RESUMEN
The development of functional neurons is a complex orchestration of multiple signaling pathways controlling cell proliferation and differentiation. Because the balance of antioxidants is important for neuronal survival and development, we hypothesized that ferroptosis must be suppressed to gain neurons. We find that removal of antioxidants diminishes neuronal development and laminar organization of cortical organoids, which is fully restored when ferroptosis is inhibited by ferrostatin-1 or when neuronal differentiation occurs in the presence of vitamin A. Furthermore, iron-overload-induced developmental growth defects in C. elegans are ameliorated by vitamin E and A. We determine that all-trans retinoic acid activates the Retinoic Acid Receptor, which orchestrates the expression of anti-ferroptotic genes. In contrast, retinal and retinol show radical-trapping antioxidant activity. Together, our study reveals an unexpected function of vitamin A in coordinating the expression of essential cellular gatekeepers of ferroptosis, and demonstrates that suppression of ferroptosis by radical-trapping antioxidants or by vitamin A is required to obtain mature neurons and proper laminar organization in cortical organoids.
Asunto(s)
Antioxidantes , Caenorhabditis elegans , Ferroptosis , Neuronas , Vitamina A , Animales , Ferroptosis/efectos de los fármacos , Vitamina A/farmacología , Vitamina A/metabolismo , Caenorhabditis elegans/metabolismo , Caenorhabditis elegans/efectos de los fármacos , Antioxidantes/farmacología , Neuronas/metabolismo , Neuronas/efectos de los fármacos , Neuronas/citología , Ciclohexilaminas/farmacología , Diferenciación Celular/efectos de los fármacos , Vitamina E/farmacología , Receptores de Ácido Retinoico/metabolismo , Receptores de Ácido Retinoico/genética , Tretinoina/farmacología , Organoides/efectos de los fármacos , Organoides/metabolismo , Neurogénesis/efectos de los fármacos , Ratones , Humanos , Proteínas de Caenorhabditis elegans/metabolismo , Proteínas de Caenorhabditis elegans/genética , Transducción de Señal/efectos de los fármacos , FenilendiaminasRESUMEN
Intracerebral hemorrhage is a lethal cerebrovascular disease, and the inevitable secondary brain injury (SBI) is responsible for serious disability and death. Perfect therapeutic goal is to minimize SBI and restore neurobehavioral functions. Recently, neuroprotection is highlighted to reduce SBI, but it still faces "Neuronal survival but impaired functions" dilemma. Herein, this work further proposes a novel combinational therapeutic strategy of neuroprotection and neurogenesis toward this goal. However, appropriate therapeutic agents are rarely reported, and their discovery and development are urgently needed. Selenium participates in various physiological/pathological processes, which is hypothesized as a potential targeting molecule. To explore this effect, this work formulates an ultra-small selenium nanodot with a seleno-amino acid derived carbon dot domain and a hydrophilic PEG layer, surprisingly finding that it increases various selenoproteins levels at perihematomal region, to not only exert multiple neuroprotective roles at acute phase but promote neurogenesis and inhibit glial scar formation at recovery phase. At a safe dose, this combinational strategy effectively prevents SBI and recovers neurobehavioral functions to a normal level. Furthermore, its molecular mechanisms are revealed to broaden application scopes in other complex diseases.
Asunto(s)
Lesiones Encefálicas , Accidente Cerebrovascular Hemorrágico , Fármacos Neuroprotectores , Selenio , Animales , Selenio/química , Selenio/farmacología , Selenio/uso terapéutico , Fármacos Neuroprotectores/farmacología , Fármacos Neuroprotectores/química , Fármacos Neuroprotectores/uso terapéutico , Lesiones Encefálicas/tratamiento farmacológico , Accidente Cerebrovascular Hemorrágico/tratamiento farmacológico , Neurogénesis/efectos de los fármacos , Masculino , Ratones , Selenoproteínas/metabolismo , Nanopartículas/química , Neuronas/efectos de los fármacos , Encéfalo/efectos de los fármacosRESUMEN
Major depressive disorder (MDD) is a mental health disorder associated with cognitive impairment, dysregulated appetite, fatigue, insomnia or hypersomnia, and severe mood changes that significantly impact the ability of the affected individual to perform day-to-day tasks, leading to suicide in the worst-case scenario. As MDD is becoming more prevalent, affecting roughly 300 million individuals worldwide, its treatment has become a major point of interest. Antidepressants acting as selective serotonin reuptake inhibitors (SSRIs) are currently used as the first line of treatment for MDD. Other antidepressants currently used for the treatment of MDD include the serotonin and norepinephrine reuptake inhibitors (SNRIs), tricyclic antidepressants (TCAs), and monoamine oxidase inhibitors (MAOIs). However, although effective in alleviating symptoms of MDD, most antidepressants require weeks or even months of regular administration prior to eliciting a rational clinical effect. Owing to the strong evidence showing a relationship between neural plasticity, neurogenesis, and MDD, researchers have also looked at the possibility of using treatment modalities that target these processes in an attempt to improve clinical outcome. The overarching aim of this chapter is to highlight the role of neural plasticity and neurogenesis in the pathophysiology of MDD and discuss the most recently studied treatment strategies that target these processes by presenting supporting evidence from both animal and human studies.
