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Glioblastoma multiforme (GBM) exhibits genetic alterations that induce the deregulation of oncogenic pathways, thus promoting metabolic adaptation. The modulation of metabolic enzyme activities is necessary to generate nucleotides, amino acids, and fatty acids, which provide energy and metabolic intermediates essential for fulfilling the biosynthetic needs of glioma cells. Moreover, the TCA cycle produces intermediates that play important roles in the metabolism of glucose, fatty acids, or non-essential amino acids, and act as signaling molecules associated with the activation of oncogenic pathways, transcriptional changes, and epigenetic modifications. In this review, we aim to explore how dysregulated metabolic enzymes from the TCA cycle and oxidative phosphorylation, along with their metabolites, modulate both catabolic and anabolic metabolic pathways, as well as pro-oncogenic signaling pathways, transcriptional changes, and epigenetic modifications in GBM cells, contributing to the formation, survival, growth, and invasion of glioma cells. Additionally, we discuss promising therapeutic strategies targeting key players in metabolic regulation. Therefore, understanding metabolic reprogramming is necessary to fully comprehend the biology of malignant gliomas and significantly improve patient survival.
Assuntos
Neoplasias Encefálicas , Ciclo do Ácido Cítrico , Glioblastoma , Fosforilação Oxidativa , Humanos , Glioblastoma/metabolismo , Neoplasias Encefálicas/metabolismo , AnimaisRESUMO
Parkinson's disease (PD) is a complex disorder, primarily of idiopathic origin, with environmental stressors like rotenone and manganese linked to its development. This study explores their potential interaction and resulting neurotoxicity, aiming to understand how environmental factors contribute to PD. In an eight-day experiment, male Wistar rats weighing 280-300 g were subjected to rotenone, manganese, or a combination of both. Various parameters were assessed, including body weight, behavior, serum markers, tissue damage, protein levels (tyrosine hydroxylase, Dopamine- and cAMP-regulated neuronal phosphoprotein -DARPP-32-, and α-synuclein), and mitochondrial function. Manganese heightened rotenone's impact on reducing food intake without causing kidney or liver dysfunction. However, the combined exposure intensified neurotoxicity, which was evident in augmented broken nuclei and decreased tyrosine hydroxylase and DARPP-32 levels in the striatum. While overall mitochondrial function was preserved, co-administration reduced complex IV activity in the midbrain and liver. In conclusion, our findings revealed a parallel toxic effect induced by rotenone and manganese. Notably, while these substances do not target the same dopaminergic regions, a notable escalation in toxicity is evident in the striatum, the brain region where their toxic effects converge. This study highlights the need for further exploration regarding the interaction of environmental factors and their possible impact on the etiology of PD.
Assuntos
Manganês , Ratos Wistar , Rotenona , Tirosina 3-Mono-Oxigenase , Animais , Rotenona/toxicidade , Masculino , Manganês/toxicidade , Ratos , Tirosina 3-Mono-Oxigenase/metabolismo , Encéfalo/efeitos dos fármacos , Encéfalo/metabolismo , Fosfoproteína 32 Regulada por cAMP e Dopamina/metabolismo , Mitocôndrias/efeitos dos fármacos , Mitocôndrias/metabolismo , alfa-Sinucleína/metabolismo , Síndromes Neurotóxicas/metabolismo , Corpo Estriado/metabolismo , Corpo Estriado/efeitos dos fármacosRESUMO
The metabolic reprogramming that promotes tumorigenesis in glioblastoma is induced by dynamic alterations in the hypoxic tumor microenvironment, as well as in transcriptional and signaling networks, which result in changes in global genetic expression. The signaling pathways PI3K/AKT/mTOR and RAS/RAF/MEK/ERK stimulate cell metabolism, either directly or indirectly, by modulating the transcriptional factors p53, HIF1, and c-Myc. The overexpression of HIF1 and c-Myc, master regulators of cellular metabolism, is a key contributor to the synthesis of bioenergetic molecules that mediate glioma cell transformation, proliferation, survival, migration, and invasion by modifying the transcription levels of key gene groups involved in metabolism. Meanwhile, the tumor-suppressing protein p53, which negatively regulates HIF1 and c-Myc, is often lost in glioblastoma. Alterations in this triad of transcriptional factors induce a metabolic shift in glioma cells that allows them to adapt and survive changes such as mutations, hypoxia, acidosis, the presence of reactive oxygen species, and nutrient deprivation, by modulating the activity and expression of signaling molecules, enzymes, metabolites, transporters, and regulators involved in glycolysis and glutamine metabolism, the pentose phosphate cycle, the tricarboxylic acid cycle, and oxidative phosphorylation, as well as the synthesis and degradation of fatty acids and nucleic acids. This review summarizes our current knowledge on the role of HIF1, c-Myc, and p53 in the genic regulatory network for metabolism in glioma cells, as well as potential therapeutic inhibitors of these factors.
