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SUMMARY: Stroke is the leading cause of acquired physical disability in adults and second leading cause of mortality throughout the world. Treatment strategies to curb the effects of stroke would be of great benefit. Pongamia pinnata is a recent attraction in medicine, owing to its abundant medicinal benefits with minimal side effects. The present study aimed to examine acute and subacute effect of Pongamia pinnata leaf extract on transient cerebral hypoperfusion and reperfusion (tCHR) in Wistar rats. 24 adult Wistar rats (12 each for acute and subacute study) were divided in to four groups each viz normal control group, tCHR + NS group, tCHR + 200mg/kg bw and tCHR + 400mg/kg bw groups. Cerebral ischemia induction was carried out by bilateral common carotid artery occlusion and reperfusion. Ethanolic extract of Pongamia pinnata leaves were orally administered for 7 days and 21 days after the surgical procedure for acute and subacute study respectively. Behavioural analysis, histological assessment, and estimation of mRNA levels of HIF-1, GDNF, BDNF and NF-kB were performed. In both acute and subacute study, there was significant improvement in the beam walking assay, neuronal count, decreased neuronal damage in histological sections and higher mRNA expression of BDNF and GDNF in the treatment groups. There was no significant difference in the expression of HIF1 and NF-kB. Thus, Pongamia pinnata has excellent neurorestorative property reversing many of the effects of ischemic stroke induced by tCHR in rats with the underlying mechanism being an improvement in the expression of neurotrophic factors GDNF and BDNF.
El ataque cerebrovascular es la principal causa de discapacidad física adquirida en adultos y la segunda causa de mortalidad en todo el mundo. Las estrategias de tratamiento para frenar los efectos del ataque cerebrovascular serían de gran beneficio. Pongamia pinnata es una atracción reciente en la medicina, debido a sus abundantes beneficios medicinales con mínimos efectos secundarios. El presente estudio tuvo como objetivo examinar el efecto agudo y subagudo del extracto de hoja de Pongamia pinnata sobre la hipoperfusión y reperfusión cerebral transitoria (tCHR) en ratas Wistar. Se dividieron 24 ratas Wistar adultas (12 cada una para el estudio agudo y subagudo) en cuatro grupos, el grupo control normal, el grupo tCHR + NS, los grupos tCHR + 200 mg/kg de peso corporal y tCHR + 400 mg/kg de peso corporal. La inducción de la isquemia cerebral se llevó a cabo mediante oclusión y reperfusión bilateral de la arteria carótida común. El extracto etanólico de hojas de Pongamia pinnata se administró por vía oral durante 7 días y 21 días después del procedimiento quirúrgico para estudio agudo y subagudo respectivamente. Se realizaron análisis de comportamiento, evaluación histológica y estimación de los niveles de ARNm de HIF-1, GDNF, BDNF y NF-kB. Tanto en el estudio agudo como en el subagudo, hubo una mejora significativa en el ensayo de desplazamiento del haz, el recuento neuronal, una disminución del daño neuronal en las secciones histológicas y una mayor expresión de ARNm de BDNF y GDNF en los grupos con tratamiento. No hubo diferencias significativas en la expresión de HIF1 y NF-kB. Por lo tanto, Pongamia pinnata tiene una excelente propiedad neurorestauradora que revierte muchos de los efectos del ataque cerebrovascular isquémico inducido por tCHR en ratas, siendo el mecanismo subyacente una mejora en la expresión de los factores neurotróficos GDNF y BDNF.
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Animales , Ratas , Extractos Vegetales/administración & dosificación , Accidente Cerebrovascular/tratamiento farmacológico , Millettia/química , Extractos Vegetales/farmacología , Corteza Cerebral/efectos de los fármacos , Isquemia Encefálica/tratamiento farmacológico , Administración Oral , FN-kappa B , Ratas Wistar , Factor Neurotrófico Derivado del Encéfalo/genética , Modelos Animales de Enfermedad , Factor 1 Inducible por Hipoxia/genética , Factor Neurotrófico Derivado de la Línea Celular Glial/genética , Reacción en Cadena en Tiempo Real de la Polimerasa , Factores de Crecimiento Nervioso/administración & dosificaciónRESUMEN
S100B, a homodimeric Ca2+-binding protein, is produced and secreted by astrocytes, and its extracellular levels have been used as a glial marker in brain damage and neurodegenerative and psychiatric diseases; however, its mechanism of secretion is elusive. We used primary astrocyte cultures and calcium measurements from real-time fluorescence microscopy to investigate the role of intracellular calcium in S100B secretion. In addition, the dimethyl sulfoxide (DMSO) effect on S100B was investigated in vitro and in vivo using Wistar rats. We found that DMSO, a widely used vehicle in biological assays, is a powerful S100B secretagogue, which caused a biphasic response of Ca2+ mobilization. Our data show that astroglial S100B secretion is triggered by the increase in intracellular Ca2+ and indicate that this increase is due to Ca2+ mobilization from the endoplasmic reticulum. Also, blocking plasma membrane Ca2+ channels involved in the Ca2+ replenishment of internal stores decreased S100B secretion. The DMSO-induced S100B secretion was confirmed in vivo and in ex vivo hippocampal slices. Our data support a nonclassic vesicular export of S100B modulated by Ca2+, and the results might contribute to understanding the mechanism underlying the astroglial release of S100B.