Asunto(s)
Antidepresivos , Trastorno Depresivo Mayor , Neurogénesis , Plasticidad Neuronal , Humanos , Trastorno Depresivo Mayor/tratamiento farmacológico , Trastorno Depresivo Mayor/fisiopatología , Neurogénesis/efectos de los fármacos , Plasticidad Neuronal/efectos de los fármacos , Antidepresivos/uso terapéutico , Antidepresivos/farmacología , Animales , Inhibidores Selectivos de la Recaptación de Serotonina/uso terapéutico , Inhibidores Selectivos de la Recaptación de Serotonina/farmacologíaRESUMEN
The Ribosomal S6 Kinase (RSK) family of serine/threonine kinases function as key downstream effectors of the MAPK signaling cascade. In the nervous system, RSK signaling plays crucial roles in neuronal development and contributes to activity-dependent neuronal plasticity. This study examined the role of RSK signaling in cell viability during neuronal development and in neuroprotection in the mature nervous system. Using neuronal cell-culture-based profiling, we found that suppressing RSK signaling led to significant cell death in developing primary neuronal cultures. To this end, treatment with the RSK inhibitors BiD1870 or SL0101 on the first day of culturing resulted in over 80% cell death. In contrast, more mature cultures showed attenuated cell death upon RSK inhibition. Inhibition of RSK signaling during early neuronal development also disrupted neurite outgrowth and cell growth. In maturing hippocampal explant cultures, treatment with BiD1870 had minimal effects on cell viability, but led to a striking augmentation of NMDA-induced cell death. Finally, we used the endothelin 1 (ET-1) model of ischemia to examine the neuroprotective effects of RSK signaling in the mature hippocampus in vivo. Notably, in the absence of RSK inhibition, the granule cell layer (GCL) was resistant to the effects of ET-1; However, disruption of RSK signaling (via the microinjection of BiD1870) prior to ET-1 injection triggered cell death within the GCL, thus indicating a neuroprotective role for RSK signaling in the mature nervous system. Together these data reveal distinct, developmentally-defined, roles for RSK signaling in the nervous system.
Asunto(s)
Muerte Celular , Supervivencia Celular , Neuronas , Proteínas Quinasas S6 Ribosómicas , Transducción de Señal , Animales , Neuronas/efectos de los fármacos , Neuronas/metabolismo , Muerte Celular/efectos de los fármacos , Muerte Celular/fisiología , Supervivencia Celular/efectos de los fármacos , Supervivencia Celular/fisiología , Proteínas Quinasas S6 Ribosómicas/metabolismo , Transducción de Señal/efectos de los fármacos , Transducción de Señal/fisiología , Hipocampo/efectos de los fármacos , Hipocampo/metabolismo , Células Cultivadas , Endotelina-1/farmacología , Endotelina-1/metabolismo , N-Metilaspartato/farmacología , Ratas Sprague-Dawley , Ratas , Neurogénesis/fisiología , Neurogénesis/efectos de los fármacos , PteridinasRESUMEN
BACKGROUND: Aflatoxin B1, which can penetrate the blood-brain barrier and kill neural cells, can contaminate traditional herbal medicines, posing a significant risk to human health. The present study examined cellular, cognitive and behavioral consequences of aflatoxin B1 contamination of the anti-osteoporotic medicine Radix Dipsaci. METHODS: A mouse model of osteoporosis was created by treating the animals with all-trans-retinoic acid. Then the animals were treated intragastically with water decoctions of Radix Dipsaci that contained detectable aflatoxin B1 or not. The animals were compared in terms of mineral density and mineral salt content of bone, production of pro-inflammatory factors, neurogenesis and microglial activation in hippocampus, as well as behavior and cognitive function. RESULTS: Contamination of Radix Dipsaci with aflatoxin B1 significantly reduced the medicine's content of bioactive saponins. It destroyed the ability of the herbal decoction to improve mineral density and mineral salt content in the bones of diseased mice, and it induced the production of the oxidative stress marker malondialdehyde as well as the pro-inflammatory cytokines interleukin-1ß and tumor necrosis factor-α. Aflatoxin B1 contamination inhibited formation of new neurons and increased the proportion of activated microglia in the hippocampus. These neurological changes were associated with anhedonia, behavioral despair, and deficits in short-term memory and social memory. CONCLUSION: Contamination of Radix Dipsaci with aflatoxin B1 not only eliminates the herbal decoction's anti-osteoporotic effects, but it also induces neurotoxicity that can lead to cognitive decline and behavioral abnormalities. Such contamination should be avoided through tightly regulated production and quality control of medicinal herbs.
Asunto(s)
Aflatoxina B1 , Cognición , Modelos Animales de Enfermedad , Hipocampo , Neurogénesis , Osteoporosis , Animales , Hipocampo/efectos de los fármacos , Aflatoxina B1/toxicidad , Ratones , Osteoporosis/tratamiento farmacológico , Osteoporosis/inducido químicamente , Cognición/efectos de los fármacos , Neurogénesis/efectos de los fármacos , Dipsacaceae/química , Masculino , Contaminación de Medicamentos , Medicamentos Herbarios Chinos/farmacologíaRESUMEN
Benzo[a]pyrene (B[a]P) is known to inhibit neurodifferentiation and induce neurodegeneration. Agarwood or Aquilaria crassna (AC), a plant with health-promoting properties, may counteract the neurotoxic effects of B[a]P by promoting neuronal growth and survival. This study investigated the protective effect of AC leaf ethanolic extract (ACEE) on the B[a]P-induced impairment of neuronal differentiation. A transcriptomic analysis identified the canonical pathway, the biological network, and the differentially expressed genes (DEGs) that are changed in response to neuronal differentiation and neurogenesis. Several genes, including CXCR4, ENPP2, GAP43, GFRA2, NELL2, NFASC, NSG2, NGB, BASP1, and NEUROD1, in B[a]P-treated SH-SY5Y cells were up-regulated after treatment with ACEE. Notably, a Western blot analysis further confirmed that ACEE increased the protein levels of GAP43 and neuroglobin. B[a]P treatment led to decreased phosphorylation of Akt and increased phosphorylation of ERK in SH-SY5Y cells; however, ACEE was able to reverse these effects. Clionasterol and lupenone were identified in ACEE. Molecular docking showed that these two phytochemicals had significant interactions with CXCR4, GDNF family receptor alpha (GFRA), and retinoid X receptors (RXRs). In conclusion, ACEE may be a potential alternative medicine for the prevention of impaired neuronal differentiation and neurodegenerative diseases.
