tropomyosin receptor kinase B (TrkB, encoded by the NTRK2 gene) is an increasingly important target in various cancer types, including glioblastoma (GBM). EGFR is among the most frequently altered oncogenes in GBM, and EGFR inhibition has been tested as an experimental therapy. Functional interactions between EGFR and TrkB have been demonstrated. In the present study, we investigated the role of TrkB and EGFR, and their interactions, in GBM. Analyses of NTRK2 and EGFR gene expression from The Cancer Genome Atlas (TCGA) datasets showed an increase in NTRK2 expression in the proneural subtype of GBM, and a strong correlation between NTRK2 and EGFR expression in glioma CpG island methylator phenotype (G-CIMP+) samples. We showed that when TrkB and EGFR inhibitors were combined, the inhibitory effect on A172 human GBM cells was more pronounced than when either inhibitor was given alone. When U87MG GBM cells were xenografted into the flank of nude mice, tumor growth was delayed by treatment with TrkB and EGFR inhibitors, given alone or combined, only at specific time points. Intracranial GBM growth in mice was not significantly affected by drug treatments. Our findings indicate that correlations between NTRK2 and EGFR expression occur in specific GBM subgroups. Also, our results using cultured cells suggest for the first time the potential of combining TrkB and EGFR inhibition for the treatment of GBM.

Spermidine-induced improvement of memory consolidation involves PI3K/Akt signaling pathway.

Spermidine (SPD) is an endogenous polyamine that plays a facilitatory role in memory acquisition and consolidation. Memory consolidation occurs immediately after learning and again around 3-6 hours later. Current evidence indicates that the polyamine binding site at the NMDA receptor (NMDAr) mediates the effects of SPD on memory. While NMDAr activation increases brain-derived neurotrophic factor (BDNF) release, no study has investigated whether BDNF-activated signaling pathways, such as the phosphatidylinositol 3-kinase (PI3K)/Akt pathway play a role in SPD-induced improvement of memory consolidation. Therefore, the aim of the current study was to evaluate whether the TrkB receptor and the PI3K/Akt pathway are involved in the facilitatory effect of SPD on memory consolidation. Male Wistar rats were trained in the contextual conditioned fear task. SPD, ANA-12 (TrkB antagonist), and LY294002 (PI3K inhibitor) were administered immediately after training. The animals were tested 24 h after training. We found that SPD improved fear memory consolidation and that both ANA-12 and LY294002 prevented the facilitatory effect of SPD on memory. These results suggest that SPD-induced improvement of memory consolidation involves the activation of the TrkB receptor and PI3K/Akt pathway.

Antidepressant-like effect of (3Z)-5-Chloro-3-(hydroxyimino)indolin-2-one in rats exposed to malathion: Involvement of BDNF-Trkß pathway and AChE.

BACKGROUND: Organophosphorus pesticides exert their toxic effects mainly by the inhibition of acetylcholinesterase (AChE), which is related to emotional disorders, such as depression. Atropine-oximes therapy is commonly used; however, the efficacy of oximes in the reactivation of AChE has been inconsistent. The objective of this study was to investigate the possible neuroprotective effect of (3Z)-5-Chloro-3-(hydroxyimino)indolin-2-one (Cℓ-HIN), a compound that combines the isatin and oxime functional groups, in rats exposed to malathion. The effect of Cℓ-HIN on the AChE activity and the BDNF-Trkß pathway in the prefrontal cortex of malathion-exposed rats were tested. METHODS: Wistar male rats were co-treated with Cℓ-HIN [50 mg/kg (p.o.) (3 mL/kg)] and/or malathion [250 mg/kg (i.p.) (5 mL/kg)] and performed behavioral tests twelve hours after these exposures. RESULTS: The Cℓ-HIN reversed the increased immobility time in the forced swimming test and the decreased grooming time in the splash test induced by malathion, but any significant difference was observed in locomotion analysis. These results demonstrate the antidepressant-like effect of Cℓ-HIN. The cortical AChE activity was reactivated by Cℓ-HIN in rats exposed to malathion. Malathion induced an increase in Trkß and a decrease in BDNF levels in the prefrontal cortex of rats, which were avoided by Cℓ-HIN. CONCLUSION: These findings support the hypothesis that Cℓ-HIN is an AChE reactivator with antidepressant-like properties, which is related to the improvement of BDNF-Trkß signaling after acute exposure to malathion in rats. Thus, the results allow suggesting the potential use of Cℓ-HIN as an oxime-based therapy against the neurotoxic effects of malathion.

