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1.
Ecotoxicol Environ Saf ; 205: 111344, 2020 Dec 01.
Artigo em Inglês | MEDLINE | ID: mdl-32977283

RESUMO

Rotenone is an insecticide that generates oxidative stress in the CNS and induces locomotor dysfunction and neurodegeneration in rodents. Biochanin A [BioA] is an isoflavone with antioxidant and anti-inflammatory actions. The antioxidant and the modulatory action of BioA on PI3K/Akt/mTOR signaling and autophagy were tested in rotenone-Parkinsonian mice. Mice were allocated into; Group I: oil control group, Group II: rotenone group [1-mg/kg/48h, subcutaneously], group III: rotenone and BioA [10-mg/kg]. Rotenone injection resulted in locomotor disturbances in mice, degeneration in dopaminergic neurons [tyrosine hydroxylase-immunoreactive cells], low striatal dopamine, increased malondialdehyde and decreased level of glutathione. Neuroinflammation was evidenced by upregulation of astrocytes [glia fibrillary acidic protein, GFAP] and elevated levels of cytokines. The phosphorylation of PI3K/Akt/mTOR and the autophagy-related protein, beclin-1, were decreased significantly as indicated by Western blot analysis. BioA treatment enhanced locomotor activity and afforded nigral neuroprotection. The mechanism by which BioA produced this effect includes increased antioxidant defenses, lessened proinflammatory cytokines, increased phosphorylation of PI3K/Akt/mTOR proteins and upregulated beclin-1. Importantly, BioA suppressed the striatal astrocyte marker [GFAP]. Overall, the currents study highlighted that BioA activates PI3K/Akt/mTOR signaling and enhances beclin-1 leading to neuroprotection for nigral dopaminergic neurons.


Assuntos
Genisteína/farmacologia , Inseticidas/toxicidade , Fármacos Neuroprotetores/farmacologia , Rotenona/toxicidade , Animais , Autofagia/efeitos dos fármacos , Proteína Beclina-1/metabolismo , Citocinas/metabolismo , Neurônios Dopaminérgicos/efeitos dos fármacos , Glutationa/metabolismo , Masculino , Camundongos , Síndromes Neurotóxicas/metabolismo , Estresse Oxidativo/efeitos dos fármacos , Fosfatidilinositol 3-Quinases/metabolismo , Proteínas Proto-Oncogênicas c-akt/metabolismo , Transdução de Sinais/efeitos dos fármacos , Serina-Treonina Quinases TOR/metabolismo
2.
APMIS ; 128(11): 583-592, 2020 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-32865844

RESUMO

Multiple sclerosis (MS) is an immune-mediated inflammatory disease which affects the central nervous system (CNS). In the present study, the in vivo effects of ATRA, calcitriol, and their combinations on the expression of murine CD4+ T cell cytokines and their specific transcription factors in experimental autoimmune encephalomyelitis (EAE)-induced mice were explored. Thirty-two EAE induced inbred C57BL/6 female mice with an age ranged from 8 to 10 weeks were divided into four categories in a random manner. The first, second, and third groups received ATRA, calcitriol, ATRA+ calcitriol, respectively, and the fourth group received vehicle. The treatment started on the day prior to immunization and through the IP injections every other days for 21 days. The dosages of administration for calcitriol, ATRA, and calcitriol+ ATRA were 100 ng, 250 µg, and 50ng + 125 µg, respectively per mouse. An equal volume of excipient was administered for the vehicle group. T-bet, IFN-γ, GATA-3, and IL-4 genes expression were assessed in the splenocytes of EAE -induced mice. The expression of T-bet and IFN-γ genes in the splenocytes of ATRA, calcitriol and combination- treated mice were significantly reduced compared to vehicle group (p < 0.05). A significant decrease in T-bet expression was observed in the combination-treated group compared to the ATRA-treated group (p < 0.05). The expression of GATA3 and IL-4 genes was significantly increased in the ATRA-, calcitriol-, and combination-treated mice when compared with the control group (p < 0.05). Furthermore, the effect of calcitriol alone and in combination with ATRA was more considerable than that of ATRA alone. The nutraceutical approaches may be promising in the prevention and/or treatment of MS.


Assuntos
Calcitriol/farmacologia , Encefalomielite Autoimune Experimental/tratamento farmacológico , Regulação da Expressão Gênica/efeitos dos fármacos , Fatores Imunológicos/farmacologia , Fármacos Neuroprotetores/farmacologia , Tretinoína/farmacologia , Animais , Linfócitos T CD4-Positivos/efeitos dos fármacos , Linfócitos T CD4-Positivos/imunologia , Linfócitos T CD4-Positivos/patologia , Esquema de Medicação , Quimioterapia Combinada , Encefalomielite Autoimune Experimental/induzido quimicamente , Encefalomielite Autoimune Experimental/imunologia , Encefalomielite Autoimune Experimental/patologia , Feminino , Fator de Transcrição GATA3/genética , Fator de Transcrição GATA3/imunologia , Interferon gama/genética , Interferon gama/imunologia , Interleucina-4/genética , Interleucina-4/imunologia , Camundongos , Camundongos Endogâmicos C57BL , Glicoproteína Mielina-Oligodendrócito/administração & dosagem , Transdução de Sinais , Medula Espinal/efeitos dos fármacos , Medula Espinal/imunologia , Medula Espinal/patologia , Proteínas com Domínio T/genética , Proteínas com Domínio T/imunologia
3.
Zhonghua Yi Xue Za Zhi ; 100(31): 2462-2466, 2020 Aug 18.
Artigo em Chinês | MEDLINE | ID: mdl-32819064

