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1.
J Toxicol Sci ; 45(10): 639-650, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-33012732

RESUMO

Bisphenol A (BPA), an endocrine disruptor with estrogenic effects, is widely used as a raw material for manufacturing polycarbonate plastic and epoxy resins. Prenatal and postnatal exposure to BPA affects brain morphogenesis. However, the effects of prenatal and postnatal BPA exposure on postnatal neurogenesis in mice are poorly understood. In this study, we developed a mouse model of prenatal and postnatal BPA exposure and analyzed its effects on hippocampal neurogenesis. The hippocampal dentate gyrus is vulnerable to chemical exposure, as neurogenesis continues in this region even after birth. Our results showed that in mice, prenatal and postnatal BPA exposure decreased the number of type-1, 2a, 2b, and 3 neural progenitor cells, as well as in granule cells, in the hippocampal dentate gyrus on postnatal days 16 and 70. The effect of prenatal and postnatal BPA exposure on neural progenitors were affected at all differentiation stages. In addition, prenatal and postnatal BPA exposure affects the maintenance of long-term memory on postnatal day 70. Our results suggest that neurodevelopmental toxicity due to prenatal and postnatal BPA exposure might affect postnatal morphogenesis and functional development of the hippocampal dentate gyrus.


Assuntos
Animais Recém-Nascidos , Compostos Benzidrílicos/toxicidade , Giro Denteado/efeitos dos fármacos , Disruptores Endócrinos/toxicidade , Hipocampo/efeitos dos fármacos , Exposição Materna/efeitos adversos , Troca Materno-Fetal/efeitos dos fármacos , Células-Tronco Neurais/efeitos dos fármacos , Neurogênese/efeitos dos fármacos , Fenóis/toxicidade , Animais , Diferenciação Celular/efeitos dos fármacos , Feminino , Masculino , Camundongos , Modelos Animais , Gravidez
2.
J Stroke Cerebrovasc Dis ; 29(10): 105128, 2020 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-32912509

RESUMO

BACKGROUND: The insulin-like growth factor 2 (IGF-2) is a growth factor and anti-inflammatory cytokine that plays a crucial role in memory consolidation. However, the precise role of this factor in acute brain damage is still unclear. The present study aimed to evaluate the variations in hippocampal IGF-2 distribution on different days and investigate the effect of recombinant IGF-2 on memory cell density, and IGF-2 distribution following acute hippocampal damage resulting from intracerebral hemorrhage (ICH). METHODS: ICH was induced by injection of 100 µL of autologous blood into the left hippocampus of 72 male Sprague-Dawley rats. Recombinant IGF-2 was injected into the damaged hippocampus 30 min post-induction of ICH in the ICH-IGF-2 group. Then, on postoperative days 1, 3, 7, and 14, samples of brain tissue were collected to perform histopathological and immunohistochemical examinations. RESULTS: The stereological study indicated that the volume of the hippocampus and the number of neurons had a significant reduction, and the infarct volume had a significant increase following ICH. Following the injection of IGF-2, a significant improvement was observed in stereological studies. Immunohistochemical data showed that IGF-2 distribution increased in the hippocampus on different days after ICH, and IGF-2 injection led to a dramatic reduction in this distribution. CONCLUSIONS: In summary, the gradual increase of endogenous IGF-2 as growth and anti-inflammatory factor following hemorrhagic stroke reveals a critical role of this factor in brain recovery after injury. Moreover, the injection of IGF-2 can prevent cell death and alleviate the damage caused by the hemorrhagic stroke.


Assuntos
Hemorragia Cerebral/tratamento farmacológico , Hipocampo/efeitos dos fármacos , Fator de Crescimento Insulin-Like II/administração & dosagem , Neurônios/efeitos dos fármacos , Fármacos Neuroprotetores/administração & dosagem , Animais , Morte Celular/efeitos dos fármacos , Hemorragia Cerebral/metabolismo , Hemorragia Cerebral/patologia , Hipocampo/metabolismo , Hipocampo/patologia , Fator de Crescimento Insulin-Like II/metabolismo , Masculino , Neurônios/metabolismo , Neurônios/patologia , Fármacos Neuroprotetores/metabolismo , Ratos Sprague-Dawley , Proteínas Recombinantes/administração & dosagem , Fatores de Tempo , Distribuição Tecidual
3.
Zhongguo Ying Yong Sheng Li Xue Za Zhi ; 36(3): 235-239, 2020 May.
Artigo em Chinês | MEDLINE | ID: mdl-32981278

RESUMO

Objective: To investigate the effects of exogenous NaHS on myelin basic protein (MBP) and learning and memory of hippocampal neurons in mice with spinocerebellar ataxia type 3 (SCA3) and its therapeutic significance.Methods: Twelve male normal mice were randomly selected as normal control group (NC Group), and 48 SCA3 mice were randomly selected as SCA3 model group (M Group), low dose group (NL Group, 10 µmol/kg), medium dose group (NM Group, 50µmol/kg) and high dose group (NH Group, 100 µmol/kg), 12 rats in each group. The drug treated groups were injected with NaHS intraperitoneally once a day for 4 weeks. The changes of learning and memory ability of SCA3 mice before and after the intervention of different doses of NaHS were determined by Morris water maze, the content of hydrogen sulfide (H2S) in hippocampus was measured by spectrophotometry, the expression of MBP was detected by immunohistochemistry, and the morphological changes of neuron myelin sheath were observed by electron microscope. Results: Compared with the control group, the learning and memory ability of SCA3 mice was decreased significantly (P<0.05), and the content of H2S in hippocampus was decreased (P<0.05). After different doses of exogenous NaHS treatment, the learning and memory ability was improved in different degrees (P<0.05), and the contents of H2S and MBP in hippocampus of SCA3 mice were also improved in different degrees (P<0.05). Conclusion: Exogenous NaHS may increase the contents of H2S and MBP in the hippocampus of SCA3 mice, which may have a protective effect on the neurons, and then improve the learning and memory ability of SCA3 mice, and provide a new idea for the treatment of SCA3.