Asunto(s)
Benzo(a)pireno , Fármacos Neuroprotectores , Extractos Vegetales , Thymelaeaceae , Humanos , Extractos Vegetales/farmacología , Fármacos Neuroprotectores/farmacología , Benzo(a)pireno/toxicidad , Línea Celular Tumoral , Thymelaeaceae/química , Perfilación de la Expresión Génica , RNA-Seq , Hojas de la Planta/química , Neuronas/efectos de los fármacos , Neuronas/metabolismo , Transcriptoma/efectos de los fármacos , Diferenciación Celular/efectos de los fármacos , Neurogénesis/efectos de los fármacos , Simulación del Acoplamiento Molecular , Supervivencia Celular/efectos de los fármacosRESUMEN
Autism spectrum disorder (ASD) is a multifactorial neurodevelopmental condition with several identified risk factors, both genetic and non-genetic. Among these, prenatal exposure to valproic acid (VPA) has been extensively associated with the development of the disorder. The zebrafish, a cost- and time-effective model, is useful for studying ASD features. Using validated VPA-induced ASD zebrafish models, we aimed to provide new insights into VPA exposure effects during embryonic development and to identify new potential biomarkers associated with ASD-like features. Dose-response analyses were performed in vivo to study larval phenotypes and mechanisms underlying neuroinflammation, mitochondrial dysfunction, oxidative stress, microglial cell status, and motor behaviour. Wild-type and transgenic Tg(mpeg1:EGFP) zebrafish were water-exposed to VPA doses (5 to 500 µM) from 6 to 120 h post-fertilisation (hpf). Embryos and larvae were monitored daily to assess survival and hatching rates, and numerous analyses and tests were conducted from 24 to 120 hpf. VPA doses higher than 50 µM worsened survival and hatching rates, while doses of 25 µM or more altered morphology, microglial status, and larval behaviours. VPA 50 µM also affected mRNA expression of inflammatory cytokines and neurogenesis-related genes, mitochondrial respiration, and reactive oxygen species accumulation. The study confirmed that VPA alters brain homeostasis, synaptic interconnections, and neurogenesis-related signalling pathways, contributing to ASD aetiopathogenesis. Further studies are essential to identify novel ASD biomarkers for developing new drug targets and tailored therapeutic interventions for ASD.
Asunto(s)
Trastorno del Espectro Autista , Modelos Animales de Enfermedad , Ácido Valproico , Pez Cebra , Animales , Ácido Valproico/farmacología , Ácido Valproico/efectos adversos , Trastorno del Espectro Autista/inducido químicamente , Trastorno del Espectro Autista/genética , Trastorno del Espectro Autista/patología , Larva/efectos de los fármacos , Animales Modificados Genéticamente , Estrés Oxidativo/efectos de los fármacos , Mitocondrias/efectos de los fármacos , Mitocondrias/metabolismo , Microglía/efectos de los fármacos , Microglía/patología , Microglía/metabolismo , Encéfalo/efectos de los fármacos , Encéfalo/patología , Encéfalo/metabolismo , Embrión no Mamífero/efectos de los fármacos , Embrión no Mamífero/metabolismo , Neurogénesis/efectos de los fármacosRESUMEN
Traumatic brain injury (TBI) presents a significant public health challenge, necessitating innovative interventions for effective treatment. Recent studies have challenged conventional perspectives on neurogenesis, unveiling endogenous repair mechanisms within the adult brain following injury. However, the intricate mechanisms governing post-TBI neurogenesis remain unclear. The microenvironment of an injured brain, characterized by astrogliosis, neuroinflammation, and excessive cell death, significantly influences the fate of newly generated neurons. Adenosine kinase (ADK), the key metabolic regulator of adenosine, emerges as a crucial factor in brain development and cell proliferation after TBI. This study investigates the hypothesis that targeting ADK could enhance brain repair, promote neuronal survival, and facilitate differentiation. In a TBI model induced by controlled cortical impact, C57BL/6 male mice received intraperitoneal injections of the small molecule ADK inhibitor 5-iodotubercidin (ITU) for three days following TBI. To trace the fate of TBI-associated proliferative cells, animals received intraperitoneal injections of BrdU for seven days, beginning immediately after TBI. Our results show that ADK inhibition by ITU improved brain repair 14 days after injury as evidenced by a diminished injury size. Additionally, the number of mature neurons generated after TBI was increased in ITU-treated mice. Remarkably, the TBI-associated pathological events including astrogliosis, neuroinflammation, and cell death were arrested in ITU-treated mice. Finally, ADK inhibition modulated cell death by regulating the PERK signaling pathway. Together, these findings demonstrate a novel therapeutic approach to target multiple pathological mechanisms involved in TBI. This research contributes valuable insights into the intricate molecular mechanisms underlying neurogenesis and gliosis after TBT.
Asunto(s)
Adenosina Quinasa , Lesiones Traumáticas del Encéfalo , Diferenciación Celular , Supervivencia Celular , Ratones Endogámicos C57BL , Neurogénesis , Neuronas , Animales , Lesiones Traumáticas del Encéfalo/patología , Lesiones Traumáticas del Encéfalo/tratamiento farmacológico , Lesiones Traumáticas del Encéfalo/metabolismo , Neurogénesis/efectos de los fármacos , Neurogénesis/fisiología , Masculino , Ratones , Adenosina Quinasa/antagonistas & inhibidores , Adenosina Quinasa/metabolismo , Diferenciación Celular/efectos de los fármacos , Neuronas/efectos de los fármacos , Neuronas/metabolismo , Supervivencia Celular/efectos de los fármacos , Supervivencia Celular/fisiología , Tubercidina/análogos & derivadosRESUMEN
5-Methoxy-3-(5-methoxyindolin-2-yl)-1H-indole (3), whose structure was unambiguously elucidated by X-ray analysis, was identified as a multi-target compound with potential application in neurodegenerative diseases. It is a low nanomolar inhibitor of QR2 (IC50 = 7.7 nM), with greater potency than melatonin and comparable efficacy to the most potent QR2 inhibitors described to date. Molecular docking studies revealed the potential binding mode of 3 to QR2, which explains its superior potency compared to melatonin. Furthermore, compound 3 inhibits hMAO-A, hMAO-B and hLOX-5 in the low micromolar range and is an excellent ROS scavenger. In phenotypic assays, compound 3 showed neuroprotective activity in a cellular model of oxidative stress damage, it was non-toxic, and was able to activate neurogenesis from neural stem-cell niches of adult mice. These excellent biological properties, together with its both good in silico and in vitro drug-like profile, highlight compound 3 as a promising drug candidate for neurodegenerative diseases.