RESUMO

Objective: To investigate the protective mechanism of ginsenoside Rb-1 on the brain in a rat model of Alzheimer's disease. Methods: Fifty-six male Sprague-Dawley rats were randomly divided into control group, model group, low-dose Rb-1 group (Rb-1: 25 mg•kg(-1)•d(-1)) and high-dose Rb-1 group (Rb-1:50 mg•kg(-1)•d(-1)). Morris water maze was designed to observe the changes of learning and memory ability in rats. Flow cytometry was used to detect the apoptosis of hippocampal neurons. Immunohistochemistry and Western blot were employed to detect the expression levels of apoptosis-related genes (p53, Bax, cytochrome C (Cyto C), Caspase-3 and caspase-9) and anti-oxidative stress-associated genes (nuclear Factor-E2-related factor 2 (Nrf2), kelch-like ECH-associated protein 1 (keap-1), heme oxygenase 1(HO-1) and NADPH quinone dehydrogenase 1 (NQO1)).The activities of catalase (CAT), glutathione peroxidase (GSH-Px) and superoxide dismutase (SOD) were detected by relevant kits. ANOVA and Tukey-Kramer test were used for statistical analysis. Results: The learning and memory ability of rats in the model group was lower than that of the control group (P<0.01).The learning and memory ability of rats in the high-dose Rb-1 treatment group was significantly higher than that of the model group [(80±8) s vs (100±11) s, t=5.390, P<0.01]. The expression levels of apoptosis-related genes (p53, Bax, Cyto C, caspase-3 and caspase-9) in the model group were significantly higher than those in the control group (P<0.01), while the expression levels of these genes in low-dose and high-dose Rb-1 groups were significantly lower than those of the model group (P<0.01). The expression levels of Nrf2, HO-1 and NQO1 genes in the model group were significantly lower than those in the control group (P<0.05), while the expression of these genes in low-dose and high-dose Rb-1 groupswere significantly higher than those of the model group (P<0.01). The activities of CAT, GSH-Px and SOD in the model group were lower than those in the control group (P<0.01), however the activities of CAT, GSH-Px and SOD in low-dose and high-dose Rb-1 groups were higher than those of model group (P<0.05). Conclusions: Both low-dose and high-dose Rb-1 have protective effect on memory and cognitive function of Alzheimer's disease rats by reducing the damage and apoptosis of hippocampal neurons, down-regulating the expression levels of p53, Bax, Cyto C, caspase-3 and caspase-9, up-regulating the expression of Nrf2, HO-1 and NQO1 genes, and increasing the activities of CAT, GSH-Px and SOD. Moreover, the protective effect of Rb-1 on rat brain may be dose-dependent.


Assuntos
Doença de Alzheimer , Ginsenosídeos/farmacologia , Fármacos Neuroprotetores/farmacologia , Animais , Masculino , Fator 2 Relacionado a NF-E2 , Estresse Oxidativo/efeitos dos fármacos , Ratos , Ratos Sprague-Dawley , Superóxido Dismutase
4.
Curr Opin Anaesthesiol ; 33(5): 655-660, 2020 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-32826628

RESUMO

PURPOSE OF REVIEW: The current systematic review summarizes recent, basic clinical achievements regarding the neuroprotective effects of molecular hydrogen in distinct central nervous system conditions. RECENT FINDINGS: Perioperative neuroprotection remains a major topic of clinical anesthesia. Various gaseous molecules have previously been explored as a feasible therapeutic option in neurological disorders. Among them, molecular hydrogen, which has emerged as a novel and potential therapy for perioperative neuroprotection, has received much attention. SUMMARY: Fundamental and clinical evidence supports the antioxidant, antiinflammation, antiapoptosis and mitochondrial protective effects of hydrogen in the pathophysiology of nervous system diseases. The clinically preventive and therapeutic effects of hydrogen on different neural diseases, however, remain uncertain, and the lack of support by large randomized controlled trials has delayed its clinical application.


Assuntos
Hidrogênio/farmacologia , Doenças do Sistema Nervoso/tratamento farmacológico , Neuroproteção , Fármacos Neuroprotetores/farmacologia , Assistência Perioperatória/métodos , Humanos , Período Perioperatório , Complicações Pós-Operatórias/prevenção & controle
5.
PLoS One ; 15(8): e0237153, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32791516

RESUMO

Alzheimer's disease (AD) is the most prevalent neurodegenerative disease characterized by cognitive dysfunction and memory loss as the main symptoms. The deposition of amyloid beta (Aß) and tau hyperphosphorylation are hallmarks of AD and are major therapeutic targets. However, the exact etiology has not yet been fully elucidated; thus, no drug that cures the disease has been approved. JBPOS0101 is a phenyl carbamate compound that has been tested as a drug for epileptic diseases. In our previous study, we showed that JBPOS0101 attenuated the accumulation of Aß as well as the deficits in learning and memory in the 5xFAD mouse model. Here, we tested the dose effect (70 or 35 mg/kg) of JBPOS0101 on the memory defect and pathological markers and further investigated the underlying mechanisms in 5xFAD mice. In the behavior tests, JBPOS0101 treatment ameliorated deficits in learning and memory. Moreover, JBPOS0101 attenuated Aß accumulation and tau phosphorylation. The elevated phosphorylation levels of the active GSK3ß form (GSK3ß-y216) in 5xFAD, which are responsible for tau phosphorylation, decreased in the JBPOS0101-treated groups. Furthermore, the elevation of reactive astrocytes and microglia in 5xFAD mice was attenuated in JBPOS0101-treated groups. These data suggest that JBPOS0101 may be a new drug candidate to lessen amyloid- and tau-related pathology by regulating glial cells.


Assuntos
Doença de Alzheimer/tratamento farmacológico , Peptídeos beta-Amiloides/metabolismo , Microglia/efeitos dos fármacos , Fármacos Neuroprotetores/farmacologia , Proteínas tau/metabolismo , Animais , Feminino , Glicogênio Sintase Quinase 3 beta/metabolismo , Memória , Camundongos , Microglia/metabolismo , Fármacos Neuroprotetores/uso terapêutico
6.
Nat Commun ; 11(1): 3848, 2020 07 31.
Artigo em Inglês | MEDLINE | ID: mdl-32737286

RESUMO

Amyotrophic Lateral Sclerosis (ALS) is a fatal disease characterized by the degeneration of upper and lower motor neurons (MNs). We find a significant reduction of the retromer complex subunit VPS35 in iPSCs-derived MNs from ALS patients, in MNs from ALS post mortem explants and in MNs from SOD1G93A mice. Being the retromer involved in trafficking of hydrolases, a pathological hallmark in ALS, we design, synthesize and characterize an array of retromer stabilizers based on bis-guanylhydrazones connected by a 1,3-phenyl ring linker. We select compound 2a as a potent and bioavailable interactor of VPS35-VPS29. Indeed, while increasing retromer stability in ALS mice, compound 2a attenuates locomotion impairment and increases MNs survival. Moreover, compound 2a increases VPS35 in iPSCs-derived MNs and shows brain bioavailability. Our results clearly suggest the retromer as a valuable druggable target in ALS.