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Glioma cells exhibit genetic and metabolic alterations that affect the deregulation of several cellular signal transduction pathways, including those related to glucose metabolism. Moreover, oncogenic signaling pathways induce the expression of metabolic genes, increasing the metabolic enzyme activities and thus the critical biosynthetic pathways to generate nucleotides, amino acids, and fatty acids, which provide energy and metabolic intermediates that are essential to accomplish the biosynthetic needs of glioma cells. In this review, we aim to explore how dysregulated metabolic enzymes and their metabolites from primary metabolism pathways in glioblastoma (GBM) such as glycolysis and glutaminolysis modulate anabolic and catabolic metabolic pathways as well as pro-oncogenic signaling and contribute to the formation, survival, growth, and malignancy of glioma cells. Also, we discuss promising therapeutic strategies by targeting the key players in metabolic regulation. Therefore, the knowledge of metabolic reprogramming is necessary to fully understand the biology of malignant gliomas to improve patient survival significantly.
Assuntos
Glioblastoma , Glioma , Humanos , Glioblastoma/genética , Glioblastoma/metabolismo , Glutamina/metabolismo , Reprogramação Metabólica , Glicólise/fisiologia , Glioma/patologia , Transdução de Sinais , Apoptose , Proliferação de Células/fisiologiaRESUMO
Parkinson's disease (PD) is usually diagnosed through motor symptoms that make the patient incapable of carrying out daily activities; however, numerous non-motor symptoms include olfactory disturbances, constipation, depression, excessive daytime sleepiness, and rapid eye movement at sleep; they begin years before motor symptoms. Therefore, several experimental models have been studied to reproduce several PD functional and neurochemical characteristics; however, no model mimics all the PD motor and non-motor symptoms to date, which becomes a limitation for PD study. It has become increasingly relevant to find ways to study the disease from its slowly progressive nature. The experimental models most frequently used to reproduce PD are based on administering toxic chemical compounds, which aim to imitate dopamine deficiency. The most used toxic compounds to model PD have been 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) and 6-hydroxydopamine (6-OHDA), which inhibit the complex I of the electron transport chain but have some limitations. Another toxic compound that has drawn attention recently is rotenone, the classical inhibitor of mitochondrial complex I. Rotenone triggers the progressive death of dopaminergic neurons and α-synuclein inclusions formation in rats; also, rotenone induces microtubule destabilization. This review presents information about the experimental model of PD induced by rotenone, emphasizing its molecular characteristics beyond the inhibition of mitochondrial complex I.
Assuntos
Doença de Parkinson , Ratos , Animais , Rotenona , 1-Metil-4-Fenil-1,2,3,6-Tetra-Hidropiridina , Dopamina/fisiologia , Oxidopamina , Complexo I de Transporte de Elétrons , Modelos Animais de DoençasRESUMO
Cobalt protoporphyrin (CoPP) is a potent heme oxygenase-1 inductor that produces temporary hypophagia and chronic weight loss. A complete description of this effect and the underlying mechanisms are unknown. In this work, we challenged the ability of CoPP to produce changes in rat behavior and cellular alterations in the Nucleus Accumbens that would explain those effects. We subcutaneously administered 25 µmol/kgbody weight CoPP in female rats and determined body weight, food intake, hyperactivity, and anxiety-like behavior, as well as the number of neurons and glial cells in the Nucleus Accumbens. CoPP significantly reduced food intake, water consumption, and body weight. Behavioral tests showed that anxiety-like behaviors and locomotor activity were not modified five days after the administration of CoPP. We also found a reduced number of neurons in the Nucleus Accumbens Shell. The above results could be relevant to diseases like anorexia, so it is necessary to deepen the study about the molecular mechanisms involved in reducing the food intake and weight loss elicited by CoPP.