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Astrocitos , Dimetilsulfóxido , Ratas , Animales , Ratas Wistar , Dimetilsulfóxido/farmacología , Dimetilsulfóxido/metabolismo , Astrocitos/metabolismo , Colforsina/farmacología , Secretagogos/farmacología , Calcio/metabolismo , Factores de Crecimiento Nervioso/metabolismo , Subunidad beta de la Proteína de Unión al Calcio S100/metabolismo , Retículo Endoplásmico/metabolismo , Células CultivadasRESUMEN
The pathophysiology of post-traumatic brain injury (TBI) behavioral and cognitive changes is not fully understood, especially in its mild presentation. We designed a weight drop TBI model in mice to investigate the role of neuroinflammation in behavioral and cognitive sequelae following mild TBI. C57BL/6 mice displayed depressive-like behavior at 72 h after mild TBI compared with controls, as indicated by a decrease in the latency to first immobility and climbing time in the forced swim test. Additionally, anxiety-like behavior and hippocampal-associated spatial learning and memory impairment were found in the elevated plus maze and in the Barnes maze, respectively. Levels of a set of inflammatory mediators and neurotrophic factors were analyzed at 6 h, 24 h, 72 h, and 30 days after injury in ipsilateral and contralateral hemispheres of the prefrontal cortex and hippocampus. Principal components analysis revealed two principal components (PC), which represented 59.1% of data variability. PC1 (cytokines and chemokines) expression varied between both hemispheres, while PC2 (neurotrophic factors) expression varied only across the investigated brain areas. Our model reproduces mild TBI-associated clinical signs and pathological features and might be a valuable tool to broaden the knowledge regarding mild TBI pathophysiology as well as to test potential therapeutic targets.
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Conmoción Encefálica , Lesiones Traumáticas del Encéfalo , Ratones , Animales , Conmoción Encefálica/complicaciones , Ratones Endogámicos C57BL , Encéfalo/patología , Lesiones Traumáticas del Encéfalo/complicaciones , Factores de Crecimiento Nervioso , Cognición , Aprendizaje por Laberinto/fisiología , Modelos Animales de EnfermedadRESUMEN
Parkinson's disease (PD) is characterized by the loss of dopaminergic neurons in the substantia nigra pars compact (SNpc), and no effective treatment has yet been established to prevent PD. Neurotrophic factors, such as cerebral dopamine neurotrophic factor (CDNF), have shown a neuroprotective effect on dopaminergic neurons. Previously, we developed a cell-penetrating-peptide-based delivery system that includes Asn194Lys mutation in the rabies virus glycoprotein-9R peptide (mRVG9R), which demonstrated a higher delivery rate than the wild-type. In this study, using a mouse PD-like model, we evaluated the intrastriatal mRVG9R-KP-CDNF gene therapy through motor and cognitive tests and brain cell analysis. The mRVG9R-KP-CDNF complex was injected into the striatum on days 0 and 20. To induce the PD-like model, mice were intraperitoneally administered Paraquat (PQ) twice a week for 6 weeks. Our findings demonstrate that mRVG9R-KP-CDNF gene therapy effectively protects brain cells from PQ toxicity and prevents motor and cognitive dysfunction in mice. We propose that the mRVG9R-KP-CDNF complex inhibits astrogliosis and microglia activation, safeguarding dopaminergic neurons and oligodendrocytes from PQ-induced damage. This study presents an efficient CDNF delivery system, protecting neurons and glia in the nigrostriatal pathway from PQ-induced damage, which is known to lead to motor and cognitive dysfunction in neurodegenerative diseases such as PD.