Binge and Subchronic Exposure to Ketamine Promote Memory Impairments and Damages in the Hippocampus and Peripheral Tissues in Rats: Gallic Acid Protective Effects.

Ketamine (KET) is a dissociative anesthetic for restrict medical use with high potential for abuse and neurotoxicity which does not prevent its recreational use. Gallic acid (GA) is a natural free radical "scavenger." We evaluated the GA protective role regarding binge or subchronic (SbChro) KET-induced toxicity in adolescent rats. In the binge protocol, animals were treated with GA (one dose of 13.5 mg/kg, p.o. every 2 h, totaling 3 doses) 12 h after KET exposure (one dose of 10 mg/kg, i.p., every 3 h, totaling 5 doses). In the SbChro, animals were treated with GA (one dose of 13.5 mg/kg/day, p.o., for 3 days) 48 h following KET exposure (one dose of 10 mg/kg/day, i.p) for 10 days. Our findings show that binge-KET impaired memory, increased pro-BDNF and TrkB levels in the hippocampus, and increased lipid peroxidation (LP) in the kidney and hippocampus, while SbChro-KET impaired memory, increased pro-BDNF, and decreased both BDNF and TrkB levels in the hippocampus, and increased LP in the kidney, liver, and hippocampus. GA treatment reversed the subchronically KET-induced harmful influences better. Interestingly, only memory impairment observed in the SbChro-KET protocol was reversed by GA. Memory impairments showed a positive correlation with hippocampal BDNF levels and negative with LP levels in the same brain area. This last hippocampal damage (LP) showed a negative correlation with BDNF levels in the hippocampus, indicating an interesting and close causal connection. Our outcomes show that the deleterious effects of SbChro-KET exposure can be attenuated or abolished with GA administration, a natural antioxidant that could be considered in KET abuse treatment.

Activation of BDNF/TrkB/Akt pathway is associated with aggressiveness and unfavorable survival in oral squamous cell carcinoma.

OBJECTIVES: To evaluate the expression of brain-derived neurotrophic factor (BDNF), its tyrosine kinase receptor B (TrkB), and two downstream targets of this pathway, Akt and ribosomal protein S6 (RPS6), in normal oral mucosa (NOM), oral leukoplakia (OL), and oral squamous cell carcinoma (OSCC) and correlate this expression with OSCC patients' outcomes, cell senescence, and "stemness" profile. MATERIALS AND METHODS: Ten cases of NOM, 32 OL, and 72 primary OSCC were included. Immunohistochemical analysis for BDNF, TrkB, p-TrkB, p-Akt, and p-RPS6 was performed. Cell senescence and stemness profile of OSCC were evaluated through p16 and BMI-1 immunohistochemical expression, respectively. The slides were scanned into high-resolution images and quantified through digital analysis. RESULTS: Oral squamous cell carcinoma presented increased expression of BDNF/TrkB/Akt pathway compared to NOM and OL. OSCC diagnosed in advanced clinical stages presented an upregulation of BDNF and p-TrkB. BDNF and p-Akt were identified as predictors of poor disease-specific survival. The increase in stemness profile was correlated with a decrease in p-TrkB and p-Akt expression. CONCLUSIONS: BDNF/TrkB/Akt pathway is significantly increased in malignant cells from OSCC. Moreover, BDNF and Akt represent biomarkers capable to predict a poor prognosis of OSCC patients.