Assuntos
Esclerose Amiotrófica Lateral/tratamento farmacológico , Hidrazonas/farmacologia , Neurônios Motores/efeitos dos fármacos , Fármacos Neuroprotetores/farmacologia , Proteínas de Transporte Vesicular/genética , Esclerose Amiotrófica Lateral/genética , Esclerose Amiotrófica Lateral/metabolismo , Esclerose Amiotrófica Lateral/patologia , Animais , Encéfalo/efeitos dos fármacos , Encéfalo/metabolismo , Encéfalo/patologia , Diferenciação Celular , Sobrevivência Celular/efeitos dos fármacos , Modelos Animais de Doenças , Humanos , Hidrazonas/síntese química , Células-Tronco Pluripotentes Induzidas/citologia , Células-Tronco Pluripotentes Induzidas/efeitos dos fármacos , Células-Tronco Pluripotentes Induzidas/metabolismo , Locomoção/efeitos dos fármacos , Locomoção/fisiologia , Masculino , Camundongos , Camundongos Transgênicos , Neurônios Motores/metabolismo , Neurônios Motores/patologia , Neuroproteção/efeitos dos fármacos , Fármacos Neuroprotetores/síntese química , Ligação Proteica/efeitos dos fármacos , Multimerização Proteica , Relação Estrutura-Atividade , Superóxido Dismutase-1/genética , Superóxido Dismutase-1/metabolismo , Proteínas de Transporte Vesicular/metabolismo
7.
Life Sci ; 257: 118037, 2020 Sep 15.
Artigo em Inglês | MEDLINE | ID: mdl-32622942

RESUMO

Palmitoylethanolamide (PEA) is an endogenous lipid mediator that, also by blunting astrocyte activation, demonstrated beneficial properties in several in vitro and in vivo models of Alzheimer's disease (AD). In the present study, we used astrocyte-neuron co-cultures from 3xTg-AD mouse (i.e. an animal model of AD) cerebral cortex to further investigate on the role of astrocytes in PEA-induced neuroprotection. To this aim, we evaluated the number of viable cells, apoptotic nuclei, microtubule-associated protein-2 (MAP2) positive cells and morphological parameters in cortical neurons co-cultured with cortical astrocytes pre-exposed, or not, to Aß42 (0.5 µM; 24 h) or PEA (0.1 µM; 24 h). Pre-exposure of astrocytes to Aß42 failed to affect the viability, the number of neuronal apoptotic nuclei, MAP2 positive cell number, neuritic aggregations/100 µm, dendritic branches per neuron, the neuron body area, the length of the longest dendrite and number of neurites/neuron in 3xTg-AD mouse astrocyte-neuron co-cultures. Compared to neurons from wild-type (non-Tg) mouse co-cultures, 3xTg-AD mouse neurons co-cultured with astrocytes from this mutant mice displayed higher number of apoptotic nuclei, lower MAP2 immunoreactivity and several morphological changes. These signs of neuronal suffering were significantly counteracted when the 3xTg-AD mouse cortical neurons were co-cultured with 3xTg-AD mouse astrocytes pre-exposed to PEA. The present data suggest that in astrocyte-neuron co-cultures from 3xTg-AD mice, astrocytes contribute to neuronal damage and PEA, by possibly counteracting reactive astrogliosis, improved neuronal survival. These findings further support the role of PEA as a possible new therapeutic opportunity in AD treatment.


Assuntos
Astrócitos/efeitos dos fármacos , Astrócitos/metabolismo , Etanolaminas/farmacologia , Ácidos Palmíticos/farmacologia , Doença de Alzheimer/tratamento farmacológico , Doença de Alzheimer/metabolismo , Peptídeos beta-Amiloides/metabolismo , Animais , Sobrevivência Celular/efeitos dos fármacos , Córtex Cerebral/metabolismo , Técnicas de Cocultura , Modelos Animais de Doenças , Etanolaminas/metabolismo , Gliose , Humanos , Masculino , Camundongos , Camundongos Transgênicos , Proteínas Associadas aos Microtúbulos , Neurônios/efeitos dos fármacos , Fármacos Neuroprotetores/farmacologia , Ácidos Palmíticos/metabolismo , Proteínas tau/metabolismo
8.
Life Sci ; 257: 118050, 2020 Sep 15.
Artigo em Inglês | MEDLINE | ID: mdl-32634425

RESUMO

BACKGROUND AND PURPOSE: Early brain injury is an essential pathological process after subarachnoid hemorrhage (SAH), with many cell death modalities. Ferroptosis is a newly discovered regulated cell death caused by the iron-dependent accumulation of lipid peroxidation, which can be prevented by glutathione peroxidase 4 (GPX4). Our study aimed to investigate the role of GPX4 in neuronal cell death after experimental SAH. METHODS: In vivo experimental SAH was induced by injecting autologous arterial blood into the prechiasmatic cistern in male Sprague-Dawley rats. Meanwhile, the in vitro SAH model was performed with primary rat cortical neurons cultured in medium containing hemoglobin (Hb). Adenovirus was used to overexpress GPX4 before experimental SAH. GPX4 expression was detected by western blot and immunofluorescence experiments. Malondialdehyde (MDA) was measured to evaluate the level of lipid peroxidation. Nissl staining was employed to assess cell death in vivo, whereas lactate dehydrogenase (LDH) release was used to evaluate cell damage in vitro. The brain water content and neurological deficits were evaluated to determine brain injury. RESULTS: Endogenous GPX4 was mainly expressed in neurons, and its expression decreased at 24 h after experimental SAH. Overexpression of GPX4 significantly reduced lipid peroxidation and cell death in the experimental SAH models both in vivo and in vitro. Moreover, overexpression of GPX4 ameliorated brain edema and neurological deficits at 24 h after SAH. CONCLUSIONS: The decrease of GPX4 expression potentially plays an important role in ferroptosis during early brain injury after SAH. Overexpression of GPX4 has a neuroprotective effect after SAH.