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Enfermedad de Parkinson , Animales , Enfermedad de Parkinson/terapia , Enfermedad de Parkinson/metabolismo , Factores de Crecimiento Nervioso/genética , Factores de Crecimiento Nervioso/metabolismo , Sustancia Negra , Modelos Animales de Enfermedad , Neuronas DopaminérgicasRESUMEN
Addiction is a serious public health problem, and the current pharmacotherapy is unable to prevent drug use reinstatement. Studies have focused on physical exercise as a promising coadjuvant treatment. Our research group recently showed beneficial neuroadaptations in the dopaminergic system related to amphetamine-relapse prevention involving physical exercise-induced endogenous opioid system activation (EXE-OS activation). In this context, additional mechanisms were explored to understand the exercise benefits on drug addiction. Male rats previously exposed to amphetamine (AMPH, 4.0 mg/kg) for 8 days were submitted to physical exercise for 5 weeks. EXE-OS activation was blocked by naloxone administration (0.3 mg/kg) 5 min before each physical exercise session. After the exercise protocol, the rats were re-exposed to AMPH for 3 days, and in sequence, euthanasia was performed and the VTA and NAc were dissected. In the VTA, our findings showed increased immunocontent of proBDNF, BDNF, and GDNF and decreased levels of AMPH-induced TrkB; therefore, EXE-OS activation increased all these markers and naloxone administration prevented this exercise-induced effect. In the NAc, the same molecular markers were also increased by AMPH and decreased by EXE-OS activation. In this study, we propose a close relation between EXE-OS activation beneficial influence and a consequent neuroadaptation on neurotrophins and dopaminergic system levels in the mesolimbic brain area, preventing the observed AMPH-relapse behavior. Our outcomes bring additional knowledge concerning addiction neurobiology understanding and show that EXE-OS activation may be a potential adjuvant tool in drug addiction therapy.
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Trastornos Relacionados con Anfetaminas , Analgésicos Opioides , Ratas , Masculino , Animales , Factores de Crecimiento Nervioso/farmacología , Anfetamina , Encéfalo , Naloxona/farmacología , Núcleo AccumbensRESUMEN
BACKGROUND/AIMS: Recombinant adeno-associated viruses (rAAV) are an important tool for lung targeted gene therapy. Substitution of tyrosine with phenylalanine residues (Y-F) in the capsid have been shown to protect the AAV vector from ubiquitin/proteasome degradation, increasing transduction efficiency. We tested the mutant Y733F-AAV8 vector for mucus diffusion, as well as the safety and efficacy of pigment epithelium-derived factor (PEDF) gene transfer to the lung. METHODS: For this purpose, Y733F-AAV8-PEDF (1010 viral genome) was administered intratracheally to C57BL/6 mice. Lung mechanics, morphometry, and inflammation were evaluated 7, 14, 21, and 28 days after injection. RESULTS: The tyrosine-mutant AAV8 vector was efficient at penetrating mucus in ex vivo assays and at transferring the gene to lung cells after in vivo instillation. Increased levels of transgene mRNA were observed 28 days after vector administration. Overexpression of PEDF did not affect in vivo lung parameters. CONCLUSION: These findings provide a basis for further development of Y733F-AAV8-based gene therapies for safe and effective delivery of PEDF, which has anti-angiogenic, anti-inflammatory and anti-fibrotic activities and might be a promising therapy for lung inflammatory disorders.