Assuntos
Peso Corporal/efeitos dos fármacos , Ingestão de Alimentos/efeitos dos fármacos , Neurônios/efeitos dos fármacos , Núcleo Accumbens/efeitos dos fármacos , Protoporfirinas/farmacologia , Animais , Feminino , Ratos , Ratos WistarRESUMO
Glioblastoma multiforme is the most malignant and aggressive type of brain tumor, with a mean life expectancy of less than 15 months. This is due in part to the high resistance to apoptosis and moderate resistant to autophagic cell death in glioblastoma cells, and to the poor therapeutic response to conventional therapies. Autophagic cell death represents an alternative mechanism to overcome the resistance of glioblastoma to pro-apoptosis-related therapies. Nevertheless, apoptosis induction plays a major conceptual role in several experimental studies to develop novel therapies against brain tumors. In this review, we outline the different components of the apoptotic and autophagic pathways and explore the mechanisms of resistance to these cell death pathways in glioblastoma cells. Finally, we discuss drugs with clinical and preclinical use that interfere with the mechanisms of survival, proliferation, angiogenesis, migration, invasion, and cell death of malignant cells, favoring the induction of apoptosis and autophagy, or the inhibition of the latter leading to cell death, as well as their therapeutic potential in glioma, and examine new perspectives in this promising research field.
Assuntos
Antineoplásicos/farmacologia , Apoptose/efeitos dos fármacos , Autofagia/efeitos dos fármacos , Glioblastoma/metabolismo , Transdução de Sinais/efeitos dos fármacos , Animais , Biomarcadores , Transformação Celular Neoplásica/genética , Transformação Celular Neoplásica/metabolismo , Ensaios Clínicos como Assunto , Descoberta de Drogas , Regulação Neoplásica da Expressão Gênica , Glioblastoma/tratamento farmacológico , Glioblastoma/genética , Glioblastoma/patologia , Glioma/tratamento farmacológico , Glioma/genética , Glioma/metabolismo , Glioma/patologia , Humanos , Terapia de Alvo Molecular , Resultado do TratamentoRESUMO
Epidemiological studies suggest that including fruits, vegetables, and whole grains in regular dietary intake might prevent and reverse cellular carcinogenesis, reducing the incidence of primary tumours. Bioactive components present in food can simultaneously modulate more than one carcinogenic process, including cancer metabolism, hormonal balance, transcriptional activity, cell-cycle control, apoptosis, inflammation, angiogenesis and metastasis. Some studies have shown an inverse correlation between a diet rich in fruits, vegetables, and carotenoids and a low incidence of different types of cancer. Lycopene, the predominant carotenoid found in tomatoes, exhibits a high antioxidant capacity and has been shown to prevent cancer, as evidenced by clinical trials and studies in cell culture and animal models. In vitro studies have shown that lycopene treatment can selectively arrest cell growth and induce apoptosis in cancer cells without affecting normal cells. In vivo studies have revealed that lycopene treatment inhibits tumour growth in the liver, lung, prostate, breast, and colon. Clinical studies have shown that lycopene protects against prostate cancer. One of the main challenges in cancer prevention is the integration of new molecular findings into clinical practice. Thus, the identification of molecular biomarkers associated with lycopene levels is essential for improving our understanding of the mechanisms underlying its antineoplastic activity.
RESUMO
Ginkgo biloba extracts have long been used in Chinese traditional medicine for hundreds of years. The most significant extract obtained from Ginkgo biloba leaves has been EGb 761, a widely used phytopharmaceutical product in Europe. EGb 761 is a well-defined mixture of active compounds, which contains two main active substances: flavonoid glycosides (24-26%) and terpene lactones (6-8%). These compounds have shown antiapoptotic effects through the protection of mitochondrial membrane integrity, inhibition of mitochondrial cytochrome c release, enhancement of antiapoptotic protein transcription, and reduction of caspase transcription and DNA fragmentation. Other effects include the reduction of oxidative stress (which has been related to the occurrence of vascular, degenerative, and proliferative diseases), coupled to strong induction of phase II-detoxifying and cellular defense enzymes by Nrf2/ARE activation, in addition to the modulation of transcription factors, such as CREB, HIF-1 α , NF- κ B, AP-1, and p53, involved in the apoptosis process. This work reviews experimental results about the antiapoptotic effects induced by the standardized extract of Ginkgo biloba leaves (EGb 761).