Asunto(s)
Melatonina , Simulación del Acoplamiento Molecular , Neurogénesis , Fármacos Neuroprotectores , Fármacos Neuroprotectores/farmacología , Fármacos Neuroprotectores/química , Fármacos Neuroprotectores/síntesis química , Melatonina/farmacología , Melatonina/química , Animales , Ratones , Humanos , Relación Estructura-Actividad , Neurogénesis/efectos de los fármacos , Estructura Molecular , Descubrimiento de Drogas , Quinona Reductasas/antagonistas & inhibidores , Quinona Reductasas/metabolismo , Inhibidores Enzimáticos/farmacología , Inhibidores Enzimáticos/química , Inhibidores Enzimáticos/síntesis química , Relación Dosis-Respuesta a DrogaRESUMEN
BACKGROUND: Depression is a heterogeneous disorder with high morbidity and disability rates that poses serious problems regarding mental health care. It is now well established that N-methyl D-aspartate receptor (NMDAR) modulators are being increasingly explored as potential therapeutic options for treating depression, although relatively little is known about their mechanisms of action. NMDARs are glutamate-gated ion channels that are ubiquitously expressed in the central nervous system (CNS), and they have been shown to play key roles in excitatory synaptic transmission. GluN2A, the predominant Glu2N subunit of functional NMDARs in neurons, is involved in various physiological processes in the CNS and is associated with diseases such as anxiety, depression, and schizophrenia. However, the role of GluN2A in the pathophysiology of depression has not yet been elucidated. METHODS: We reviewed several past studies to better understand the function of GluN2A in depression. Additionally, we also summarized the pathogenesis of depression based on the regulation of GluN2A expression, particularly its interaction with neuroinflammation and neurogenesis, which has received considerable critical attention and is highly implicated in the onset of depression. RESULTS: These evidence suggests that GluN2A overexpression impairs structural and functional synaptic plasticity, which contributes to the development of depression. Consequently, this knowledge is vital for the development of selective antagonists targeting GluN2A subunits using pharmacological and molecular methods. CONCLUSIONS: Specific inhibition of the GluN2A NMDAR subunit is resistant to chronic stress-induced depressive-like behaviors, making them promising targets for the development of novel antidepressants.
Asunto(s)
Antidepresivos , Receptores de N-Metil-D-Aspartato , Receptores de N-Metil-D-Aspartato/antagonistas & inhibidores , Receptores de N-Metil-D-Aspartato/metabolismo , Humanos , Antidepresivos/farmacología , Animales , Depresión/tratamiento farmacológico , Depresión/metabolismo , Plasticidad Neuronal/efectos de los fármacos , Plasticidad Neuronal/fisiología , Trastorno Depresivo/tratamiento farmacológico , Trastorno Depresivo/metabolismo , Desarrollo de Medicamentos , Neurogénesis/efectos de los fármacosRESUMEN
The aim of this study was to investigate the possible protective effects of apelin, which is known to have antioxidant and anti-inflammatory effects, on changes in neurogenesis in newborns of pregnant rats with L-NAME-induced preeclampsia. Wistar albino female rats were divided into four experimental groups: Control, Apelin, Preeclampsia and Preeclampsia + Apelin. Blood pressure was measured on the 5th, 11th and 17th days of gestation, urine protein was analyzed from urine samples collected for 24 h on the 6th, 12th and 18th days and serum creatinine was analyzed from serum samples. Maternal kidney and placenta tissues were obtained to establish the preeclampsia model, and neonatal brain tissues including the cortex, hippocampus and cerebellum regions were obtained to investigate neurogenesis and examined by histological and immunohistochemical methods. The number of newborns, body weight and brain weight of the newborns were measured. eNOS, IL-10, nNOS and NO levels in the brain analyzed via ELISA. Mean arterial pressure, urine protein and serum creatinine increased in the preeclampsia. Newborn weight decreased in the Preeclampsia group, the values in the Preeclampsia + Apelin group were closer to the Control and Apelin groups. In the Preeclampsia group, edema and dilatation in the proximal and distal tubules of kidneys, perivillous fibrin deposition and increase in syncytial nodules of placenta were observed. VEGF immunoreactivity decreased and iNOS immunoreactivity increased in both kidney and placenta. In neonatal brain tissue examinations, cytotoxic edema accompanied by thinning of cortex, delayed migration and lower cell counts in the hippocampus, and increase in intercellular spaces and EGL thickening in the cerebellum were observed in the preeclampsia. Expression of NeuN, GFAP, MBP, IL-10, eNOS, nNOS and NO levels decreased, whereas expression of Iba-1 increased in the preeclampsia. In the Preeclampsia + Apelin group, these findings were similar to the Control and Apelin groups. Apelin administration was found to be beneficial for preventing the adverse consequences of preeclampsia, but further experimental and clinical studies are needed to better understand these effects.