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Proteínas del Ojo , Técnicas de Transferencia de Gen , Serpinas , Animales , Ratones , Proteínas del Ojo/genética , Ratones Endogámicos C57BL , Factores de Crecimiento Nervioso/genética , Serpinas/genéticaRESUMEN
Whether RNA-RNA interactions of cytoplasmic RNA viruses, such as Betacoronavirus, might end in the biogenesis of putative virus-derived small RNAs as miRNA-like molecules has been controversial. Even more, whether RNA-RNA interactions of wild animal viruses may act as virus-derived small RNAs is unknown. Here, we address these issues in four ways. First, we use conserved RNA structures undergoing negative selection in the genomes of SARS-CoV, MERS-CoV, and SARS-CoV-2 circulating in different bat species, intermediate animals, and human hosts. Second, a systematic literature review was conducted to identify Betacoronavirus-targeting hsa-miRNAs involved in lung cell infection. Third, we employed sophisticated long-range RNA-RNA interactions to refine the seed sequence homology of hsa-miRNAs with conserved RNA structures. Fourth, we used high-throughput RNA sequencing of a Betacoronavirus-infected epithelial lung cancer cell line (Calu-3) to validate the results. We proposed nine potential virus-derived small RNAs: two vsRNAs in SARS-CoV (Bats: SB-vsRNA-ORF1a-3p; SB-vsRNA-S-5p), one vsRNA in MERS-CoV (Bats: MB-vsRNA-ORF1b-3p), and six vsRNAs in SARS-CoV-2 (Bats: S2B-vsRNA-ORF1a-5p; intermediate animals: S2I-vsRNA-ORF1a-5p; and humans: S2H-vsRNA-ORF1a-5p, S2H-vsRNA-ORF1a-3p, S2H-vsRNA-ORF1b-3p, S2H-vsRNA-ORF3a-3p), mainly encoded by nonstructural protein 3. Notably, Betacoronavirus-derived small RNAs targeted 74 differentially expressed genes in infected human cells, of which 55 upregulate the molecular mechanisms underlying acute respiratory distress syndrome (ARDS), and the 19 downregulated genes might be implicated in neurotrophin signaling impairment. These results reveal a novel small RNA-based regulatory mechanism involved in neuropathogenesis that must be further studied to validate its therapeutic use.
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COVID-19 , Quirópteros , Neoplasias Pulmonares , MicroARNs , Coronavirus del Síndrome Respiratorio de Oriente Medio , Animales , Humanos , SARS-CoV-2/genética , Neoplasias Pulmonares/genética , MicroARNs/genética , Línea Celular , Pulmón , Factores de Crecimiento NerviosoRESUMEN
The increase in people's longevity has, consequently, led to more brain involvement and neurodegenerative diseases, which can become complicated and lead to chronic degenerative diseases, thereby presenting greater public health problems. Medicinal plants have been used since ancient times and contain high concentrations of molecules, including polyphenols. It has been proven that polyphenols, which are present in various natural sources can provide curative effects against various diseases and brain disorders through neuroprotective effects. These neuroprotective effects are mainly attributed to their ability to cross the blood-brain barrier, eliminate reactive oxygen species, and cause the chelation of metal ions. Polyphenols increase the concentration of neurotrophic factors and bind directly to the membrane receptors of these neurotrophic factors, to modulate and activate the signaling cascades that allow the plasticity, survival, proliferation, and growth of neuronal cells, thereby allowing for better learning, memory, and cognition. Moreover, polyphenols have no serious adverse side effects resulting from their consumption.
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Enfermedades Neurodegenerativas , Fármacos Neuroprotectores , Humanos , Polifenoles/farmacología , Polifenoles/uso terapéutico , Enfermedades Neurodegenerativas/metabolismo , Neuroprotección , Flavonoides , Fármacos Neuroprotectores/farmacología , Fármacos Neuroprotectores/uso terapéutico , Antioxidantes/metabolismo , Factores de Crecimiento NerviosoRESUMEN
Five new brassinosteroid analogues were synthetized from 3ß-acetoxy-23,24-dinorchol-4-en-22-oic acid. All the obtained compound showed significant activity in the Rice Lamina Inclination Test. Interestingly the effects of the methyl ester of 3ß-hydroxy-6-oxo-23,24-dinorcholan-22-oic acid (14) at concentrations of 1â¯×â¯10-7 and 1â¯×â¯10-6 M proved to be higher than those produced by brassinolide. In silico Molecular Docking and Induced fit docking (IFD) simulations for the compounds with the highest biological activity data were carried out to investigate the binding mode interactions into the brassinolide-binding groove which revealed that the compound 14 had high binding energy values and a good affinity.