Assuntos
Sulfeto de Hidrogênio , Aprendizagem , Memória , Ataxias Espinocerebelares , Sulfetos , Animais , Hipocampo/efeitos dos fármacos , Aprendizagem/efeitos dos fármacos , Masculino , Memória/efeitos dos fármacos , Camundongos , Proteína Básica da Mielina , Fármacos Neuroprotetores/farmacologia , Fármacos Neuroprotetores/uso terapêutico , Ratos , Ataxias Espinocerebelares/tratamento farmacológico , Sulfetos/farmacologia , Sulfetos/uso terapêutico
4.
Zhongguo Ying Yong Sheng Li Xue Za Zhi ; 36(3): 240-244, 2020 May.
Artigo em Chinês | MEDLINE | ID: mdl-32981279

RESUMO

Objective: To investigate the inflammatory mechanism of nasal instillation of fine particulate matter (PM2.5)on hippocampal tissue injury in mice.Methods: Thirty C57BL/6J mice were randomly divided into 3 groups(n=10):control group, low-dose group, high-dose group. The nasal instillation doses of PM2.5 in the low-dose group and the high-dose group were 1.5 mg/kg BW and 7.5 mg/kg BW, respectively, and the control group was given saline with an equal volume. Saline was sprayed once every other time for 12 times. The serum levels of tumor necrosis factor-α (TNF-α), interleukin-1ß (IL-1ß) and interleukin-6 (IL-6) were determined by ELISA method. HE staining and electron microscopy were used to observe the pathological changes and ultrastructure of lung tissue and hippocampus. The inflammatory cytokine levels in hippocampus were detected by antibody chip technique. Results: There was no significant effect of PM2.5 nasal instillation on serum TNF-α, IL-1ß and IL-6 levels (P>0.05), and there was no obvious pathological changes in lung tissue structure. In hippocampus, low-dose and high-dose PM2.5 exposure could lead to disordered neuronal arrangement in the hippocampal CA3 region, and there were neurological changes around the neuron cells and ultrastructural changes such as edema around small blood vessels. Compared with the control group, the levels of inflammatory cytokines such as CX3CL1, CSF2 and TECK in the low-dose group were increased significantly (P <0.05), while sTNFR1 was decreased significantly (P<0.05); the inflammatory factors CX3CL1, CSF2, and TCA-3 were significantly increased in the high-dose group (P<0.05), while leptin, MIG, and FASLG were significantly decreased (P<0.05). Conclusion: Nasal instillation of PM2.5 can induce tissue damage in the hippocampus of mice, and its mechanism of action may be the olfactory brain pathway. The increasing of TNF-α and IL-6 and the decreasing of sTNFR1 and FASLG may be involved in inflammatory mechanisms.


Assuntos
Lesões Encefálicas , Hipocampo , Material Particulado , Administração Intranasal , Animais , Lesões Encefálicas/induzido quimicamente , Lesões Encefálicas/fisiopatologia , Citocinas/sangue , Hipocampo/efeitos dos fármacos , Hipocampo/lesões , Pulmão/efeitos dos fármacos , Pulmão/patologia , Lesão Pulmonar/patologia , Camundongos , Camundongos Endogâmicos C57BL , Material Particulado/toxicidade
5.
Medicine (Baltimore) ; 99(33): e21711, 2020 Aug 14.
Artigo em Inglês | MEDLINE | ID: mdl-32872049

RESUMO

BACKGROUND: This study will investigate the effects of Spore Powder of Ganoderma Lucidum (SPGL) on CaSR and apoptosis-related proteins (ARP) in hippocampus tissue of epilepsy following dementia. METHODS: This study will retrieve all potential studies from both electronic databases (Cochrane Library, EMBASE, MEDLINE, CINAHL, AMED, and CNKI) and other literature sources to assess the effects of SPGL on CaSR and ARP in hippocampus tissue of epilepsy following dementia. We will search all literature sources from the inception to the present. All eligible case-control studies will be included in this study. Two authors will independently carry out literature selection, data collection, and study quality evaluation. Any divergence will be resolved by another author through discussion. RevMan 5.3 software will be employed for data analysis. RESULTS: This study will summarize existing evidence to assess the effects of SPGL on CaSR and ARP in hippocampus tissue of epilepsy following dementia. CONCLUSIONS: The findings of this study may provide helpful evidence of SPGL on CaSR and ARP in hippocampus tissue of epilepsy following dementia. SYSTEMATIC REVIEW REGISTRATION: INPLASY202070041.


Assuntos
Demência/tratamento farmacológico , Medicamentos de Ervas Chinesas/uso terapêutico , Epilepsia/tratamento farmacológico , Hipocampo/efeitos dos fármacos , Reishi , Animais , Demência/complicações , Medicamentos de Ervas Chinesas/farmacologia , Epilepsia/etiologia , Hipocampo/metabolismo , Receptores de Detecção de Cálcio/metabolismo , Revisões Sistemáticas como Assunto
6.
Int J Nanomedicine ; 15: 6339-6353, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32922005

RESUMO

Introduction: Epilepsy is a chronic neurological condition characterized by behavioral, molecular, and neurochemical alterations. Current antiepileptic drugs are associated with various adverse impacts. The main goal of the current study is to investigate the possible anticonvulsant effect of selenium nanoparticles (SeNPs) against pentylenetetrazole (PTZ)-mediated epileptic seizures in mice hippocampus. Sodium valproate (VPA) was used as a standard anti-epileptic drug. Methods: Mice were assigned into five groups (n=15): control, SeNPs (5 mg/kg, orally), PTZ (60 mg/kg, intraperitoneally), SeNPs+PTZ and VPA (200 mg/kg)+PTZ. All groups were treated for 10 days. Results: PTZ injection triggered a state of oxidative stress in the hippocampal tissue as represented by the elevated lipoperoxidation, heat shock protein 70 level, and nitric oxide formation while decreased glutathione level and antioxidant enzymes activity. Additionally, the blotting analysis showed downregulation of nuclear factor erythroid 2-related factor 2 (Nrf2) and heme oxygenase-1 (HO-1) in the epileptic mice. A state of neuroinflammation was recorded following the developed seizures represented by the increased pro-inflammatory cytokines. Moreover, neuronal apoptosis was recorded following the development of epileptic convulsions. At the neurochemical level, acetylcholinesterase activity and monoamines content were decreased in the epileptic mice, accompanied by high glutamate and low GABA levels in the hippocampal tissue. However, SeNP supplementation was found to delay the onset and decreased the duration of tonic, myoclonic, and generalized seizures following PTZ injection. Moreover, SeNPs were found to provide neuroprotection through preventing the development of oxidative challenge via the upregulation of Nrf2 and HO-1, inhibiting the inflammatory response and apoptotic cascade. Additionally, SeNPs reversed the changes in the activity and levels of neuromodulators following the development of epileptic seizures. Conclusion: The obtained results suggest that SeNPs could be used as a promising anticonvulsant drug due to its potent antioxidant, anti-inflammatory, and neuromodulatory activities.