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Ginkgo Biloba extract 761 (EGb 761) is a patented and well-defined mixture of active compounds extracted from Ginkgo biloba leaves. This extract contains two main groups of active compounds, flavonoids (24%) and terpenoids (6%). EGb 761 is used clinically to treat dementia and vaso-occlusive and cochleovestibular disorders. This extract has neuroprotective effects, exerted probably by means of its antioxidant function. Parkinson's disease (PD) is a neurodegenerative disorder that affects 2% of the population older than 60 y. It produces a progressive loss of dopaminergic neurons and depletion of dopamine (DA), leading to movement impairment. The production of reactive oxygen species, which act as mediators of oxidative damage, is linked to PD. This disease is routinely treated with the DA precursor, L-3,4-dihydroxyphenylalanine. However, this produces severe side effects, and its neurotoxic properties can be due to a free radical production. Thus, administration of antioxidant drugs might be used to prevent neuronal death produced by oxidative mechanisms. The use of synthetic antioxidants has decreased because of their suspected activity as carcinogenic promoters. We describe the studies related to the antioxidant effect of EGb 761 in an animal model of PD. It has been shown that EGb761 can provide a neuroprotective/neurorecovery effect against the damage to midbrain DA neurons in an animal model of PD. EGb 761 also has been found to lessen the impairment of locomotion, correlating with an increase of DA and other morphologic and biochemical parameters related to its antioxidant effect in an animal model of PD. These studies suggest it as an alternative in the future treatment of PD.
Assuntos
Antiparkinsonianos/uso terapêutico , Suplementos Nutricionais , Modelos Animais de Doenças , Doença de Parkinson/prevenção & controle , Fitoterapia , Extratos Vegetais/uso terapêutico , Animais , Anti-Inflamatórios não Esteroides/efeitos adversos , Anti-Inflamatórios não Esteroides/química , Anti-Inflamatórios não Esteroides/uso terapêutico , Antioxidantes/efeitos adversos , Antioxidantes/química , Antioxidantes/uso terapêutico , Antiparkinsonianos/efeitos adversos , Antiparkinsonianos/química , Apoptose , Suplementos Nutricionais/efeitos adversos , Suplementos Nutricionais/análise , Neurônios Dopaminérgicos/metabolismo , Ginkgo biloba , Humanos , Mesencéfalo/metabolismo , Fármacos Neuroprotetores/efeitos adversos , Fármacos Neuroprotetores/química , Fármacos Neuroprotetores/uso terapêutico , Estresse Oxidativo , Doença de Parkinson/dietoterapia , Doença de Parkinson/metabolismo , Extratos Vegetais/efeitos adversos , Extratos Vegetais/químicaRESUMO
EGb761 is a well-defined mixture of active compounds extracted from Ginkgo biloba leaves. This extract is used clinically due to its neuroprotective effects, exerted probably via its potent antioxidant or free radical scavenger action. Previous studies suggest that oxidative stress, via free radical production, may play an important role in depression and animal models for depression-like behavior. Preclinical studies have suggested that antioxidants may have antidepressants properties. The aim of this study was to investigate the antidepressant-like of EGb761 due to its antioxidant role against oxidative stress induced in the forced swimming test, the most widely used preclinical model for assessing antidepressant-like behavior. Male BALB/c mice were pretreated with EGb761 (10mg/kg, ip) daily for 17 days followed by the forced swimming test and spontaneous locomotor activity. Animals were sacrificed to evaluate lipid peroxidation, different antioxidant enzyme activities, serotonin and dopamine content in midbrain, hippocampus and prefrontal cortex. EGb761 significantly decreased the immobility time (39%) in the forced swimming test. This antidepressant-like effect of EGb761 was associated with a reduction in lipid peroxidation and superoxide radical production (indicated by a downregulation of Mn-superoxide dismutase activity), both of which are indicators of oxidative stress. The protective effect of EGb761 is not related to excitatory or inhibitory effects in locomotor activity, and was also associated with the modulation of serotonergic and dopaminergic neurotransmission. It is suggested that EGb761 produces an antidepressant-like effect, and that an antioxidant effect against oxidative stress may be partly responsible for its observed neuroprotective effects.