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Brasinoesteroides , Ésteres , Brasinoesteroides/farmacología , Simulación del Acoplamiento Molecular , Factores de Crecimiento NerviosoRESUMEN
PURPOSE: Compare tracking groups with cognitive control functions and plasma brain-derived neurotrophic factors concentrations from childhood to adolescence. METHODS: This is a prospective study with 3 years of follow-up. At baseline, data from 394 individuals were collected (11.7 y), and data were obtained from 134 adolescents (14.9 y) at the 3-year follow-up. At both time points, anthropometric and maximal oxygen uptake data were collected. Cardiorespiratory fitness (CRF) groups were classified into high or low CRF. At follow-up, cognitive outcomes were collected via the Stroop and Corsi block test; plasma brain-derived neurotrophic factors concentrations were also analyzed. RESULTS: Comparisons demonstrated that maintaining high CRF over 3 years results in shorter reaction time, better inhibitory control, and higher working memory values. Likewise, the group that moved from low to high CRF over 3 years presented better reaction time. Plasma brain-derived neurotrophic factors concentrations were higher for the group that increased its CRF over the 3 years in relation to the low-low group (90.58 pg·mL-1; P = .004). However, after scaling by an allometric approach, differences were only found for reaction time and working memory between high-high and high-low groups. CONCLUSION: Maintaining high CRF over 3 years was positively related to reaction time and working memory in relation to adolescents that decreased their levels of CRF.
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Capacidad Cardiovascular , Humanos , Adolescente , Niño , Capacidad Cardiovascular/psicología , Estudios Prospectivos , Cognición , Memoria a Corto Plazo , Factores de Crecimiento NerviosoRESUMEN
Melatonin, N-acetyl-5-hydroxytryptamine, is a hormone that synchronizes the internal environment with the photoperiod. It is synthesized in the pineal gland and greatly depends on the endogenous circadian clock located in the suprachiasmatic nucleus and the retina's exposure to different light intensities. Among its most studied functions are the regulation of the waking-sleep rhythm and body temperature. Furthermore, melatonin has pleiotropic actions, which affect, for instance, the modulation of the immune and the cardiovascular systems, as well as the neuroprotection achieved by scavenging free radicals. Recent research has supported that melatonin contributes to neuronal survival, proliferation, and differentiation, such as dendritogenesis and axogenesis, and its processes are similar to those caused by Nerve Growth Factor, Brain-Derived Neurotrophic Factor, Neurotrophin-3, and Neurotrophin-4/5. Furthermore, this indolamine has apoptotic and anti-inflammatory actions in specific brain regions akin to those exerted by neurotrophic factors. This review presents evidence suggesting melatonin's role as a neurotrophic factor, describes the signaling pathways involved in these processes, and, lastly, highlights the therapeutic implications involved.
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Melatonina , Glándula Pineal , Melatonina/farmacología , Melatonina/metabolismo , Glándula Pineal/metabolismo , Factores de Crecimiento Nervioso/metabolismo , Núcleo Supraquiasmático/metabolismo , Sueño/fisiología , Factor de Crecimiento Transformador beta/metabolismoRESUMEN
OBJECTIVE: We aimed to determine whether vitamin C has a protective effect on cisplatin-induced neuropathy in rats. METHODS: In total, 24 rats were included in the study of which 8 rats (no drug administered) were categorized as the control group. The remaining 16 rats were given a total dose of 20 mg/kg cisplatin to induce neuropathy. These drug-administered rats (16 rats) were randomly divided into two groups, namely, group-1 (n=8): cisplatin+saline and group-2 (n=8): cisplatin+vitamin C (500 mg/kg/day). All rats were tested for motor function and electromyographic activity 3 days after cisplatin. Motor performance was evaluated by an inclined-plane test. Compound muscle action potential was evaluated. Plasma malondialdehyde, glutathione, tumor necrosis factor-α, interleukin 6, and sciatic nerve HSP 70 levels were measured. Axon diameter and nerve growth factor expression levels were analyzed. RESULTS: Plasma malondialdehyde, tumor necrosis factor-α, and interleukin 6 levels were higher in the cisplatin+saline group than control group (p<0.001). But vitamin C significantly reduced malondialdehyde and inflammatory cytokine levels when compared with the cisplatin+saline group (p<0.001). Glutathione levels were lower in both cisplatin+saline and cisplatin+vitamin C groups than control group, but vitamin C significantly ameliorated the glutathione levels (p<0.05). Sciatic heat shock protein-70 levels were significantly higher in the cisplatin+vitamin C group than cisplatin+saline group. Compound muscle action potential amplitude and inclined plane test scores were significantly improved in the vitamin C group (p<0.05). Axon diameter and nerve growth factor expression ameliorated with vitamin C (p<0.05). CONCLUSIONS: We demonstrated the ameliorated effects of vitamin C on cisplatin-induced neuropathy through increased heat shock protein-70, nerve growth factor levels, and reduced inflammatory and oxidant effects. The results are promising to improve the neurotoxic effects of cisplatin in cancer patients.