Assuntos
Nanopartículas/química , Neurônios/patologia , Estresse Oxidativo/efeitos dos fármacos , Convulsões/tratamento farmacológico , Selênio/uso terapêutico , Aminoácidos , Animais , Anti-Inflamatórios/farmacologia , Anti-Inflamatórios/uso terapêutico , Anticonvulsivantes/efeitos adversos , Anticonvulsivantes/farmacologia , Anticonvulsivantes/uso terapêutico , Apoptose/efeitos dos fármacos , Colinérgicos/metabolismo , Hipocampo/efeitos dos fármacos , Hipocampo/patologia , Masculino , Camundongos , Nanopartículas/administração & dosagem , Neurônios/efeitos dos fármacos , Neurotransmissores/metabolismo , Oxirredução , Pentilenotetrazol , Convulsões/induzido quimicamente , Convulsões/prevenção & controle , Selênio/administração & dosagem , Selênio/farmacologia
7.
PLoS One ; 15(8): e0237929, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32822403

RESUMO

BACKGROUND: Neuroinflammation causes neurodegenerative conditions like Alzheimer's disease (AD). Ipriflavone (IP), therapeutic compound to postmenopausal osteoporosis, has limited estrogenic activity and is accounted as AChE inhibitor. The developing of drug delivery systems to enable drug targeting to specific sites increases the drug therapeutic effect. OBJECTIVE: The aim of the present study was to formulate and evaluate ipriflavone loaded albumin nanoparticles (IP-Np) along with free ipriflavone against lipopolysaccharide (LPS) induced neuroinflammation in rats. METHODS: Neuroinflammation was induced by intra-peritoneal (i.p) injection of LPS (250 µg/kg rat body weight) then treatments were conducted with (1) ipriflavone at two doses 50 mg/kg and 5 mg/kg, (2) IP-Np (5 mg ipriflavone/kg) or (3) IP-Np coated with polysorbate 80 (IP-Np-T80) (5 mg ipriflavone/kg). The alteration of the inflammatory response in male adult Wistar rats' brain hippocampus was investigated by examining associated indices using biochemical and molecular analyses. RESULTS: A significant upsurge in inflammatory mediators and decline in antioxidant status were observed in LPS-induced rats. In one hand, ipriflavone (50 mg/kg), IP-Np and IP-Np-T80 ameliorated LPS induced brain hippocampal inflammation where they depreciated the level of pro-inflammatory cytokines (TNF-α, IL-6, IL-1ß) and enhanced antioxidant status. In another hand, ipriflavone at dose (5 mg/kg) didn't show the same therapeutic effect. CONCLUSION: The current study provides evidence for the potential neuroprotective effect of ipriflavone (50 mg/kg) against LPS-induced neuroinflammation in rats through its anti-inflammatory and antioxidant activities. Moreover, nanoparticles significantly attenuated neuroinflammation in concentration lower than the effective therapeutic dose of free drug ten times.


Assuntos
Hipocampo/efeitos dos fármacos , Inflamação/tratamento farmacológico , Isoflavonas/uso terapêutico , Nanopartículas , Fármacos Neuroprotetores/uso terapêutico , Acetilcolinesterase/metabolismo , Peptídeos beta-Amiloides/metabolismo , Animais , Inibidores da Colinesterase/farmacologia , Citocinas/metabolismo , Sistemas de Liberação de Medicamentos , Hipocampo/enzimologia , Hipocampo/metabolismo , Hipocampo/fisiopatologia , Inflamação/metabolismo , Inflamação/fisiopatologia , Isoflavonas/administração & dosagem , Isoflavonas/farmacologia , Lipopolissacarídeos/toxicidade , Masculino , Microscopia Eletrônica de Transmissão , Nanopartículas/química , Nanopartículas/ultraestrutura , Fármacos Neuroprotetores/farmacologia , Estresse Oxidativo/efeitos dos fármacos , Ratos , Ratos Wistar , Soroalbumina Bovina/química , Proteínas Quinases p38 Ativadas por Mitógeno/metabolismo
8.
Life Sci ; 260: 118338, 2020 Nov 01.
Artigo em Inglês | MEDLINE | ID: mdl-32841662

RESUMO

AIMS: Fluoxetine (FLX) is a common selective serotonin reuptake inhibitor, which is used in adolescents with psychiatric disorders. Controversial results have been obtained in different studies about the effects of FLX on cognitive functions. The present study was designed to examine the effects of chronic FLX exposure during adolescence on cognitive function, anxiety-like behaviors, and hippocampal brain-derived neurotrophic factor (BDNF) mRNA expression among adult male and female rats. MAIN METHODS: The sex-dependent effects of FLX chronic administration during adolescence (5 mg/kg/day, gavage) on short-term novel object recognition memory (NORM), anxiety-like behaviors, and BDNF mRNA expression in the hippocampus were examined. NORM and anxiety-like behaviors were assessed by novel object recognition, open field, and elevated plus-maze (EPM) tests, respectively. The expression of BDNF mRNA was also evaluated by quantitative reverse transcriptase-polymerase chain reaction (RT-PCR). KEY FINDINGS: The present findings revealed the dysfunction of short-term NORM among the adolescent male and female rats exposed to FLX, while the mRNA expression of BDNF was significantly higher among the males. Moreover, adolescent FLX administration had different effects on the anxiety-like behaviors of the male and female rats. Adolescent FLX treatment also decreased the body weight of the male animals. SIGNIFICANCE: In conclusion, adolescent FLX treatment impairs cognitive functions in both sexes and increases BDNF mRNA expression in the hippocampus of the male animals. FLX administration during adolescence has sex-dependent effects on anxiety-like behaviors. These findings indicate that the impairment of cognitive functions can occur following the adolescent manipulation of the serotonergic system. Therefore, the side effects of chronic FLX administration during adolescence should be more considered.