Assuntos
Antidepressivos/farmacologia , Estresse Oxidativo/efeitos dos fármacos , Extratos Vegetais/farmacologia , Natação/psicologia , Animais , Western Blotting , Dopamina/metabolismo , Ginkgo biloba , Glutationa Peroxidase/metabolismo , Glutationa Redutase/metabolismo , Hipocampo/efeitos dos fármacos , Hipocampo/metabolismo , Peroxidação de Lipídeos/efeitos dos fármacos , Masculino , Mesencéfalo/efeitos dos fármacos , Mesencéfalo/metabolismo , Camundongos , Camundongos Endogâmicos BALB C , Atividade Motora/efeitos dos fármacos , Córtex Pré-Frontal/efeitos dos fármacos , Córtex Pré-Frontal/metabolismo , Serotonina/metabolismo , Superóxido Dismutase/metabolismo , Transmissão Sináptica/efeitos dos fármacosRESUMO
S-Allylcysteine (SAC), the most abundant organosulfur compound in aged garlic extract, has multifunctional activity via different mechanisms and neuroprotective effects that are exerted probably via its antioxidant or free radical scavenger action. The 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine-treated mouse has been the most widely used model for assessing neuroprotective agents for Parkinson's disease. 1-Methyl-4-phenylpyridinium (MPP(+)) is the stable metabolite of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine, and it causes nigrostriatal dopaminergic neurotoxicity. Previous studies suggest that oxidative stress, via free radical production, is involved in MPP(+)-induced neurotoxicity. Here, we report on the neuroprotective effect of SAC against oxidative stress induced by MPP(+) in the striatum of C57BL/6J mice. Mice were pretreated with SAC (125 mg/kg ip) daily for 17 days, followed by administration of MPP(+) (0.72 mg/kg icv), and were sacrificed 24 h later to evaluate lipid peroxidation, different antioxidant enzyme activities, spontaneous locomotor activity and dopamine (DA) content. MPP(+) administration resulted in a significant decrease in DA levels in the striatum. Mice receiving SAC (125 mg/kg ip) had significantly attenuated MPP(+)-induced loss of striatal DA levels (32%). The neuroprotective effect of SAC against MPP(+) neurotoxicity was associated with blocked (100% of protection) of lipid peroxidation and reduction of superoxide radical production - indicated by an up-regulation of Cu-Zn-superoxide dismutase activity - both of which are indices of oxidative stress. Behavioral analyses showed that SAC improved MPP(+)-induced impairment of locomotion (35%). These findings suggest that in mice, SAC attenuates MPP(+)-induced neurotoxicity in the striatum and that an antioxidant effect against oxidative stress may be partly responsible for its observed neuroprotective effects.
Assuntos
Cisteína/análogos & derivados , Alho/química , Fármacos Neuroprotetores/uso terapêutico , Estresse Oxidativo , Transtornos Parkinsonianos/prevenção & controle , 1-Metil-4-fenilpiridínio , Animais , Corpo Estriado/efeitos dos fármacos , Corpo Estriado/metabolismo , Cisteína/farmacologia , Cisteína/uso terapêutico , Glutationa Redutase/metabolismo , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Fármacos Neuroprotetores/farmacologia , Transtornos Parkinsonianos/induzido quimicamente , Transtornos Parkinsonianos/metabolismo , Superóxido Dismutase/metabolismoRESUMO
OBJECTIVE: EGb761 is a well-defined mixture of active compounds extracted from Ginkgo biloba leaves with neuroprotective effects in an animal model of Parkinson's disease induced by 1-methyl-4-phenylpyridinium (MPP(+)). Because copper has been implicated in Parkinson's disease, we investigated whether the protective effect of EGb761 in MPP(+) neurotoxicity is related to the regulation of copper in the brain. METHODS: C-57BL/6 mice were pretreated with EGb761 (10 mg/kg) daily for 17 d followed by administration of MPP(+) (0.72 mg/kg); the mice were sacrificed 24 h later. The copper content of the striatum, midbrain, hippocampus, frontal cortex, and cerebellum was analyzed by graphite furnace atomic absorption spectrophotometry. Copper content is expressed as mug of copper per gram of wet tissue. RESULTS: Copper content was reduced in the corpus striatum (45%; P < 0.05), and increased in the midbrain (65%; P < 0.05) and hippocampus (116%; P < 0.001) after MPP(+) administration. EGb761 pretreatment of the MPP(+) group prevented changes in the copper content of the striatum, midbrain, and hippocampus. No significant changes were found in the copper content of the cerebellum and frontal cortex in all treatment groups. CONCLUSION: We showed that the protective effect of EGb761 against MPP(+) neurotoxicity may be due in part to the regulation of copper homeostasis in the brain.