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Antineoplásicos , Enfermedades del Sistema Nervioso Periférico , Animales , Antineoplásicos/efectos adversos , Antioxidantes/metabolismo , Antioxidantes/farmacología , Antioxidantes/uso terapéutico , Ácido Ascórbico/farmacología , Ácido Ascórbico/uso terapéutico , Cisplatino/efectos adversos , Citocinas/metabolismo , Glutatión , Proteínas HSP70 de Choque Térmico , Interleucina-6 , Malondialdehído , Factores de Crecimiento Nervioso/metabolismo , Factores de Crecimiento Nervioso/farmacología , Oxidantes/farmacología , Estrés Oxidativo , Enfermedades del Sistema Nervioso Periférico/inducido químicamente , Enfermedades del Sistema Nervioso Periférico/tratamiento farmacológico , Enfermedades del Sistema Nervioso Periférico/prevención & control , Ratas , Factor de Necrosis Tumoral alfa , VitaminasRESUMEN
INTRODUCTION: Despite possible risks of mania switching with the long-term use of antidepressants in patients with bipolar disorder (BD), these drugs may help in depressive episodes. Alterations in neurotrophic factor levels seem to be involved in the pathophysiology of BD. The present study aimed to evaluate the effect of acute treatment of imipramine on behavior and neurotrophic levels in rats submitted to the animal model for BD induced by ouabain. METHODS: Wistar rats received a single intracerebroventricular (ICV) injection of artificial cerebrospinal fluid or ouabain (10-3 M). Following the ICV administration, the rats were treated for 14 days with saline (NaCl 0.9%, i.p.), lithium (47.5 mg/kg, i.p.), or valproate (200 mg/kg, i.p.). On the 13th and 14th days of treatment, the animals received an additional injection of saline or imipramine (10 mg/kg, i.p.). Behavior tests were evaluated 7 and 14 days after ICV injection. Adrenal gland weight and concentrations of ACTH were evaluated. Levels of neurotrophins BDNF, NGF, NT-3, and GDNF were measured in the frontal cortex and hippocampus by ELISA test. RESULTS: The administration of ouabain induced mania- and depressive-like behavior in the animals 7 and 14 days after ICV, respectively. The treatment with lithium and valproate reversed the mania-like behavior. All treatments were able to reverse most of the depressive-like behaviors induced by ouabain. Moreover, ouabain increased HPA-axis parameters in serum and decreased the neurotrophin levels in the frontal cortex and hippocampus. All treatments, except imipramine, reversed these alterations. CONCLUSION: It can be suggested that acute administration of imipramine alone can be effective on depressive-like symptoms but not on neurotrophic factor alterations present in BD.
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Trastorno Bipolar , Animales , Ratas , Antimaníacos/farmacología , Antimaníacos/uso terapéutico , Trastorno Bipolar/inducido químicamente , Factor Neurotrófico Derivado del Encéfalo/uso terapéutico , Modelos Animales de Enfermedad , Imipramina/farmacología , Imipramina/uso terapéutico , Litio/farmacología , Litio/uso terapéutico , Manía , Factores de Crecimiento Nervioso , Ouabaína/farmacología , Ouabaína/uso terapéutico , Ratas Wistar , Ácido ValproicoRESUMEN
Prenatal hypoxic−ischemic (HI) injury inflicts severe damage on the developing brain provoked by a pathophysiological response that leads to neural structural lesions, synaptic loss, and neuronal death, which may result in a high risk of permanent neurological deficits or even newborn decease. It is known that growth hormone (GH) can act as a neurotrophic factor inducing neuroprotection, neurite growth, and synaptogenesis after HI injury. In this study we used the chicken embryo to develop both in vitro and in vivo models of prenatal HI injury in the cerebral pallium, which is the equivalent of brain cortex in mammals, to examine whether GH exerts neuroprotective and regenerative effects in this tissue and the putative mechanisms involved in these actions. For the in vitro experiments, pallial cell cultures obtained from chick embryos were incubated under HI conditions (<5% O2, 1 g/L glucose) for 24 h and treated with 10 nM GH, and then collected for analysis. For the in vivo experiments, chicken embryos (ED14) were injected in ovo with GH (2.25 µg), exposed to hypoxia (12% O2) for 6 h, and later the pallial tissue was obtained to perform the studies. Results show that GH exerted a clear anti-apoptotic effect and promoted cell survival and proliferation in HI-injured pallial neurons, in both in vitro and in vivo models. Neuroprotective actions of GH were associated with the activation of ERK1/2 and Bcl-2 signaling pathways. Remarkably, GH protected mature neurons that were particularly harmed by HI injury, but was also capable of stimulating neural precursors. In addition, GH stimulated restorative processes such as the number and length of neurite outgrowth and branching in HI-injured pallial neurons, and these effects were blocked by a specific GH antibody, thus indicating a direct action of GH. Furthermore, it was found that the local expression of several synaptogenic markers (NRXN1, NRXN3, GAP-43, and NLG1) and neurotrophic factors (GH, BDNF, NT-3, IGF-1, and BMP4) were increased after GH treatment during HI damage. Together, these results provide novel evidence supporting that GH exerts protective and restorative effects in brain pallium during prenatal HI injury, and these actions could be the result of a joint effect between GH and endogenous neurotrophic factors. Also, they encourage further research on the potential role of GH as a therapeutic complement in HI encephalopathy treatments.