Assuntos
Ansiedade/tratamento farmacológico , Fator Neurotrófico Derivado do Encéfalo/metabolismo , Fluoxetina/administração & dosagem , Hipocampo/metabolismo , Transtornos da Memória/tratamento farmacológico , Reconhecimento Psicológico/efeitos dos fármacos , Inibidores de Captação de Serotonina/administração & dosagem , Animais , Ansiedade/patologia , Fator Neurotrófico Derivado do Encéfalo/genética , Feminino , Fluoxetina/farmacologia , Hipocampo/efeitos dos fármacos , Masculino , Transtornos da Memória/metabolismo , Transtornos da Memória/patologia , Ratos , Inibidores de Captação de Serotonina/farmacologia
9.
Zhongguo Ying Yong Sheng Li Xue Za Zhi ; 36(2): 138-142, 2020 Mar.
Artigo em Chinês | MEDLINE | ID: mdl-32744007

RESUMO

Objective: To investigate the effects of butylphthalide (NBP) on learning and memory related ability, hydrogen sulfide (H2S) content in hippocampus and amygdala, cystathionine-ß-synthase (CBS) expression and mitochondrial ATPase activity in rats with chronic alcoholism. Methods: Ninety SD male rats were randomly divided into three groups: normal control group (NC), model group (M) and butylphthalide remedy group (BR). Except for the control group, the water solution containing 6% (v/v) alcohol was used as the sole source of drinking water in the other two groups. After 14 days of feeding, the butylphthalide remedy group was injected with NBP intraperitoneally at the dose of 5 mg/kg once a day for 14 consecutive days, and the remaining two groups were injected with the same dose of normal saline. The control group subsequently used the Morris water maze method to observe and record the animals after entering the water. The time required for the underwater platform, their strategies and their swimming trajectories could analyze and infer the animal's ability to learn and remember. H2S concentration, CBS expression and mitochondrial ATPase activity in hippocampus and amygdale were dectected. Results: Compared with NC group, the latency period and swimming distance of M group were increased, the content of H2S and the mean optical density of CBS in hippocampus and amygdala were increased, and the activity of mitochondrial ATPase in hippocampus and amygdala was decreased significantly (P<0. 01) . Compared with the M group, the latency period and swimming distance of learning and memory performance of BR group were decreased, the content of H2S and the mean optical density of CBS in hippocampus and amygdala were decreased, and the activity of mitochondrial ATPase in hippocampus and amygdala was increased significantly (P<0. 01) . Conclusion: NBP can alleviate the effect of ethanol on learning and memory in rats, which may be related to the effect of NBP on the concentration of H2S and the expression of CBS in the amygdala of hippocampus and the increase of ATPase activity.


Assuntos
Alcoolismo , Tonsila do Cerebelo/efeitos dos fármacos , Benzofuranos/farmacologia , Cistationina beta-Sintase/metabolismo , Hipocampo/efeitos dos fármacos , Sulfeto de Hidrogênio/metabolismo , Animais , Aprendizagem , Masculino , Memória , Distribuição Aleatória , Ratos , Ratos Sprague-Dawley
10.
Sichuan Da Xue Xue Bao Yi Xue Ban ; 51(4): 480-487, 2020 Jul.
Artigo em Chinês | MEDLINE | ID: mdl-32691554

RESUMO

Objective: To investigate the effects and the mechanism of geniposide on the neuroinflammation occured in the neurodegeneration course of a chronic cerebral hypoperfusion rat model. Methods: Permanent bilateral common carotid arteries occlusions was performed to induce gradient cognitive deficit in rats. The sham group was used as control group. Then 18 rats that met the Screening Criteria were randomly selected 8 weeks post surgery, and were randomly divided into three groups, the 2-VO rats with saline solution group (2-VO+saline group), 2-VO rats with 50 mg/kg per day geniposide group (2-VO+G50) and 2-VO rats with 100 mg/kg per day geniposide group (2-VO+G100). All intervention groups were daily administered with geniposide or saline for 4 weeks. The sham-operated rats were administrated with saline. Then the rats were tested for Morris water maze to evaluate the memory and learning ability. Rats were sacrificed to obtain cortex and hippocampus tissues for HE staining and to detect expression level of glial fibrillary acidic protein (GFAP), inducible nitric oxide synthase (iNOS) and nuclear factor-kappa B (NF-κB), and the level of inflammatory factors tumor necrosis factor-α (TNF-α) and interleukin (IL)-6. Results: The 2-VO+saline group rats showed significant longer escape latency and less percent time in target quadrant, compared with sham-operation group ( P<0.05). The escape latency of 2-VO+G50 and 2-VO+G100 groups were shorter than the 2-VO+saline group ( P<0.05), but still longer than the sham group ( P<0.05), the percent time in target quadrant of which were more than the 2-VO+saline group and less than the sham group. However, there was no significant difference between these two groups. HE staining of sham group showed that neurons in the cortex and hippocampus lined up in order, cellar nucleus were big and globular. HE staining results showed that there were obviously neuoral cells loss, severe cytomorphosis, structural disappearance and nuclear fragmentation in the 2-VO+saline group. The 2-VO+G50 and 2-VO+G100 groups showed less neurodamage than the 2-VO+saline group with less neuoral cells loss, cytomorphosis and ambiguous nucleus. GFAP, iNOS, NF-κB were all highly expressed in the process of cognitive dysfunction in rats after chronic cerebral ischemia, however geniposide intervention (50 and 100 mg/kg per day) significantly decreased the expression of the above proteins. In addition, much more TNF-α and IL-6 were released in brain induced by chronic cerebral ischemia, and the levels were decreased after chronic geniposide oral treatment. No significant differences were detected between 2-VO+G50 and 2-VO+G100 groups. Conclusion: These findings demonstrated that geniposide significantly prevented cognition deterioration induced by chronic cerebral hypoperfusion in rats. Geniposide inhibited neuroinflammation occurred in the process of chronic cerebral ischemia probably via reducing iNOS and NF-κB expression and suppressing the release of inflammatory factor TNF-α and IL-6.