Asunto(s)
Animales Recién Nacidos , Apelina , Encéfalo , NG-Nitroarginina Metil Éster , Neurogénesis , Preeclampsia , Ratas Wistar , Femenino , Embarazo , Preeclampsia/inducido químicamente , Preeclampsia/metabolismo , Animales , Apelina/metabolismo , Neurogénesis/efectos de los fármacos , Ratas , Encéfalo/metabolismo , Encéfalo/patología , Encéfalo/efectos de los fármacos , NG-Nitroarginina Metil Éster/farmacología , Placenta/metabolismo , Modelos Animales de Enfermedad , Óxido Nítrico Sintasa de Tipo III/metabolismo , Óxido Nítrico/metabolismo , Interleucina-10/metabolismo , Interleucina-10/sangre , Óxido Nítrico Sintasa de Tipo I/metabolismoRESUMEN
BACKGROUND: Chronic Gulf War Illness (GWI) is characterized by cognitive and mood impairments, as well as persistent neuroinflammation and oxidative stress. This study aimed to investigate the efficacy of Epidiolex®, a Food and Drug Administration (FDA)-approved cannabidiol (CBD), in improving brain function in a rat model of chronic GWI. METHODS: Six months after exposure to low doses of GWI-related chemicals [pyridostigmine bromide, N,N-diethyl-meta-toluamide (DEET), and permethrin (PER)] along with moderate stress, rats with chronic GWI were administered either vehicle (VEH) or CBD (20 mg/kg, oral) for 16 weeks. Neurobehavioral tests were conducted on 11 weeks after treatment initiation to evaluate the performance of rats in tasks related to associative recognition memory, object location memory, pattern separation, and sucrose preference. The effect of CBD on hyperalgesia was also examined. The brain tissues were processed for immunohistochemical and molecular studies following behavioral tests. RESULTS: GWI rats treated with VEH exhibited impairments in all cognitive tasks and anhedonia, whereas CBD-treated GWI rats showed improvements in all cognitive tasks and no anhedonia. Additionally, CBD treatment alleviated hyperalgesia in GWI rats. Analysis of hippocampal tissues from VEH-treated rats revealed astrocyte hypertrophy and increased percentages of activated microglia presenting NOD-, LRR- and pyrin domain-containing protein 3 (NLRP3) complexes as well as elevated levels of proteins involved in NLRP3 inflammasome activation and Janus kinase/signal transducers and activators of the transcription (JAK/STAT) signaling. Furthermore, there were increased concentrations of proinflammatory and oxidative stress markers along with decreased neurogenesis. In contrast, the hippocampus from CBD-treated GWI rats displayed reduced levels of proteins mediating the activation of NLRP3 inflammasomes and JAK/STAT signaling, normalized concentrations of proinflammatory cytokines and oxidative stress markers, and improved neurogenesis. Notably, CBD treatment did not alter the concentration of endogenous cannabinoid anandamide in the hippocampus. CONCLUSIONS: The use of an FDA-approved CBD (Epidiolex®) has been shown to effectively alleviate cognitive and mood impairments as well as hyperalgesia associated with chronic GWI. Importantly, the improvements observed in rats with chronic GWI in this study were attributed to the ability of CBD to significantly suppress signaling pathways that perpetuate chronic neuroinflammation.
Asunto(s)
Cannabidiol , Disfunción Cognitiva , Hiperalgesia , Neurogénesis , Enfermedades Neuroinflamatorias , Síndrome del Golfo Pérsico , Animales , Cannabidiol/farmacología , Cannabidiol/uso terapéutico , Ratas , Síndrome del Golfo Pérsico/tratamiento farmacológico , Síndrome del Golfo Pérsico/complicaciones , Masculino , Hiperalgesia/tratamiento farmacológico , Enfermedades Neuroinflamatorias/tratamiento farmacológico , Disfunción Cognitiva/tratamiento farmacológico , Disfunción Cognitiva/etiología , Neurogénesis/efectos de los fármacos , Modelos Animales de Enfermedad , Ratas Sprague-Dawley , Transducción de Señal/efectos de los fármacos , Trastornos del Humor/tratamiento farmacológico , Estrés Oxidativo/efectos de los fármacos , Hipocampo/efectos de los fármacos , Bromuro de Piridostigmina/farmacología , Bromuro de Piridostigmina/uso terapéuticoRESUMEN
BACKGROUND: Salidroside is the major bioactive and pharmacological active substance in Rhodiola rosea L. It has been reported to have neuroprotective effects on cerebral ischemia/reperfusion (I/R). However, whether salidroside can enhance neural regeneration after cerebral I/R is still unknown. This study investigated the effects of salidroside on the endogenous neural regeneration after cerebral I/R and the related mechanism. METHODS: Focal cerebral I/R was induced in rats by transient middle cerebral artery occlusion/reperfusion (MCAO/R). The rats were intraperitoneally treated salidroside once daily for 7 consecutive days. Neurobehavioral assessments were performed at 3 days and 7 days after the injury. TTC staining was performed to assess cerebral infarct volume. To evaluate the survival of neurons, immunohistochemical staining of Neuronal Nuclei (NeuN) in the ischemic hemisphere were conducted. Also, immunofluorescence double or triple staining of the biomarkers of proliferating neural progenitor cells in Subventricular Zone (SVZ) and striatum of the ischemia hemisphere were performed to investigate the neurogenesis. Furthermore, reverse transcription-polymerase chain reaction (RT-PCR) and enzyme-linked immunosorbent assay (ELISA) were used to detect the expression of neurotrophic factors (NTFs) brain-derived neurotrophic factor (BDNF) and nerve growth factor (NGF). Expression of Notch1 and its target molecular Hes1 were also analyzed by western-blotting and RT-PCR. RESULTS: Salidroside treatment ameliorated I/R induced neurobehavioral impairment, and reduced infarct volume. Salidroside also restored NeuN positive cells loss after I/R injury. Cerebral I/R injury significantly increased the expression of 5-Bromo-2'-Deoxyuridine (BrdU) and doublecotin (DCX), elevated the number of BrdU/Nestin/DCX triple-labeled cells in SVZ, and BrdU/Nestin/glial fibrillary acidic protein (GFAP) triple-labeled cells in striatum. Salidroside treatment further promoted the proliferation of BrdU/DCX labeled neuroblasts and BrdU/Nestin/GFAP labeled reactive astrocytes. Furthermore, salidroside elevated the mRNA expression and protein concentration of BDNF and NGF in ischemia periphery area, as well. Mechanistically, salidroside elevated Notch1/Hes1 mRNA expression in SVZ. The protein levels of them were also increased after salidroside administration. CONCLUSIONS: Salidroside enhances the endogenous neural regeneration after cerebral I/R. The mechanism of the effect may involve the regulation of BDNF/NGF and Notch signaling pathway.