Assuntos
Fosfolipídeo Hidroperóxido Glutationa Peroxidase/metabolismo , Fosfolipídeo Hidroperóxido Glutationa Peroxidase/uso terapêutico , Hemorragia Subaracnóidea/tratamento farmacológico , Animais , Antioxidantes/farmacologia , Encéfalo/metabolismo , Edema Encefálico/patologia , Lesões Encefálicas/etiologia , Morte Celular/efeitos dos fármacos , Modelos Animais de Doenças , Ferroptose/efeitos dos fármacos , Peroxidação de Lipídeos/efeitos dos fármacos , Masculino , Malondialdeído/metabolismo , Neurônios/efeitos dos fármacos , Fármacos Neuroprotetores/metabolismo , Fármacos Neuroprotetores/farmacologia , Ratos , Ratos Sprague-Dawley , Hemorragia Subaracnóidea/metabolismo
9.
Life Sci ; 257: 118049, 2020 Sep 15.
Artigo em Inglês | MEDLINE | ID: mdl-32634430

RESUMO

AIMS: Mild traumatic brain injury (mTBI) is an important risk factor for cognitive impairment. Despite intense efforts to develop efficient treatments, the current therapies are not often effective and far from satisfactory. Silymarin has been suggested as a therapeutic agent in the treatment of traumatic brain injury. This study aimed to determine whether silymarin can exert neuroprotective effects on memory impairment following mTBI in mice. MAIN METHODS: After mTBI induction, mice were treated with silymarin once daily for 20 consecutive days by oral gavage. To investigate cognitive functions, animals were subjected to Y-maze, novel-object recognition, and Morris-water maze. Levels of tumor necrosis factor (TNF)-α, glutamate, and brain derived neurotrophic factor (BDNF) were measured in the hippocampus. KEY FINDINGS: Our findings showed that mTBI resulted in a significant decline in memory in the Y-maze and Morris-water maze in both sexes, whereas only impaired cognitive function in males in the novel-object recognition. We found notable increases in TNF-α and glutamate levels in the hippocampus of both sexes, while there was only a significant decrease in hippocampal BDNF in mTBI-induced females. In addition, silymarin treatment improved cognitive impairments in mTBI-induced males but not in females. Silymarin significantly reduced TNF-α and glutamate levels, and increased BDNF levels in the hippocampus of mTBI-induced male but not in female mice. SIGNIFICANCE: This study demonstrates that silymarin treatment sex-dependently improves cognitive impairment in mTBI-induced mice, and suggests that silymarin may be a therapeutic agent for cognitive decline following mTBI in males. Further studies are needed to establish the validity of these findings in humans.


Assuntos
Concussão Encefálica/tratamento farmacológico , Cognição/efeitos dos fármacos , Silimarina/uso terapêutico , Animais , Animais não Endogâmicos , Concussão Encefálica/metabolismo , Lesões Encefálicas/tratamento farmacológico , Fator Neurotrófico Derivado do Encéfalo/metabolismo , Cognição/fisiologia , Disfunção Cognitiva/tratamento farmacológico , Modelos Animais de Doenças , Feminino , Ácido Glutâmico/metabolismo , Hipocampo/metabolismo , Masculino , Aprendizagem em Labirinto/efeitos dos fármacos , Memória/efeitos dos fármacos , Camundongos , Fármacos Neuroprotetores/farmacologia , Estresse Oxidativo/efeitos dos fármacos , Fatores Sexuais , Silimarina/metabolismo , Fator de Necrose Tumoral alfa/metabolismo
10.
Life Sci ; 257: 118019, 2020 Sep 15.
Artigo em Inglês | MEDLINE | ID: mdl-32629002

RESUMO

Parkinson's disease (PD) is a disease of the human nervous system with an onset, in the sixth and seventh decades of the human life. Chiefly perceived as progressive degeneration of dopaminergic (DA) neurons in the substantia nigra pars compacta (SNpc) with the ensued loss of dopamine in the striatum and the presence of Lewy bodies, consisting of α-synuclein agglomeration. In which the neuronal bridge between substantia nigra and striatum plays an advent role in the motor system. Dilapidation of these neurons results in dopamine depletion which in-turn makes hay to PD. Eventually, the etiology and pathogenesis of PD were still on a hike of dilemma. Traditional Chinese medicine (TCM), including Chinese herbal remedies, acupuncture, and manipulative therapies, is commonly used as an adjunctive therapy in different diseases, particularly neurological diseases, in Asian countries. Additionally, TCM might improve the prognoses and the quality of life of patients with PD because it induces less adverse drug reactions. The present review describes research on the various neuroprotective components and herbal extracts from herbal medicines in the context of addressing the effects of PD.


Assuntos
Medicina Tradicional Chinesa/métodos , Doença de Parkinson/tratamento farmacológico , Doença de Parkinson/terapia , Animais , Encéfalo/metabolismo , Corpo Estriado/metabolismo , Modelos Animais de Doenças , Dopamina , Neurônios Dopaminérgicos/efeitos dos fármacos , Humanos , Camundongos , Camundongos Endogâmicos C57BL , Fármacos Neuroprotetores/farmacologia , Parte Compacta da Substância Negra/metabolismo , Substância Negra/efeitos dos fármacos , Tirosina 3-Mono-Oxigenase/metabolismo , alfa-Sinucleína/metabolismo
11.
J Thorac Cardiovasc Surg ; 160(2): e55-e66, 2020 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-32689704

RESUMO

OBJECTIVES: This study aims to evaluate the protective effects of progesterone on white matter injury and brain immaturity in neonatal rats with chronic hypoxia. METHODS: Three-day old Sprague-Dawley rats were randomly divided into 3 groups: (1) control (n = 48), rats were exposed to normoxia (fraction of inspired oxygen: 21% ± 0%); (2) chronic hypoxia (n = 48), rats were exposed to hypoxia (fraction of inspired oxygen: 10.5% ± 1.0%); and (3) progesterone (n = 48), rats were exposed to hypoxia and administrated with progesterone (8 mg/kg/d). Hematoxylin-eosin staining, immunohistochemistry, real-time quantitative polymerase chain reaction, and Western blot analyses were compared on postnatal day 14 in different groups. Motor skill and coordination abilities of rats were assessed via rotation experiments. RESULTS: Increased brain weights (P < .05), narrowed ventricular sizes (P < .01), and rotarod experiment scores (P < .01) were better in the progesterone group than in the chronic hypoxia group. The number of mature oligodendrocytes and myelin basic protein expression increased in the progesterone group compared with the chronic hypoxia group (P < .01). The polarization of M1 microglia cells in the corpus callosum of chronic hypoxia-induced hypomyelination rats was significantly increased, whereas there were fewer M2 microglia cells. Conversely, progesterone therapy had an opposite effect and caused an increase in M2 microglia polarization versus a reduction in M1 microglia cells. CONCLUSIONS: Progesterone could prevent white matter injury and improve brain maturation in a neonatal hypoxic rat model; this may be associated with inducing a switch from M1 to M2 in microglia.