Assuntos
Isquemia Encefálica , Transtornos Cognitivos , Hipocampo , Iridoides , Animais , Anti-Inflamatórios/farmacologia , Anti-Inflamatórios/uso terapêutico , Isquemia Encefálica/complicações , Isquemia Encefálica/tratamento farmacológico , Modelos Animais de Doenças , Hipocampo/efeitos dos fármacos , Iridoides/farmacologia , Iridoides/uso terapêutico , Aprendizagem em Labirinto/efeitos dos fármacos , Distribuição Aleatória , Ratos
11.
Toxicol Lett ; 332: 192-201, 2020 Oct 10.
Artigo em Inglês | MEDLINE | ID: mdl-32693020

RESUMO

Fenvalerate, a synthetic pyrethroid insecticide, is an environmental endocrine disruptor and neurodevelopmental toxicant. An early report found that pubertal exposure to high-dose fenvalerate impaired cognitive and behavioral development. Here, we aimed to further investigate the effect of pubertal exposure to low-dose fenvalerate on cognitive and behavioral development. Mice were orally administered with fenvalerate (0.2, 1.0 and 5.0 mg/kg) daily from postnatal day (PND) 28 to PND56. Learning and memory were assessed by Morris water maze. Anxiety-related activities were detected by open-field and elevated plus-maze. Increased anxiety activities were observed only in females exposed to fenvalerate. Spatial learning and memory were damaged only in females exposed to fenvalerate. Histopathology observed numerous scattered shrinking neurons and nuclear pyknosis in hippocampal CA1 region. Neuronal density was reduced in hippocampal CA1 region of fenvalerate-exposed mice. Mechanistically, hippocampal thyroid hormone receptor (TR)ß1 was down-regulated in a dose-dependent manner in females. In addition, TRα1 was declined only in females exposed to 5.0 mg/kg fenvalerate. Taken together, these suggests that pubertal exposure to low-dose fenvalerate impairs cognitive and behavioral development in a gender-dependent manner. Hippocampal TR signaling may be, at least partially, involved in fenvalerate-induced impairment of cognitive and behavioral development.


Assuntos
Transtornos Cognitivos/induzido quimicamente , Hipocampo/metabolismo , Inseticidas/toxicidade , Nitrilos/toxicidade , Piretrinas/toxicidade , Transdução de Sinais/efeitos dos fármacos , Hormônios Tireóideos , Animais , Ansiedade/induzido quimicamente , Ansiedade/psicologia , Peso Corporal/efeitos dos fármacos , Região CA1 Hipocampal/efeitos dos fármacos , Região CA1 Hipocampal/metabolismo , Transtornos Cognitivos/psicologia , Relação Dose-Resposta a Droga , Regulação para Baixo/efeitos dos fármacos , Ingestão de Alimentos/efeitos dos fármacos , Disruptores Endócrinos , Feminino , Hipocampo/efeitos dos fármacos , Masculino , Aprendizagem em Labirinto/efeitos dos fármacos , Camundongos , Camundongos Endogâmicos ICR , Neurônios/patologia , Receptores dos Hormônios Tireóideos/efeitos dos fármacos , Caracteres Sexuais
12.
Bratisl Lek Listy ; 121(8): 580-583, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32726121

RESUMO

OBJECTIVES: We investigated the effect of low, medium and high doses of oral vitamin A, on the number of fetal hippocampal neurons. BACKGROUND: High doses of vitamin A during pregnancy may cause embryonic malformations. There are reports about dosages that don't cause macroscopic malformations, but may cause mental and behavioral disorders. Still, quantitative morphological studies explaining this topic are lacking. METHODS: We administered oral vitamin A to pregnant rats on the 10th-12th days of pregnancy at doses of 10000, 20000, 30000, 40000, 50000, 100000 and 200000 IU/kg. We collected the fetuses on the 19th day and removed their brains. After staining with cresyl violet and immunolabeling with Tunel and Ki67 antibody, we examined the hippocampi with stereological methods. RESULTS: Vitamin A decreased hippocampal neuron numbers beginning from 20000 IU/kg. While the number of Ki67 positive cells increased with the dosage, the increase of apoptotic cells begun at the dose of 50000 IU/kg. CONCLUSION: Our study demonstrates that vitamin A, beginning from the dosage of 20000 IU/kg, is decreasing the total hippocampal neuron numbers during the critical period of embryonic brain development and that apoptosis may not be the only factor in this outcome (Tab. 1, Fig. 3, Ref. 27).


Assuntos
Hipocampo , Neurônios , Vitamina A , Vitaminas , Animais , Apoptose , Feminino , Hipocampo/efeitos dos fármacos , Marcação In Situ das Extremidades Cortadas , Neurônios/efeitos dos fármacos , Gravidez , Ratos , Vitamina A/farmacologia , Vitaminas/farmacologia
13.
Life Sci ; 258: 118107, 2020 Oct 01.
Artigo em Inglês | MEDLINE | ID: mdl-32682919

RESUMO

Cognitive impairment has been widely recognized as a common symptom of chronic stress. Ginsenoside Rd (GRd), the major active compound in Panax ginseng, was previously reported in various neurological researches. However, little research is available regarding on the effect of GRd on cognitive improvement in mice subjected to chronic stress. In the present study, we investigated the neuroprotective effects of GRd in chronic restraint stress (CRS)-induced cognitive deficits and explored the potential mechanism in male C57BL/6J mice. Our results demonstrated that oral administration of GRd for 28 days markedly increased the spontaneous alternation in Y-maze and the relative discrimination index in novel object or location recognition tests following CRS. Additionally, GRd treatment considerably increased the antioxidant enzymes activities in the hippocampus. The expression levels of hippocampus and serum inflammation factors in the CRS groups were also counter-regulated by GRd treatment. Meanwhile, GRd treatment could reverse CRS-induced the decrease in phosphorylated phosphoinositide 3-kinase (PI3K), camp-reflecting element binding protein (CREB), brain-derived neurotrophic factor (BDNF) and tyrosine kinase B (TrkB) expression in the hippocampus. These findings provided evidences that GRd improves cognitive impairment in CRS mice by mitigating oxidative stress and inflammation, while upregulating the hippocampal BDNF-mediated CREB signaling pathway.