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Hormona de Crecimiento Humana , Hipoxia-Isquemia Encefálica , Fármacos Neuroprotectores , Animales , Animales Recién Nacidos , Embrión de Pollo , Pollos/metabolismo , Hormona del Crecimiento/metabolismo , Hormona de Crecimiento Humana/uso terapéutico , Hipoxia/tratamiento farmacológico , Hipoxia-Isquemia Encefálica/metabolismo , Isquemia/tratamiento farmacológico , Mamíferos/metabolismo , Factores de Crecimiento Nervioso/uso terapéutico , Neuroprotección , Fármacos Neuroprotectores/farmacología , Fármacos Neuroprotectores/uso terapéuticoRESUMEN
ER contact sites define the position of endosome bud fission during actin-dependent cargo sorting. Disrupting endosomal actin structures prevents retrograde cargo movement; however, how actin affects ER contact site formation and endosome fission is not known. Here we show that in contrast with the WASH complex, actin, its nucleator ARP2/3, and COR1C form a contained structure at the bud neck that defines the site of bud fission. We found that actin confinement is facilitated by type I coronins. Depletion of type I coronins allows actin to extend along the length of the bud in an ARP2/3-dependent manner. We demonstrate that extension of branched actin prevents ER recruitment and stalls buds before fission. Finally, our structure-function studies show that the COR1C's coiled-coil domain is sufficient to restore actin confinement, ER recruitment, and endosome fission. Together, our data reveal how the dynamics of endosomal actin and activity of actin regulators organize ER-associated bud fission.
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Actinas/metabolismo , Retículo Endoplásmico/metabolismo , Endosomas/metabolismo , Proteínas de Microfilamentos/metabolismo , Animales , Células COS , Chlorocebus aethiops , Humanos , Factores de Crecimiento Nervioso/genética , Factores de Crecimiento Nervioso/metabolismo , Proteínas de Unión a Fosfato/metabolismo , Unión Proteica , Proteínas de Unión a GTP rab7/metabolismoRESUMEN
Cocaine-induced neuroinflammation plays an important role in the pathophysiology of drug addiction. Evidence suggests that the immune response contributes for memory consolidation related to place preference behavior underlying cocaine administration in mice. Conditioned place preference (CPP) is a protocol extensively used to study the rewarding and/or aversive motivational effects of drug abuse in rodents, reproducing cocaine-seeking behavior in humans. Besides the variety of apparatus used in the CPP protocol, whether different types of apparatus are able to induce the same conditioned behavior response and neurobiological changes remains to be fully explored. We hypothesize that the immune response is involved in the cocaine-induced CPP and that the type of apparatus might influence this response. Herein, two- and three-compartment apparatuses were tested using the behavioral model of CPP. Cocaine-induced CPP was demonstrated in both apparatuses. However, mice injected with cocaine had decreased levels of IL-1ß, IL-6, IL-10, and GDNF in the pre-frontal cortex, and decreased CX3CL1 in the striatum, in the CPP protocol using three compartments compared to controls. While similar levels were seen in the CPP protocol using two compartments. In conclusion, the current study demonstrated that the type of apparatus might influence the investigation of neurobiological mechanisms associated with cocaine-induced CPP. Our data also suggest that the three compartment-apparatus seems to be a more appropriate model to investigate the neuroinflammatory response related to cocaine addiction.