Assuntos
Encéfalo/efeitos dos fármacos , Hipóxia/tratamento farmacológico , Leucoencefalopatias/prevenção & controle , Fármacos Neuroprotetores/farmacologia , Progesterona/farmacologia , Substância Branca/efeitos dos fármacos , Animais , Animais Recém-Nascidos , Comportamento Animal/efeitos dos fármacos , Encéfalo/crescimento & desenvolvimento , Encéfalo/metabolismo , Plasticidade Celular/efeitos dos fármacos , Doença Crônica , Modelos Animais de Doenças , Feminino , Hipóxia/metabolismo , Hipóxia/patologia , Hipóxia/fisiopatologia , Leucoencefalopatias/metabolismo , Leucoencefalopatias/patologia , Leucoencefalopatias/fisiopatologia , Masculino , Microglia/efeitos dos fármacos , Microglia/metabolismo , Microglia/patologia , Atividade Motora/efeitos dos fármacos , Proteína Básica da Mielina/metabolismo , Oligodendroglia/efeitos dos fármacos , Oligodendroglia/metabolismo , Oligodendroglia/patologia , Ratos Sprague-Dawley , Substância Branca/metabolismo , Substância Branca/patologia , Substância Branca/fisiopatologia
12.
PLoS One ; 15(7): e0223633, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32701951

RESUMO

BACKGROUND: Small conductance, calcium-activated (SK3) potassium channels control the intrinsic excitability of dopaminergic neurons (DN) in the midbrain and modulate their susceptibility to toxic insults during development. METHODS: We evaluated the age-dependency of the neuroprotective effect of an SK3 agonist, 1-Ethyl-1,3-dihydro-2H-benzimidazol-2-one (1-EBIO), on Amino-3-hydroxy-5-methylisoxazole-4-propionic acid (AMPA) excitotoxicity to DN in ventral mesencephalon (VM) organotypic cultures. RESULTS: Most tyrosine hydroxylase (TH)+ neurons were also SK3+; SK3+/TH- cells (DN+) were common at each developmental stage but more prominently at day in vitro (DIV) 8. Young DN+ neurons were small bipolar and fusiform, whereas mature ones were large and multipolar. Exposure of organotypic cultures to AMPA (100 µm, 16 h) had no effect on the survival of DN+ at DIV 8, but caused significant toxicity at DIV 15 (n = 15, p = 0.005) and DIV 22 (n = 15, p<0.001). These results indicate that susceptibility of DN to AMPA excitotoxicity is developmental stage-dependent in embryonic VM organotypic cultures. Immature DN+ (small, bipolar) were increased after AMPA (100 µm, 16 h) at DIV 8, at the expense of the number of differentiated (large, multipolar) DN+ (p = 0.039). This effect was larger at DIV 15 (p<<<0.0001) and at DIV 22 (p<<<0.0001). At DIV 8, 30 µM 1-EBIO resulted in a large increase in DN+. At DIV 15, AMPA toxicity was prevented by exposure to 30 µM, but not 100 µM 1-EBIO. At DIV 22, excitotoxicity was unaffected by 30 µM 1-EBIO, and partially reduced by 100 µM 1-EBIO. CONCLUSION: The effects of the SK3 channel agonist 1-EBIO on the survival of SK3-expressing dopaminergic neurons were concentration-dependent and influenced by neuronal developmental stage.


Assuntos
Neurônios Dopaminérgicos/efeitos dos fármacos , Fármacos Neuroprotetores/farmacologia , Canais de Potássio Ativados por Cálcio de Condutância Baixa/agonistas , Animais , Benzimidazóis/farmacologia , Sobrevivência Celular/efeitos dos fármacos , Células Cultivadas , Neurônios Dopaminérgicos/metabolismo , Neurônios Dopaminérgicos/patologia , Embrião de Mamíferos/citologia , Desenvolvimento Embrionário/efeitos dos fármacos , Feminino , Mesencéfalo/citologia , Mesencéfalo/metabolismo , Ratos , Ratos Sprague-Dawley , Receptores de AMPA/metabolismo , Ácido alfa-Amino-3-hidroxi-5-metil-4-isoxazol Propiônico/toxicidade
13.
Parasitol Res ; 119(9): 2897-2905, 2020 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-32677001

RESUMO

The central nervous system of the intermediate host plays a central role in lifelong persistence of Toxoplasma gondii as well as the pathogenesis of congenital toxoplasmosis and reactivated infection in immunocompromised individuals. The purinergic system has been implicated in a wide range of immunological pathways for controlling intracellular responses to pathogens, including T. gondii. In the present study, we investigated the effect of resveratrol (RSV) on ectonucleotidases, adenosine deaminase (ADA), and purinergic receptors during chronic infection by T. gondii. For this study, Swiss mice were divided into control (CTL), resveratrol (RSV), infected (INF), and INF+RSV groups. The animals were orally infected with the VEG strain and treated with RSV (100 mg/kg, orally). Ectonucleotidase activities, P2X7, P2Y1, A1, and A2A purinergic receptor density, ROS, and thiobarbituric acid reactive substances levels were measured in the cerebral cortex of mice. T. gondii infection increased NTPDase and reduced ADA activities. Treatment with RSV also affected enzymes hydrolysing extracellular nucleotides and nucleosides. Finally, RSV affected P1 and P2 purinergic receptor expression during T. gondii infection. Overall, RSV-mediated beneficial changes in purinergic signalling and oxidative stress, possibly improving cerebral cortex homeostasis in T. gondii infection.