Assuntos
Encéfalo/metabolismo , Cobre/metabolismo , Ginkgo biloba , Doença de Parkinson/metabolismo , Fitoterapia , Extratos Vegetais/farmacologia , 1-Metil-4-fenilpiridínio , Animais , Modelos Animais de Doenças , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Doença de Parkinson/tratamento farmacológico , Extratos Vegetais/uso terapêuticoRESUMO
1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) causes nigrostriatal dopaminergic neurotoxicity and behavioral impairment in rodents. Previous studies suggest that oxidative stress, via free radical production, is involved in MPTP-induced neurotoxicity. The MPTP-treated mouse has been the most widely used model for assessing neuroprotective agents for Parkinson's disease. It has been reported previously that EGb761 prevents dopaminergic neurotoxicity of MPTP. This compound is multifunctional via different mechanisms. Here, we report the neuroprotective effect of EGb761 against oxidative stress induced by MPTP in C57BL/6J mice. EGb761 is a patented and well-defined mixture of active compounds extracted from Ginkgo biloba leaves, with neuroprotective effects, exerted probably via its antioxidant or free radical scavenger action. MPTP administration resulted in a significant decrease in striatal dopamine levels and tyrosine hydroxylase immunostaining in the striatum and substantia nigra pars compacta. Mice receiving EGb761 had significantly attenuated MPTP-induced loss of striatal dopamine levels and tyrosine hydroxylase immunostaining in the striatum and substantia nigra pars compacta. The neuroprotective effect of EGb761 against MPTP neurotoxicity is associated with blockade of lipid peroxidation and reduction of superoxide radical production (indicated by a down-regulation of Mn-superoxide dismutase activity), both of which are indices of oxidative stress. Behavioral analyses showed that EGb761 improved MPTP-induced impairment of locomotion in a manner that correlated with enhancement of striatal dopamine levels. These findings suggest that, in mice, EGb761 attenuates MPTP-induced neurodegeneration of the nigrostriatal pathway and that an inhibitory effect against oxidative stress may be partly responsible for its observed neuroprotective effects.
Assuntos
Corpo Estriado/efeitos dos fármacos , Corpo Estriado/metabolismo , Dopamina/metabolismo , Intoxicação por MPTP/prevenção & controle , Fármacos Neuroprotetores/farmacologia , Estresse Oxidativo , Extratos Vegetais/farmacologia , Substância Negra/efeitos dos fármacos , Substância Negra/metabolismo , Animais , Antioxidantes/metabolismo , Corpo Estriado/patologia , Ginkgo biloba/química , Humanos , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Atividade Motora/efeitos dos fármacos , Atividade Motora/fisiologia , Neurônios/citologia , Neurônios/metabolismo , Extratos Vegetais/química , Substância Negra/patologia , Tirosina 3-Mono-Oxigenase/metabolismoRESUMO
En el presente estudio se analizó el efecto a ratas gestantes sometidos a estrés por inmovilización. Sobre las neuronas piramidales de la capa V motora certica de la progenie, se usaron ratas hembras de la cepa Wistar que se distribuyeron al azar en dos grupos: control y experimental (n=5). Las ratas del grupo experimental fueron sometidos a estrés por inmovilización durante 2 a 6 horas diarias a lo largo de toda la gestación; las ratas grupo control se mantuvieron en condiciones normales de bioterio. Las crías de cada grupo fueron sacrificadas a los 14 y 21 días de edad. Para extraer su cerebro y obtener bloques de corteza motora que se procesaron con la técnica de Golgi Rápido. Se cuantifico el número de espinas dendríticas en segmentos de 50 micras, de una sección de 250 m de la dendrita axonal de neuronas piramidales. En el grupo experimental de 14 días, hubo reducción significativa en el número de espinas dendríticas en los segmentos de 50 a 100 y de 100 a 150 micras respecto al grupo control. Estos hallazgos sugieren que las deficiencias en la capacidad de aprendizaje, comportamiento adaptativo y de alteraciones de la actividad locomotora, reportadas en animales descendientes de madres sometidas a estrés durante la gestación pueden ser resultado de la reducción en la complejidad neuronal.