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Isquemia Encefálica , Glucósidos , Regeneración Nerviosa , Fenoles , Ratas Sprague-Dawley , Daño por Reperfusión , Transducción de Señal , Animales , Glucósidos/farmacología , Fenoles/farmacología , Ratas , Masculino , Transducción de Señal/efectos de los fármacos , Daño por Reperfusión/tratamiento farmacológico , Isquemia Encefálica/tratamiento farmacológico , Regeneración Nerviosa/efectos de los fármacos , Fármacos Neuroprotectores/farmacología , Factores de Crecimiento Nervioso/metabolismo , Modelos Animales de Enfermedad , Receptores Notch/metabolismo , Infarto de la Arteria Cerebral Media/tratamiento farmacológico , Neurogénesis/efectos de los fármacosRESUMEN
Cocoa is widely known for its health benefits, but its neurocognitive impact remains underexplored. This preclinical study aimed to investigate the effects of cocoa and cocoa polyphenols on hippocampal neuroplasticity, cognitive function and emotional behavior. Seventy young-adult C57BL/6JRj male and female mice were fed either a standard diet (CTR) or a diet enriched with 10% high-phenolic content cocoa (HPC) or low-phenolic content cocoa (LPC) for at least four weeks. In a first experiment, behavioral tests assessing exploratory behavior, emotional responses and hippocampal-dependent memory were conducted four weeks into the diet, followed by animal sacrifice a week later. Adult hippocampal neurogenesis and brain-derived neurotrophic factor (BDNF) expression in the hippocampus and prefrontal cortex were evaluated using immunohistochemistry and western blot. In a different experiment, hippocampal synaptic response, long-term potentiation and presynaptic-dependent short-term plasticity were studied by electrophysiology. Cocoa-enriched diets had minimal effects on exploratory activity and anxiety-like behavior, except for reduced locomotion in the LPC group. Only the HPC diet enhanced object recognition memory, while place recognition memory and spatial navigation remained unaffected. The HPC diet also increased adult hippocampal neurogenesis, boosting the proliferation, survival and number of young adult-born neurons. However, both cocoa-enriched diets increased immobility in the forced swimming test and hippocampal BDNF expression. Hippocampal electrophysiology revealed no alterations in neuroplasticity among diets. The results were mostly unaffected by sex. Overall, the HPC diet demonstrated greater potential regarding cognitive and neuroplastic benefits, suggesting a key role of cocoa flavanols in dietary interventions aimed at enhancing brain health.
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Factor Neurotrófico Derivado del Encéfalo , Cacao , Hipocampo , Memoria , Ratones Endogámicos C57BL , Neurogénesis , Animales , Factor Neurotrófico Derivado del Encéfalo/metabolismo , Factor Neurotrófico Derivado del Encéfalo/genética , Neurogénesis/efectos de los fármacos , Hipocampo/metabolismo , Hipocampo/efectos de los fármacos , Ratones , Masculino , Femenino , Memoria/efectos de los fármacos , Cacao/química , Plasticidad Neuronal/efectos de los fármacos , DietaRESUMEN
Postnatal hippocampal neurogenesis is essential for learning and memory. Hippocampal neural precursor cells (NPCs) can be induced to proliferate and differentiate into either glial cells or dentate granule cells. Notably, hippocampal neurogenesis decreases dramatically with age, partly due to a reduction in the NPC pool and a decrease in their proliferative activity. Alpha-melanocyte-stimulating hormone (α-MSH) improves learning, memory, neuronal survival and plasticity. Here, we used postnatally-isolated hippocampal NPCs from Wistar rat pups (male and female combined) to determine the role of the melanocortin analog [Nle4, D-Phe7]-α-MSH (NDP-MSH) in proliferation and fate acquisition of NPCs. Incubation of growth-factor deprived NPCs with 10 nM NDP-MSH for 6 days increased the proportion of Ki-67- and 5-bromo-2'-deoxyuridine (BrdU)-positive cells, compared to the control group, and these effects were blocked by the MC4R antagonist JKC-363. NDP-MSH also increased the proportion of glial fibrillar acidic protein (GFAP)/Ki-67, GFAP/sex-determining region Y-box2 (SOX2) and neuroepithelial stem cell protein (NESTIN)/Ki-67-double positive cells (type-1 and type-2 precursors). Finally, NDP-MSH induced peroxisome proliferator-activated receptor (PPAR)-γ protein expression, and co-incubation with the PPAR-γ inhibitor GW9662 prevented the effect of NDP-MSH on NPC proliferation and differentiation. Our results indicate that in vitro activation of MC4R in growth-factor-deprived postnatal hippocampal NPCs induces proliferation and promotes the relative expansion of the type-1 and type-2 NPC pool through a PPAR-γ-dependent mechanism. These results shed new light on the mechanisms underlying the beneficial effects of melanocortins in hippocampal plasticity and provide evidence linking the MC4R and PPAR-γ pathways in modulation of hippocampal NPC proliferation and differentiation.