Assuntos
Fator Neurotrófico Derivado do Encéfalo/metabolismo , Disfunção Cognitiva/tratamento farmacológico , Disfunção Cognitiva/metabolismo , Proteína de Ligação ao Elemento de Resposta ao AMP Cíclico/metabolismo , Ginsenosídeos/uso terapêutico , Restrição Física , Transdução de Sinais , Estresse Psicológico/tratamento farmacológico , Animais , Doença Crônica , Disfunção Cognitiva/sangue , Disfunção Cognitiva/fisiopatologia , Modelos Animais de Doenças , Ginsenosídeos/química , Ginsenosídeos/farmacologia , Hipocampo/efeitos dos fármacos , Hipocampo/enzimologia , Hipocampo/patologia , Hipocampo/fisiopatologia , Inflamação/sangue , Masculino , Aprendizagem em Labirinto/efeitos dos fármacos , Memória de Curto Prazo/efeitos dos fármacos , Camundongos Endogâmicos C57BL , Modelos Biológicos , Atividade Motora/efeitos dos fármacos , Estresse Oxidativo/efeitos dos fármacos , Receptor trkB/metabolismo , Transdução de Sinais/efeitos dos fármacos , Estresse Psicológico/sangue , Estresse Psicológico/fisiopatologia
14.
Adv Pharmacol ; 89: 3-41, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32616211

RESUMO

A single sub-anesthetic intravascular dose of the use-dependent NMDAR antagonist, ketamine, improves mood in patients with treatment resistant depression within hours that can last for days, creating an entirely new treatment strategy for the most seriously ill patients. However, the psychomimetic effects and abuse potential of ketamine require that new therapies be developed that maintain the rapid antidepressant effects of ketamine without the unwanted side effects. This necessitates a detailed understanding of what cellular and synaptic mechanisms are immediately activated once ketamine reaches the brain that triggers the needed changes to elicit the improved behavior. Intense research has centered on the effects of ketamine, and the other rapidly acting antidepressants, on excitatory and inhibitory circuits in hippocampus and medial prefrontal cortex to determine common mechanisms, including key modifications in synaptic transmission and the precise location of the NMDARs that mediate the rapid and sustained antidepressant response. We review data comparing the effects of ketamine with other NMDAR receptor modulators and the muscarinic M1 acetylcholine receptor antagonist, scopolamine, together with evidence supporting the disinhibition hypothesis and the direct inhibition hypothesis of ketamine's mechanism of action on synaptic circuits using preclinical models.


Assuntos
Antidepressivos/farmacologia , Hipocampo/fisiologia , Ketamina/farmacologia , Inibição Neural/efeitos dos fármacos , Transmissão Sináptica/efeitos dos fármacos , Animais , Hipocampo/efeitos dos fármacos , Humanos , Ketamina/administração & dosagem , Ketamina/uso terapêutico , Caracteres Sexuais
15.
Chem Biol Interact ; 328: 109144, 2020 Sep 01.
Artigo em Inglês | MEDLINE | ID: mdl-32653415

RESUMO

The debilitating nature of cognitive impairment in epilepsy and the potential of some traditional antiepileptics to further deteriorate cognitive function are areas of growing concern. Glucagon-like peptide-1 (GLP-1) deficiency has been linked to reduced seizure threshold as well as cognitive dysfunction. Here, we tested whether sitagliptin (SITA), by virtue of its neuroprotective properties, could alleviate both epilepsy and associated cognitive dysfunction in a rat model of kindling epilepsy. Chemical kindling was induced by subconvulsive doses of pentylenetetrazol (PTZ) (30 mg/kg; i.p). SITA (50 mg/kg; p.o) was administered 1 h before PTZ injections. SITA conceivably attenuated PTZ hippocampal histological insult, preserved neuronal integrity and amended neurotransmitter perturbations in rat hippocampi paralleled with enhanced hippocampal GLP-1 levels as well as the downstream cAMP content and protein kinase A (PKA) activity. Moreover, SITA improved cognitive functioning of rats in the Morris water maze which was coupled with hampered hippocampal p(Ser404)-tau and ß-amyloid proteins. SITA replenished p(Ser9)-glycogen synthase kinase-3ß (GSK-3ß). It also opposed the boosted matrix metalloproteinase-9 (MMP-9), brain-derived neurotrophic factor (BDNF), and insulin-like growth factor-1 (IGF-1) levels associated with PTZ administration along with mitigation of both ß-secretase-1 (BACE1) immunoreactivity and receptor for advanced glycation end products (RAGE) protein level in rat hippocampi. In conclusion, SITA subdues epileptic and cognitive upshots of PTZ kindling in rats, which might correspond to the modulation of BACE1, amyloidogenic/RAGE axis as well as GSK-3ß/MMP-9/BDNF signaling cascade. SITA effects are probably mediated via boosting GLP-1 and subsequently enhancing GLP-1/GLP-1R signaling.