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Cocaína , Animales , Ratones , Encéfalo , Cocaína/farmacología , Citocinas , Factores de Crecimiento NerviosoRESUMEN
Maple Syrup Urine Disease (MSUD) is caused by the deficiency in the activity of the branched-chain α-ketoacid dehydrogenase complex (BCKDC), resulting in the accumulation of the branched-chain amino acids (BCAA) leucine, isoleucine, and valine, and their respective branched-chain α-keto acids. Patients with MSUD are at high risk of developing chronic neuropsychiatric disorders; however, the pathophysiology of brain damage in these patients remains unclear. We hypothesize that MSUD can cause depressive symptoms in patients. To test our hypothesis, Wistar rats were submitted to the BCAA and tianeptine (antidepressant) administration for 21 days, starting seven days postnatal. Depression-like symptoms were assessed by testing for anhedonia and forced swimming after treatments. After the last test, the brain structures were dissected for the evaluation of neutrophins. We demonstrate that chronic BCAA administration induced depressive-like behavior, increased BDNF levels, and decreased NGF levels, suggesting a relationship between BCAA toxicity and brain damage, as observed in patients with MSUD. However, the administration of tianeptine was effective in preventing behavioral changes and restoring neurotrophins levels.
Asunto(s)
Enfermedad de la Orina de Jarabe de Arce , Tiazepinas , Aminoácidos de Cadena Ramificada/metabolismo , Animales , Enfermedad de la Orina de Jarabe de Arce/metabolismo , Factores de Crecimiento Nervioso/metabolismo , Ratas , Ratas Wistar , Tiazepinas/farmacologíaRESUMEN
Huntington's disease (HD), a neurodegenerative disorder caused by an expansion of the huntingtin triplet (Htt), is clinically characterized by cognitive and neuropsychiatric alterations. Although these alterations appear to be related to mutant Htt (mHtt)-induced neurotoxicity, several other factors are involved. The gut microbiota is a known modulator of brain-gut communication and when altered (dysbiosis), several complaints can be developed including gastrointestinal dysfunction which may have a negative impact on cognition, behavior, and other mental functions in HD through several mechanisms, including increased levels of lipopolysaccharide, proinflammatory cytokines and immune cell response, as well as alterations in Ca2+ signaling, resulting in both increased intestinal and blood-brain barrier (BBB) permeability. Recently, the presence of dysbiosis has been described in both transgenic mouse models and HD patients. A bidirectional influence between host brain tissues and the gut microbiota has been observed. On the one hand, the host diet influences the composition and function of microbiota; and on the other hand, microbiota products can affect BBB permeability, synaptogenesis, and the regulation of neurotransmitters and neurotrophic factors, which has a direct effect on host metabolism and brain function. This review summarizes the available evidence on the pathogenic synergism of dysbiosis and homocysteine, and their role in the transgression of BBB integrity and their potential neurotoxicity of HD.
Asunto(s)
Enfermedad de Huntington , Animales , Citocinas , Disbiosis , Homocisteína , Humanos , Lipopolisacáridos , Ratones , Factores de Crecimiento NerviosoRESUMEN
Traumatic brain injury (TBI) is considered a public health problem and is often related to motor and cognitive disabilities, besides behavioral and emotional changes that may remain for the rest of the subject's life. Resident astrocytes and microglia are the first cell types to start the inflammatory cascades following TBI. It is widely known that continuous or excessive neuroinflammation may trigger many neuropathologies. Despite the large numbers of TBI cases, there is no effective pharmacological treatment available. This study aimed to investigate the effects of the new hybrid molecule 3-ethoxycarbonyl-2-methyl-4-(2-nitrophenyl)-4,11-dihydro1H-pyrido[2,3-b][1,5]benzodiazepine (JM-20) on TBI outcomes. Male Wistar rats were submitted to a weight drop model of mild TBI and treated with a single dose of JM-20 (8 mg/kg). Twenty-four hours after TBI, JM-20-treated animals showed improvements on locomotor and exploratory activities, and short-term memory deficits induced by TBI improved as well. Brain edema was present in TBI animals and the JM-20 treatment was able to prevent this change. JM-20 was also able to attenuate neuroinflammation cascades by preventing glial cells-microglia and astrocytes-from exacerbated activation, consequently reducing pro-inflammatory cytokine levels (TNF-α and IL-1ß). BDNF mRNA level was decreased 24 h after TBI because of neuroinflammation cascades; however, JM-20 restored the levels. JM-20 also increased GDNF and NGF levels. These results support the JM-20 neuroprotective role to treat mild TBI by reducing the initial damage and limiting long-term secondary degeneration after TBI.