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Diferenciación Celular , Proliferación Celular , Hipocampo , Células-Madre Neurales , Neurogénesis , Ratas Wistar , Receptor de Melanocortina Tipo 4 , alfa-MSH , Animales , Hipocampo/efectos de los fármacos , Hipocampo/metabolismo , Hipocampo/citología , Células-Madre Neurales/efectos de los fármacos , Células-Madre Neurales/metabolismo , Células-Madre Neurales/fisiología , Proliferación Celular/efectos de los fármacos , Proliferación Celular/fisiología , Receptor de Melanocortina Tipo 4/metabolismo , alfa-MSH/farmacología , alfa-MSH/análogos & derivados , Femenino , Diferenciación Celular/efectos de los fármacos , Diferenciación Celular/fisiología , Masculino , Neurogénesis/efectos de los fármacos , Neurogénesis/fisiología , Ratas , Células Cultivadas , Factores de Transcripción SOXB1/metabolismo , Animales Recién Nacidos , Proteína Ácida Fibrilar de la Glía/metabolismo , PPAR gamma/metabolismoRESUMEN
Critical-size bone defect repair presents multiple challenges, such as osteogenesis, vascularization, and neurogenesis. Current biomaterials for bone repair need more consideration for the above functions. Organic-inorganic composites combined with bioactive ions offer significant advantages in bone regeneration. In our work, we prepared an organic-inorganic composite material by blending polylactic acid (PLA) with 3-aminopropyltriethoxysilane (APTES)-modified magnesium silicate (A-M2S) and fabricated it by 3D printing. With the increase of A-M2S proportion, the hydrophilicity and mineralization ability showed an enhanced trend, and the compressive strength and elastic modulus were increased from 15.29 MPa and 94.61 MPa to 44.30 MPa and 435.77 MPa, respectively. Furthermore, A-M2S/PLA scaffolds not only exhibited good cytocompatibility of bone marrow mesenchymal stem cells (BMSCs), human umbilical vein endothelial cells (HUVECs), and Schwann cells (SCs), but also effectively promoted osteogenesis, angiogenesis, and neurogenesis in vitro. After implanting 10% A-M2S/PLA scaffolds in vivo, the scaffolds showed the most effective repair of cranium defects compared to the blank and control group (PLA). Additionally, they promoted the secretion of proteins related to bone regeneration and neurovascular formation. These results provided the basis for expanding the application of A-M2S and PLA in bone tissue engineering and presented a novel concept for neurovascularized bone repair.
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Regeneración Ósea , Células Endoteliales de la Vena Umbilical Humana , Silicatos de Magnesio , Células Madre Mesenquimatosas , Osteogénesis , Poliésteres , Impresión Tridimensional , Andamios del Tejido , Regeneración Ósea/efectos de los fármacos , Andamios del Tejido/química , Poliésteres/química , Humanos , Células Endoteliales de la Vena Umbilical Humana/efectos de los fármacos , Células Madre Mesenquimatosas/efectos de los fármacos , Células Madre Mesenquimatosas/citología , Osteogénesis/efectos de los fármacos , Animales , Silicatos de Magnesio/química , Ingeniería de Tejidos/métodos , Materiales Biocompatibles/química , Materiales Biocompatibles/farmacología , Células de Schwann/efectos de los fármacos , Células de Schwann/citología , Silanos/química , Silanos/farmacología , Neurogénesis/efectos de los fármacos , Propilaminas/química , Propilaminas/farmacología , Neovascularización Fisiológica/efectos de los fármacosRESUMEN
OBJECTIVE: To investigate the effects of luteolin on chronic unpredictable mild stress (CUMS)-induced depressive rats and corticosterone (CORT)-induced depressive primary hippocampal neurons, and to elucidate the mechanism behind the action. METHODS: The antidepressant mechanism of luteolin was studied by using CUMS rat model and primary hippocampal neurons in fetal rats. In vivo, novelty suppressed feeding, open-field and sucrose preference tests as well as Morris water maze were evaluated. The content of brain derived neurotrophic factor (BDNF), 5-hydroxytryptamine (5-HT), norepinephrine (NE), and dopamine (DA) in serum were detected by enzyme-linked immunosorbent assay. The mechanisms of luteolin were explored based on neurotrophin and hippocampal neurogenesis, and proliferation. Survival of the septo-temporal axis in hippocampus was assayed using the 5-bromo-2-deoxyuridine (BrdU), the expression of BDNF, neurotrophin-3 (NT-3), and nerve growth factor (NGF) in hippocampus dentate gyrus region were measured by Western-blotting. In vitro, BDNF, NT-3, tropomyosin receptor kinase B (TrkB), and phosphorylated cyclic adenosine monophosphate responsive element binding protein (p-CREB) were detected through the high content analysis (HCA) to investigate neurotrophin and apoptosis. RESULTS: Induction of CUMS in rats induced depressive symptoms, while luteolin significantly enhanced sucrose consumption, decreased feeding latency, increased locomotor activity, escape latency, distance of target quadrant and regulated the content of depressive-like biomarkers. Histology analysis revealed that luteolin increased the abundance of new born neurons that had been labeled with BrdU, BrdU + neuronal nuclear antigen, and BrdU + doublecortin in septo-temporal axis of S2 (mid-septal) and T3 (mid-temporal). Moreover, expression of BDNF, NT-3, and NGF increased significantly in the septo-temporal axis of S2 and T3. HCA showed increased expression of BDNF, NT-3, TrkB and p-CREB in primary hippocampal neurons. CONCLUSION: The results provided direct evidence that luteolin has an antidepressant effect and could effectively promote the regeneration of the septotemporal axis nerve and hippocampal neuronutrition, which suggested that the antidepressant effect of luteolin may be related to hippocampal neurogenesis.