Assuntos
Córtex Cerebral/parasitologia , Inibidores Enzimáticos/farmacologia , Fármacos Neuroprotetores/farmacologia , Resveratrol/farmacologia , Toxoplasmose Animal/tratamento farmacológico , Adenosina Desaminase/metabolismo , Animais , Camundongos , Receptores Purinérgicos/metabolismo , Transdução de Sinais , Toxoplasma/imunologia
14.
J Nat Med ; 74(4): 767-776, 2020 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-32656716

RESUMO

Traumatic brain injury (TBI) is a major cause of death and disability around the world with no effective treatments currently. The present study was aimed to investigate the neuroprotective effect of licoricidin, one of the major components of licorice extract, on TBI mice and further explore the underlying mechanism. Male C57BL/6 mice were modeled by a modified weight-drop method to mimic TBI. All animals received treatment 30 min after TBI. The modified Neurological Severity Score (NSS) tests were performed at 2 h and 1-3 days after TBI. The brain edema was analyzed by dry-wet weight method. The malonaldehyde (MDA) levels and the activities of glutathione peroxidase (GSH-PX), superoxide dismutase (SOD) and catalase (CAT) were determined by Elisa. Apoptotic neurons were detected using terminal deoxynucleotidyl transferase dUTP nick end labeling (TUNEL) immunofluorescence and the expression of apoptotic proteins were measured by western blot. Activation of the FoxO3/Wnt/ß-catenin was evaluated by western blot. The results showed that treatment with licoricidin could significantly decline the NSS scores and reduce the brain edema, hence promote the recovery of neurological function in TBI mice. It also elevated the phosphorylation of p66shc, brought down the levels of MDA, as well as antagonized the decrement in activities of GSH-PX, SOD and CAT induced by TBI. Moreover, licoricidin decreased the TUNEL positive neurons, downregulated the expression of Cyt-C, cleaved-Caspase-3, cleaved-Caspase-9 and Bax and upregulated the Bcl-2, attenuated cellular apoptosis. Licoricidin decreased the expression of FoxO3 and increased the Wnt/ß-catenin in TBI mice. In conclusion, Licoricidin exerted neuroprotective effect on TBI model and the effect was possibly due to its antioxidative effect and antiapoptotic effect via regulating the FoxO3/Wnt/ß-catenin pathway. Licoricidin may be a candidate drug for TBI therapy.


Assuntos
Benzopiranos/uso terapêutico , Lesões Encefálicas Traumáticas/tratamento farmacológico , Fármacos Neuroprotetores/farmacologia , Via de Sinalização Wnt/efeitos dos fármacos , beta Catenina/metabolismo , Animais , Benzopiranos/farmacologia , Humanos , Masculino , Camundongos , Camundongos Endogâmicos C57BL
15.
PLoS One ; 15(7): e0236450, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32706792

RESUMO

Retinal ganglion cell (RGC) loss and optic neuropathy, both hallmarks of glaucoma, have been shown to involve N-methyl-D-aspartate receptor (NMDAR)-mediated excitotoxicity. This study investigated the neuroprotective effects of Philanthotoxin (PhTX)-343 in NMDA-induced retinal injury to alleviate ensuing visual impairments. Sprague-Dawley rats were divided into three; Group I was intravitreally injected with phosphate buffer saline as the control, Group II was injected with NMDA (160 nM) to induce retinal excitotoxic injury, while Group III was injected with PhTX-343 (160 nM) 24 h prior to excitotoxicity induction with NMDA. Rats were subjected to visual behaviour tests seven days post-treatment and subsequently euthanized. Rat retinas and optic nerves were subjected to H&E and toluidine blue staining, respectively. Histological assessments showed that NMDA exposure resulted in significant loss of retinal cell nuclei and thinning of ganglion cell layer (GCL). PhTX-343 pre-treatment prevented NMDA-induced changes where the RGC layer morphology is similar to the control. The numbers of nuclei in the NMDA group were markedly lower compared to the control (p<0.05). PhTX-343 group had significantly higher numbers of nuclei within 100 µm length and 100 µm2 area of GCL (2.9- and 1.7-fold, respectively) compared to NMDA group (p<0.05). PhTX-343 group also displayed lesser optic nerve fibres degeneration compared to NMDA group which showed vacuolation in all sections. In the visual behaviour test, the NMDA group recorded higher total distance travelled, and lower total immobile time and episodes compared to the control and PhTX-343 groups (p<0.05). Object recognition tests showed that the rats in PhTX-343 group could recognize objects better, whereas the same objects were identified as novel by NMDA rats despite multiple exposures (p<0.05). Visual performances in the PhTX-343 group were all comparable with the control (p>0.05). These findings suggested that PhTX-343 inhibit retinal cell loss, optic nerve damage, and visual impairments in NMDA-induced rats.


Assuntos
Fármacos Neuroprotetores , Traumatismos do Nervo Óptico/tratamento farmacológico , Nervo Óptico/efeitos dos fármacos , Fenóis , Poliaminas , Células Ganglionares da Retina/efeitos dos fármacos , Animais , Masculino , N-Metilaspartato/toxicidade , Fármacos Neuroprotetores/farmacologia , Fármacos Neuroprotetores/uso terapêutico , Nervo Óptico/patologia , Traumatismos do Nervo Óptico/induzido quimicamente , Fenóis/farmacologia , Fenóis/uso terapêutico , Poliaminas/farmacologia , Poliaminas/uso terapêutico , Ratos , Ratos Sprague-Dawley , Células Ganglionares da Retina/patologia , Visão Ocular/efeitos dos fármacos
16.
Life Sci ; 257: 118070, 2020 Sep 15.
Artigo em Inglês | MEDLINE | ID: mdl-32668327

RESUMO

AIMS: Several studies suggested that ATP-sensitive potassium channels (KATP) are potential therapeutic targets for protection against various neurodegenerative disorders, yet, there is an ongoing controversy regarding their role in Parkinson's disease (PD). Thus, the aim of the current study is to investigate the protective effect of KATP blockade and activation in the mice rotenone model of PD. MAIN METHODS: PD has been induced by 9 subcutaneous injections of rotenone (1.5 mg/kg; 3 times/week) in adult male Swiss albino mice. For 3 consecutive weeks, parkinsonian mice were either untreated or treated with L-dopa (25 mg/kg), the KATP channel blocker glibenclamide (3 mg/kg) or the KATP channel opener nicorandil (6 mg/kg). KEY FINDINGS: Glibenclamide significantly improved motor performance in the wire hanging and stair tests and halted the decline in striatal dopamine content as well as dopaminergic neurons' density. In addition, it reduced the rotenone-induced apoptosis as portrayed in the immunohistopathological examination via increasing Bcl-2 and decreasing caspases-3, -8, -9 contents. Furthermore, through its anti-inflammatory potential, glibenclamide reduced tumor necrosis factor-alpha level. On the other hand, nicorandil failed to mitigate the rotenone-induced neurodegenerative consequences. SIGNIFICANCE: KATP channel blockade by glibenclamide has neuroprotective effect against rotenone-induced neurotoxicity, that was mediated by its anti-inflammatory effect along with hindering apoptosis through extrinsic and intrinsic pathways.