Assuntos
Secretases da Proteína Precursora do Amiloide/metabolismo , Amiloide/metabolismo , Ácido Aspártico Endopeptidases/metabolismo , Transtornos Cognitivos/induzido quimicamente , Transtornos Cognitivos/metabolismo , Excitação Neurológica/efeitos dos fármacos , Receptor para Produtos Finais de Glicação Avançada/metabolismo , Transdução de Sinais , Fosfato de Sitagliptina/farmacologia , Peptídeos beta-Amiloides/metabolismo , Animais , Biomarcadores/metabolismo , Fator Neurotrófico Derivado do Encéfalo/metabolismo , Transtornos Cognitivos/patologia , Peptídeo 1 Semelhante ao Glucagon/metabolismo , Glicogênio Sintase Quinase 3 beta/metabolismo , Hipocampo/efeitos dos fármacos , Hipocampo/patologia , Fator de Crescimento Insulin-Like I/metabolismo , Masculino , Metaloproteinase 9 da Matriz/metabolismo , Inibição Neural/efeitos dos fármacos , Neurônios/efeitos dos fármacos , Neurônios/metabolismo , Neurônios/patologia , Neurotransmissores/metabolismo , Pentilenotetrazol , Ratos Wistar , Convulsões/induzido quimicamente , Convulsões/metabolismo , Convulsões/patologia , Transdução de Sinais/efeitos dos fármacos , Memória Espacial/efeitos dos fármacos , Proteínas tau/metabolismo
16.
Chem Biol Interact ; 328: 109195, 2020 Sep 01.
Artigo em Inglês | MEDLINE | ID: mdl-32707044

RESUMO

A previous study demonstrated that glutathione (GSH) produces specific antidepressant-like effect in the forced swimming test (FST), a predictive test of antidepressant activity. The present study investigated the involvement of multiple cellular targets implicated in the antidepressant-like effect of GSH in the FST. The antidepressant-like effect of GSH (300 nmol/site, icv) lasted up to 3 h when mice were submitted to FST. The central administration of oxidized GSH (GSSG, 3-300 nmol/site) did not alter the behavior of mice submitted to the FST. Furthermore, the combined treatment of sub-effective doses of GSH (100 nmol/site, icv) with a sub-effective dose of classical antidepressants (fluoxetine 10 mg/kg, and imipramine 5 mg/kg, ip) presented synergistic effect by decreasing the immobility time in the FST. The antidepressant-like effect of GSH was abolished by prazosin (1 mg/kg, ip, α1-adrenoceptor antagonist), baclofen (1 mg/kg, ip, GABAB receptor agonist), bicuculline (1 mg/kg, ip, GABAA receptor antagonist), l-arginine (750 mg/kg, ip, NO precursor), SNAP (25 µg/site, icv, NO donor), but not by yohimbine (1 mg/kg, ip, α2-adrenoceptor antagonist). The NMDA receptor antagonists, MK-801(0.001 mg/kg, ip) or GMP (0.5 mg/kg, ip), potentiated the effect of a sub-effective dose of GSH in the FST. These results suggest that the antidepressant-like effect induced by GSH is connected to the activation of α1 adrenergic and GABAA receptors, as well as the inhibition of GABAB and NMDA receptors and NO biosyntesis. We speculate that redox-mediated signaling on the extracelular portion of cell membrane receptors would be a common mechanism of action of GSH.


Assuntos
Antidepressivos/farmacologia , Glutationa/farmacologia , Terapia de Alvo Molecular , Antagonistas Adrenérgicos/farmacologia , Animais , Arginina/farmacologia , Sinergismo Farmacológico , Feminino , Glutationa/administração & dosagem , Hipocampo/efeitos dos fármacos , Hipocampo/metabolismo , Imobilização , Masculino , Camundongos , Receptores Adrenérgicos/metabolismo , Receptores de GABA/metabolismo , Receptores de N-Metil-D-Aspartato/antagonistas & inibidores , Receptores de N-Metil-D-Aspartato/metabolismo , S-Nitroso-N-Acetilpenicilamina/farmacologia , Natação
17.
Psychopharmacology (Berl) ; 237(8): 2499-2508, 2020 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-32483676

RESUMO

Evidence indicates that neuroplasticity-based cognitive training can improve cognition in patients with schizophrenia, but the individual response to training varies greatly between subjects. Hence, there is a need to understand the neurological underpinnings of cognitive training to reveal predictors of treatment response. D-serine is a crucial modulator of neuroplasticity, and decreased levels of D-serine may contribute to deficits in neuroplasticity in schizophrenia. Interestingly, we observed that training mice to identify auditory oddballs increased extracellular levels of D-serine in the hippocampus during training. Serine racemase (Srr) is the only source of brain D-serine; thus, it is possible that Srr may mediate the response to training. To test this hypothesis, we trained mice that have a mutated version of Srr (SrrY269*/SrrY269*) and reduced levels of D-serine in the same auditory training. SrrY269*/SrrY269* mice showed decreased performance during auditory training (defined as the capacity to discriminate an oddball during a sequence of tones). Importantly, auditory training improved prepulse inhibition (PPI) in SrrY269*/SrrY269* but not in wild-type mice. Finally, D-serine (100 mg/kg i.p.) given 30 min before training sessions to SrrY269*/SrrY269* mice improved training performance, but it did not enhance PPI. Taken together, our results show that D-serine is involved in the response to neuroplasticity-based auditory training and that PPI deficits can be improved by auditory oddball training even in the presence of neuroplasticity deficits.


Assuntos
Estimulação Acústica/métodos , Cognição/fisiologia , Inibição Pré-Pulso/fisiologia , Racemases e Epimerases/genética , Racemases e Epimerases/metabolismo , Animais , Cognição/efeitos dos fármacos , Hipocampo/efeitos dos fármacos , Hipocampo/metabolismo , Masculino , Camundongos , Camundongos Transgênicos , Plasticidade Neuronal/efeitos dos fármacos , Plasticidade Neuronal/fisiologia , Inibição Pré-Pulso/efeitos dos fármacos , Esquizofrenia/genética , Esquizofrenia/metabolismo , Serina/farmacologia
18.
Psychopharmacology (Berl) ; 237(8): 2531-2545, 2020 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-32488348