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Factor Neurotrófico Derivado del Encéfalo , Hipocampo , Luteolina , Neurogénesis , Neuronas , Ratas Sprague-Dawley , Animales , Luteolina/farmacología , Ratas , Hipocampo/efectos de los fármacos , Hipocampo/metabolismo , Neurogénesis/efectos de los fármacos , Masculino , Factor Neurotrófico Derivado del Encéfalo/metabolismo , Factor Neurotrófico Derivado del Encéfalo/genética , Neuronas/efectos de los fármacos , Neuronas/metabolismo , Humanos , Estrés Psicológico/fisiopatología , Estrés Psicológico/tratamiento farmacológico , Femenino , Depresión/tratamiento farmacológico , Depresión/metabolismo , Depresión/fisiopatología , Antidepresivos/farmacología , Neurotrofina 3/metabolismo , Neurotrofina 3/genéticaRESUMEN
Hypertension-induced brain renin-angiotensin system (RAS) activation and neuroinflammation are hallmark neuropathological features of neurodegenerative diseases. Previous studies from our lab have shown that inhibition of ACE/Ang II/AT1R axis (by AT1R blockers or ACE inhibitors) reduced neuroinflammation and accompanied neurodegeneration via up-regulating adult hippocampal neurogenesis. Apart from this conventional axis, another axis of RAS also exists i.e., ACE2/Ang (1-7)/MasR axis, reported as an anti-hypertensive and anti-inflammatory. However, the role of this axis has not been explored in hypertension-induced glial activation and hippocampal neurogenesis in rat models of hypertension. Hence, in the present study, we examined the effect of ACE2 activator, Diminazene aceturate (DIZE) at 2 different doses of 10 mg/kg (non-antihypertensive) and 15 mg/kg (antihypertensive dose) in renovascular hypertensive rats to explore whether their effect on glial activation, neuroinflammation, and neurogenesis is either influenced by blood-pressure. The results of our study revealed that hypertension induced significant glial activation (astrocyte and microglial), neuroinflammation, and impaired hippocampal neurogenesis. However, ACE2 activation by DIZE, even at the low dose prevented these hypertension-induced changes in the brain. Mechanistically, ACE2 activation inhibited Ang II levels, TRAF6-NFκB mediated inflammatory signaling, NOX4-mediated ROS generation, and mitochondrial dysfunction by upregulating ACE2/Ang (1-7)/MasR signaling. Moreover, DIZE-induced activation of the ACE2/Ang (1-7)/MasR axis upregulated Wnt/ß-catenin signaling, promoting hippocampal neurogenesis during the hypertensive state. Therefore, our study demonstrates that ACE2 activation can effectively prevent glial activation and enhance hippocampal neurogenesis in hypertensive conditions, regardless of its blood pressure-lowering effects.
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Enzima Convertidora de Angiotensina 2 , Hipocampo , Hipertensión , Neurogénesis , Vía de Señalización Wnt , Animales , Enzima Convertidora de Angiotensina 2/metabolismo , Neurogénesis/efectos de los fármacos , Hipocampo/metabolismo , Hipertensión/metabolismo , Ratas , Masculino , Vía de Señalización Wnt/efectos de los fármacos , Vía de Señalización Wnt/fisiología , Diminazeno/análogos & derivados , Diminazeno/farmacología , Peptidil-Dipeptidasa A/metabolismo , Ratas Sprague-DawleyRESUMEN
Parkinson's disease is a progressive neurodegenerative disease that affects the motor and non-motor circuits of the brain. Currently, there are no promising therapeutic measures for Parkinson's disease, and most strategies designed to alleviate the Parkinson's disease are palliative. The dearth of therapeutic interventions in Parkinson's disease has driven attention in the search for targets that may augment dopamine secretion, promote differentiation towards dopaminergic neuronal lineage, or aid in neuroprotection from neuronal stress and inflammation, and prevent Parkinson's disease associated motor impairment and behavioural chaos. The study first reports that Rev-erbα plays an important role in regulating the differentiation of undifferentiated neuronal cells towards dopaminergic neurons through abating Sox2 expression in human SH-SY5Y cells. Rev-erbα directly binds to the human Sox2 promoter region and represses their expression to promote differentiation towards dopaminergic neurons. We have reported a novel mechanism of Rev-erbα which effectively abrogates 1-methyl-4-phenylpyridinium induced cytotoxicity, inflammation, and oxidative stress, exerted a beneficial effect on transmembrane potential, and suppressed apoptosis in the neuronal in vitro model of Parkinson's disease. Rev-erbα ligand SR9011 was observed to ease the disease severity in 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine induced mouse model of Parkinson's disease. Rev-erbα alleviates the locomotor behavioural impairment, prevents cognitive decline and promotes motor coordination in mice. Administration of Rev-erbα ligand also helps in replenishing the dopaminergic neurons and abrogating the neurotoxin mediated toxicity in an in vitro and in vivo Parkinson's disease model. We conclude that Rev-erbα emerges as a moonlighting nuclear receptor that could be targeted in the treatment and alleviation of Parkinson disease.
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Neuronas Dopaminérgicas , Neurogénesis , Miembro 1 del Grupo D de la Subfamilia 1 de Receptores Nucleares , Factores de Transcripción SOXB1 , Neuronas Dopaminérgicas/metabolismo , Neuronas Dopaminérgicas/patología , Neuronas Dopaminérgicas/efectos de los fármacos , Animales , Miembro 1 del Grupo D de la Subfamilia 1 de Receptores Nucleares/metabolismo , Miembro 1 del Grupo D de la Subfamilia 1 de Receptores Nucleares/genética , Humanos , Ratones , Neurogénesis/efectos de los fármacos , Factores de Transcripción SOXB1/metabolismo , Factores de Transcripción SOXB1/genética , Enfermedades Neuroinflamatorias/metabolismo , Enfermedades Neuroinflamatorias/patología , Diferenciación Celular , Enfermedad de Parkinson/metabolismo , Enfermedad de Parkinson/patología , Enfermedad de Parkinson/genética , Estrés Oxidativo/efectos de los fármacos , ApoptosisRESUMEN
Schizophrenia impacts about 1 % of the global population, with clozapine (CLZ) being a critical treatment for refractory cases despite its limitations in effectiveness and adverse effects. Therefore, the search for more effective treatments remains urgent. Light treatment (LT) recognized for enhancing cognition and mood, presents a promising complementary approach. This study investigated the effects of CLZ and LT on cognitive impairments in a sub-chronic MK-801 induced schizophrenia mouse model. Results showed that both CLZ and CLZ + LT treatment elevate cognitive performance of sub-chronic MK-801 treated mice in serial behavioral tests over two months. Histological analysis revealed increased dendritic spine density and branching, and synaptic repair in the hippocampus with CLZ and CLZ + LT interventions. Furthermore, both treatments increased brain-derived neurotrophic factor (BDNF) expression in the hippocampus, likely contributing to cognitive amelioration in MK-801 treated mice. Additionally, BrdU labeling revealed that CLZ + LT further enhances neurogenesis in the dentate gyrus (DG) and lateral ventricle (LV) of sub-chronic MK-801 treated mice. These findings may have implications for the development of noninvasive and adjunctive treatment strategies aimed at alleviating cognitive impairments and improving functional outcomes in individuals with schizophrenia.