Assuntos
Glibureto/farmacologia , Canais KATP/antagonistas & inibidores , Fármacos Neuroprotetores/farmacologia , Transtornos Parkinsonianos/tratamento farmacológico , Bloqueadores dos Canais de Potássio/farmacologia , Animais , Apoptose/efeitos dos fármacos , Dopamina/metabolismo , Neurônios Dopaminérgicos/metabolismo , Canais KATP/metabolismo , Levodopa/farmacologia , Masculino , Camundongos , Nicorandil/farmacologia , Transtornos Parkinsonianos/fisiopatologia , Rotenona/toxicidade
17.
J Stroke Cerebrovasc Dis ; 29(8): 104977, 2020 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-32689608

RESUMO

BACKGROUND: Ischemic stroke is a severe neurological disorder that affected millions of people worldwide. Neuro-inflammation and apoptosis play an essential role in the pathogenesis of neuronal death during ischemic stroke. Alpha-pinene is a bicyclic terpenoid with anti-inflammatory and anti-apoptotic activities. Accordingly, the main purpose of this study was to assess the protective effect of α-pinene in ischemic stroke. MATERIALS AND METHODS: To induce ischemic stroke in male Wistar rats, the middle cerebral artery was occluded for 60 min followed by 24 h reperfusion. Alpha-pinene was injected intraperitoneally at the beginning of reperfusion. A day after reperfusion, the neurological deficits, volume of infarct area, and blood-brain barrier (BBB) permeability were evaluated. The mRNA expression of inflammatory cytokines as well as pro- and anti-apoptotic genes was assessed by using reverse transcription-polymerase chain reaction. The protein levels of inflammatory cytokines were also measured by ELISA method. RESULTS: The results showed that α-pinene (50 and 100 mg/kg) significantly improved sensorimotor function and decreased the volume of infarct area in the brain. The high permeability of BBB was also alleviated by α-pinene (50 and 100 mg/kg) in ischemic areas. Besides, α-pinene (100 mg/kg) attenuated neuro-inflammation through decreasing both the gene and protein expression of TNF-α and IL-1ß in the hippocampus, cortex, and striatum. Besides, α-pinene (100 mg/kg) suppressed apoptosis via downregulation of the pro-apoptotic Bax mRNA expression with a concomitant upregulation of anti-apoptotic Bcl-2 gene expression. CONCLUSIONS: Overall, it was concluded that α-pinene exerts neuroprotective effect during ischemic stroke through attenuating neuroinflammation and inhibition of apoptosis.


Assuntos
Anti-Inflamatórios/farmacologia , Apoptose/efeitos dos fármacos , Monoterpenos Bicíclicos/farmacologia , Encéfalo/efeitos dos fármacos , Citocinas/metabolismo , Infarto da Artéria Cerebral Média/tratamento farmacológico , Mediadores da Inflamação/metabolismo , Fármacos Neuroprotetores/farmacologia , Traumatismo por Reperfusão/prevenção & controle , Animais , Comportamento Animal/efeitos dos fármacos , Barreira Hematoencefálica/efeitos dos fármacos , Barreira Hematoencefálica/metabolismo , Encéfalo/metabolismo , Encéfalo/patologia , Encéfalo/fisiopatologia , Permeabilidade Capilar/efeitos dos fármacos , Citocinas/genética , Modelos Animais de Doenças , Infarto da Artéria Cerebral Média/metabolismo , Infarto da Artéria Cerebral Média/patologia , Infarto da Artéria Cerebral Média/fisiopatologia , Masculino , Proteínas Proto-Oncogênicas c-bcl-2/genética , Proteínas Proto-Oncogênicas c-bcl-2/metabolismo , Ratos Wistar , Traumatismo por Reperfusão/metabolismo , Traumatismo por Reperfusão/patologia , Traumatismo por Reperfusão/fisiopatologia , Transdução de Sinais , Proteína X Associada a bcl-2/genética , Proteína X Associada a bcl-2/metabolismo
18.
Int. j. morphol ; 38(3): 523-529, June 2020. graf
Artigo em Inglês | LILACS | ID: biblio-1098282

RESUMO

This study aimed to investigate the morphometric and the pattern of protein and gene expression related to the extrinsic apoptotic pathway in experimental focal cerebral ischemia and the hole of neuroprotection with hypothermia and ketoprofen. For this analysis, 120 rats were randomly divided into 3 groups (20 animals each): control - no surgery (20 animals); sham - simulation of surgery (20 animals); ischemic - focal ischemia for 1 hour, without reperfusion (80 animals) and divided into four subgroups with 20 animals each: ischemic + intraischemic hypothermia; ischemic + previous intravenous ketoprofen, and ischemic + hypothermia and ketoprofen. The infarct volume was measured using morphometric analysis of infarct areas defined by triphenyl tetrazolium chloride and the patterns of expression of the apoptosis genes (Fas, c-Flip, caspase-8 and caspase-3) and the apoptosis protein caspase-3 were evaluated by quantitative real-time PCR and immunohistochemistry, respectively. Hypo expression of genes of extrinsic pathway of apoptosis was observed: Fas receptor, c-Flip and caspase-8 in the ischemics areas. Increases in the gene and protein caspase-3 in the ischemic areas were also observed, and these increases were reduced by hypothermia and ketoprofen, also noted in the morphometric study. The caspases-3 increase suggests that this gene plays an important role in apoptosis, probably culminating in cell death and that the neuroprotective effect of hypothermia and ketoprofen is involved.