RESUMO

AIM: Indoleamine 2,3-dioxygenase 1 (IDO) is responsible for the progression of the kynurenine pathway, which has been implicated in the pathophysiology of inflammation-induced depression. It has been reported that asperosaponin VI (ASA VI) could play a neuroprotective role through anti-inflammatory and antioxidant. In this study, we examined the antidepressant effect of ASA VI in lipopolysaccharide (LPS)-treated mice and further explored its molecular mechanism by looking into the microglial kynurenine pathway. METHODS: To generate the model, LPS (0.83 mg/kg) was administered intraperitoneally to mice. The mice received ASA VI (10 mg/kg, 20 mg/kg, 40 mg/kg, and 80 mg/kg, i.p.) 30 min before LPS injection. Depressive-like behaviors were evaluated based on the duration of immobility in the forced swim test. Microglial activation and inflammatory cytokines were detected by immunohistochemistry, real-time PCR, and ELISA. The TLR4/NF-κB signaling pathway and the expression of IDO, GluA2, and CamKIIß were also measured by western blotting. RESULTS: ASA VI exhibited significant antidepressant activity in the presence of LPS on immobility and latency times in the forced swim test. The LPS-induced activation of microglia and inflammatory response were inhibited by ASA VI, which showed a dose-dependent pattern. TLR4/NF-κB signaling pathway also was suppressed by ASA VI in the hippocampus and prefrontal cortex of LPS-treated mice. Furthermore, ASA VI inhibited the increase in IDO protein expression and normalized the aberrant glutamate transmission in the hippocampus and prefrontal cortex caused by LPS administration. CONCLUSION: Our results propose a promising antidepressant effect for ASA VI possibly through the downregulation of IDO expression and normalization of the aberrant glutamate transmission. This remedying effect of ASA VI could be attributed to suppress microglia-mediated neuroinflammatory response via inhibiting the TLR4/NF-κB signaling pathway.


Assuntos
Antidepressivos/farmacologia , Indolamina-Pirrol 2,3,-Dioxigenase/antagonistas & inibidores , Microglia/efeitos dos fármacos , NF-kappa B/antagonistas & inibidores , Saponinas/farmacologia , Receptor 4 Toll-Like/antagonistas & inibidores , Animais , Anti-Inflamatórios/farmacologia , Antidepressivos/uso terapêutico , Células Cultivadas , Depressão/induzido quimicamente , Depressão/metabolismo , Depressão/psicologia , Expressão Gênica , Hipocampo/efeitos dos fármacos , Hipocampo/metabolismo , Indolamina-Pirrol 2,3,-Dioxigenase/biossíntese , Indolamina-Pirrol 2,3,-Dioxigenase/genética , Lipopolissacarídeos/toxicidade , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Microglia/metabolismo , NF-kappa B/metabolismo , Saponinas/uso terapêutico , Receptor 4 Toll-Like/metabolismo
19.
Psychopharmacology (Berl) ; 237(8): 2435-2449, 2020 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-32506234

RESUMO

RATIONALE: Νeurosteroids, like dehydroepiandrosterone (DHEA), play an important role in neurodegeneration and neural protection, but they are metabolized in androgens, estrogens, or other active metabolites. A newly developed synthetic DHEA analog, BNN27 ((20R)-3ß,21-dihydroxy-17R,20-epoxy-5-pregnene), exerts neurotrophic and neuroprotective actions without estrogenic or androgenic effects. OBJECTIVES: This study aimed to investigate potential anxiolytic or antidepressant properties of BNN27. METHODS: Male and female adult Wistar rats were treated with BNN27 (10, 30, or 90 mg/kg, i.p.) and subjected to behavioral tests measuring locomotion, exploration, and "depressive-like" behavior (open field, light/dark box, hole-board, and forced swim tests). The hippocampus and prefrontal cortex were collected for glutamate and GABA measurements, and trunk blood was collected for gonadal hormone analysis. RESULTS: Acute high-dose BNN27 reduced locomotion and exploratory behavior in both sexes. Intermediate acute doses (30 mg/kg) of BNN27 reduced exploration and testosterone levels only in males, and enhanced progesterone levels in both sexes. Notably, with the present design, BNN27 had neither anxiolytic nor antidepressant effects and did not affect estrogen levels. Interestingly, acute administration of a low BNN27 dose (10 mg/kg) increased glutamate turnover, GABA, and glutamine levels in the hippocampus. The same dose also enhanced glutamate levels in the prefrontal cortex of males only. Sex differences were apparent in the basal levels of behavioral, hormonal, and neurochemical parameters, as expected. CONCLUSIONS: BNN27 affects locomotion, progesterone, and testosterone levels, as well as the glutamatergic and GABAergic systems of the hippocampus and prefrontal cortex in a sex-dependent way.


Assuntos
Desidroepiandrosterona/farmacologia , Comportamento Exploratório/efeitos dos fármacos , Locomoção/efeitos dos fármacos , Neuroesteroides/farmacologia , Caracteres Sexuais , Animais , Desidroepiandrosterona/química , Comportamento Exploratório/fisiologia , Feminino , Hipocampo/efeitos dos fármacos , Hipocampo/metabolismo , Locomoção/fisiologia , Masculino , Neuroesteroides/química , Córtex Pré-Frontal/efeitos dos fármacos , Córtex Pré-Frontal/metabolismo , Ratos , Ratos Wistar
20.
PLoS One ; 15(6): e0232200, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32497066

RESUMO

Schizophrenia is a debilitating disorder affecting just under 1% of the population. While the symptoms of this disorder do not appear until late adolescence, pathological alterations likely occur earlier, during development in utero. While there is an increasing literature examining transcriptome alterations in patients, it is not possible to examine the changes in gene expression that occur during development in humans that will develop schizophrenia. Here we utilize three distinct rodent developmental disruption models of schizophrenia to examine potential overlapping alterations in the transcriptome, with a specific focus on markers of interneuron development. Specifically, we administered either methylazoxymethanol acetate (MAM), Polyinosinic:polycytidylic acid (Poly I:C), or chronic protein malnutrition, on GD 17 and examined mRNA expression in the developing hippocampus of the offspring 18 hours later. Here, we report alterations in gene expression that may contribute to the pathophysiology of schizophrenia, including significant alterations in interneuron development and ribosome function.


Assuntos
Perfilação da Expressão Gênica , Crescimento e Desenvolvimento , Esquizofrenia/genética , Animais , Comportamento Animal , Modelos Animais de Doenças , Feminino , Crescimento e Desenvolvimento/efeitos dos fármacos , Hipocampo/efeitos dos fármacos , Hipocampo/metabolismo , Desnutrição/complicações , Acetato de Metilazoximetanol/farmacologia , Poli I-C/farmacologia , Gravidez , Ratos , Ratos Sprague-Dawley , Esquizofrenia/etiologia , Esquizofrenia/fisiopatologia
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