Este estudio tuvo como objetivo investigar la morfometría y el patrón de expresión de proteínas y genes relacionados con la vía apoptótica extrínseca en la isquemia cerebral focal experimental y el agujero de neuroprotección con hipotermia y ketoprofeno. Se dividieron aleatoriamente 120 ratas en 3 grupos (20 animales cada uno): control - sin cirugía (20 animales); simulación - simulación de cirugía (20 animales); isquemia isquemia focal durante 1 hora, sin reperfusión (80 animales) y dividida en cuatro subgrupos con 20 animales cada uno: isquemia + hipotermia intraisquémica; isquemia + ketoprofeno intravenoso previo, e isquemia + hipotermia y ketoprofeno. El volumen del infarto se midió utilizando un análisis morfométrico de áreas de infarto definidas por cloruro de trifenil tetrazolio y los patrones de expresión de los genes de apoptosis (Fas, c-Flip, caspase-8 y caspase-3) y la proteína de apoptosis caspase-3 fueron evaluados por PCR cuantitativa en tiempo real e inmunohistoquímica, respectivamente. Se observó hipoexpresión de genes de la vía extrínseca de la apoptosis: receptor Fas, c-Flip y caspasa-8 en las áreas isquémicas. También se observaron aumentos en el gen y la proteína caspasa-3 en las áreas isquémicas y estos aumentos se redujeron por hipotermia y ketoprofeno, también observado por estudio morfométrico. El aumento de caspasas-3 sugiere que este gen tiene un papel importante en la apoptosis, y probable causa de muerte celular, involucrando el efecto neuroprotector de la hipotermia y el ketoprofeno.


Assuntos
Animais , Ratos , Isquemia Encefálica/genética , Isquemia Encefálica/metabolismo , Imuno-Histoquímica , Isquemia Encefálica/patologia , Isquemia Encefálica/terapia , Cetoprofeno/farmacologia , Apoptose/genética , Fármacos Neuroprotetores/farmacologia , Modelos Animais de Doenças , Caspase 3/genética , Caspase 8/genética , Reação em Cadeia da Polimerase em Tempo Real , Hipotermia Induzida
19.
Life Sci ; 256: 117894, 2020 Sep 01.
Artigo em Inglês | MEDLINE | ID: mdl-32502544

RESUMO

AIMS: Pathological alterations in the brain can cause microglial activation (MA). Thus, inhibiting MA could provide a new approach for treating neurodegenerative disorders. MAIN METHODS: To investigate the effect of C16 peptide and angiopoietin-1 (Ang1) on inflammation following MA, we stimulated microglial BV-2 cells with lipopolysaccharide (LPS) and used dexmedetomidine (DEX) as a positive control. Specific inhibitors of Tie2, αvß3 and α5ß1 integrins, and PI3K/Akt were applied to investigate the neuron-protective and anti-inflammatory effects and signaling pathway of C16 + Ang1 treatment in the LPS-induced BV-2 cells. KEY FINDINGS: Our results showed that C16 + Ang1 treatment reduced the microglia M1 phenotype but promoted the microglia M2 phenotype. In addition, C16 + Ang1 treatment suppressed leukocyte migration across human pulmonary microvascular endothelial cells, reduced the levels of pro-inflammatory factors [inducible nitric oxide synthase (iNOS), interleukin (IL)-1ß, tumor necrosis factor (TNF-α)], and cellular apoptosis factors (caspase-3 and p53), and decreased lactate dehydrogenase (LDH) release, but promoted anti-inflammatory cytokine (IL-10) expression and cell proliferation in the LPS-activated BV-2 cells. The signaling pathways underlying the neuron-protective and anti-inflammatory effects of C16 + Ang1 may be mediated by Tie2-PI3K/Akt, Tie2-integrin and integrin-PI3K/Akt. SIGNIFICANCE: The neuron-protective and anti-inflammatory effects of C16 + Ang1 treatment included M1 to M2 microglia phenotype switching, blocking leukocyte transmigration, decreasing apoptotic and inflammatory factors, and promoting cellular viability.


Assuntos
Angiopoietina-1/farmacologia , Inflamação/patologia , Lipopolissacarídeos/farmacologia , Microglia/patologia , Fármacos Neuroprotetores/farmacologia , Peptídeos/farmacologia , Animais , Morte Celular/efeitos dos fármacos , Linhagem Celular , Movimento Celular/efeitos dos fármacos , Células Endoteliais/efeitos dos fármacos , Células Endoteliais/metabolismo , Células Endoteliais/patologia , Humanos , Integrina alfa5beta1/metabolismo , Integrina alfaVbeta3/metabolismo , Pulmão/irrigação sanguínea , Camundongos , Microglia/efeitos dos fármacos , Microvasos/patologia , Fenótipo , Fosfatidilinositol 3-Quinases/metabolismo , Proteínas Proto-Oncogênicas c-akt/metabolismo , Receptor TIE-2/metabolismo , Transdução de Sinais/efeitos dos fármacos , Células THP-1
20.
Acta Cir Bras ; 35(4): e202000406, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32578724

RESUMO

PURPOSE: To investigate the role of Rosmarinic acid (RA) in the prevention of traumatic brain injury and the immunohistochemical analysis of IBA-1 and GFAP expressions. METHODS: Healthy male rats were randomly divided into 3 groups consisting of 10 rats. Groups were as follows; control group, traumatic brain injury (TBI) group, and TBI+RA group. After traumatic brain injury, blood samples were taken from the animals and analyzed with various biochemical markers. And then IBA-1 and GFAP expressions were evaluated immunohistochemically. RESULTS: Significant results were obtained in all biochemical parameters between groups. Immunohistochemical sections showed IBA-1 not only in microglia and macrophage activity but also in degenerative neurons in blood vessel endothelial cells. However, GFAP reaction and post-traumatic rosmarinic acid administration showed positive expression in astrocytes with regular structure around the blood vessel. CONCLUSION: Rosmarinic acid in blood vessel endothelial cells showed that preserving the integrity of astrocytic structure in the blood brain barrier may be an important antioxidant.


Assuntos
Lesões Encefálicas Traumáticas/prevenção & controle , Proteínas de Ligação ao Cálcio/análise , Cinamatos/farmacologia , Craniotomia/métodos , Depsídeos/farmacologia , Proteína Glial Fibrilar Ácida/análise , Proteínas dos Microfilamentos/análise , Fármacos Neuroprotetores/farmacologia , Animais , Astrócitos/efeitos dos fármacos , Lesões Encefálicas Traumáticas/patologia , Lesões Encefálicas Traumáticas/cirurgia , Glutationa Peroxidase/análise , Imuno-Histoquímica , Masculino , Malondialdeído/análise , Distribuição Aleatória , Ratos Sprague-Dawley , Valores de Referência , Reprodutibilidade dos Testes
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