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1.
Chemosphere ; 241: 125114, 2020 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-31683445

RESUMO

Di-(2-ethylhexyl) phthalate (DEHP) is a widely used plasticizer. It has neurotoxicity and exposure to it causes impairment of neurodevelopment, behavior and cognition. However, the molecular mechanisms responsible for the DEHP-induced neurotoxicity are not yet clearly defined. Tumor necrosis factor-induced protein 1 (TNFAIP1) was first discovered in umbilical vein endothelial cells and was further found to be important in the progress of Alzheimer's disease. Herein we explore the mechanism of TNFAIP1 in DEHP-induced neurotoxicity with the involvement of cyclic AMP response elements binding protein (CREB) signaling pathway in a mouse neuroblastoma cell line (N2a cells). We found that exposure to DEHP induced apoptosis and downregulated the expression of brain-derived neurotrophic factor (BDNF), synaptic proteins PSD 95 and synapsin-1 while upregulated the expression of TNFAIP1 and decreased the levels of phosphorylated Akt, CaMK Ⅳ, catalytic subunits of PKA and CREB in CREB signaling pathway. Knockdown of TNFAIP1 using TNFAIP1 small interfering RNA (siRNA) expression vector prevented DEHP from inhibiting CREB pathway, thus reduced apoptosis and restored expression of BDNF, PSD 95 and synapsin-1. Our data indicate that downregulation of TNFAIP1 prevents DEHP-induced neurotoxicity via activating CREB pathway. Therefore, TNFAIP1 is a potential target for relieving the DEHP-induced neurotoxicity and related neurological disorders.


Assuntos
Proteínas Adaptadoras de Transdução de Sinal/genética , Apoptose/efeitos dos fármacos , Proteína de Ligação ao Elemento de Resposta ao AMP Cíclico/metabolismo , Dietilexilftalato/toxicidade , Síndromes Neurotóxicas/prevenção & controle , Plastificantes , Proteínas Adaptadoras de Transdução de Sinal/deficiência , Animais , Linhagem Celular , Regulação para Baixo , Células Endoteliais/metabolismo , Células Endoteliais/patologia , Regulação da Expressão Gênica/efeitos dos fármacos , Camundongos , Neuroblastoma/patologia , Síndromes Neurotóxicas/etiologia , Ácidos Ftálicos , Plastificantes/toxicidade
2.
Life Sci ; 236: 116867, 2019 Nov 01.
Artigo em Inglês | MEDLINE | ID: mdl-31520598

RESUMO

AIM: Cyclophosphamide (CP) is a potent anticancer and immunosuppressant drug. Studies have shown significant oxidative stress and cognitive impairment but neuroinflammatory and histological aberrations with its administration is underexplored. Nerolidol (NER) is a lipophilic bioactive molecule with antioxidant and anti-inflammatory properties but it has not been explored for neuroprotective potential in CP-induced neurotoxic manifestations. Therefore, in the present study, we aimed to evaluate the neuroprotective potential of NER in CP-induced neuroinflammation and associated comorbid conditions like depression and cognitive dysfunctions. MATERIALS AND METHOD: In-silico study using Schrödinger software was used to assess the binding affinity of NER with Nrf2. In the In vivo study, NER 200 and 400 mg/kg p.o. were given from 1st day to 14th day. CP 200 mg/kg, i.p., was administered on the 7th day. After 24 h of the last dosing, neurobehavioral tests like spontaneous body alternation, passive avoidance and forced swim test were performed. On completion of study, mice were sacrificed, hippocampus and cortex were removed for biochemical estimations, histopathology and immunohistochemistry of p65 NF- κB and Nrf2. KEY FINDINGS: In-silico study showed significant binding of NER into the pocket domain of Nrf2. In-vivo study showed protective effect of NER against CP-induced neuroinflammation, oxidative stress, cognitive impairment and structural abnormalities in the hippocampus and cortex regions. SIGNIFICANCE: Findings of the study suggested that NER is a potential therapeutic molecule which can mitigate CP-induced neurotoxic manifestations via Nrf2 and NF-κB pathway. However, more detailed studies are needed to explicate the mechanism underlying its neuroprotective effect.


Assuntos
Disfunção Cognitiva/prevenção & controle , Ciclofosfamida/toxicidade , Inflamação/prevenção & controle , Fator 2 Relacionado a NF-E2/metabolismo , NF-kappa B/metabolismo , Síndromes Neurotóxicas/prevenção & controle , Estresse Oxidativo/efeitos dos fármacos , Sesquiterpenos/farmacologia , Animais , Disfunção Cognitiva/induzido quimicamente , Disfunção Cognitiva/metabolismo , Disfunção Cognitiva/patologia , Regulação da Expressão Gênica , Hipocampo/efeitos dos fármacos , Hipocampo/metabolismo , Imunossupressores/toxicidade , Inflamação/induzido quimicamente , Inflamação/metabolismo , Inflamação/patologia , Masculino , Camundongos , Fator 2 Relacionado a NF-E2/genética , NF-kappa B/genética , Fármacos Neuroprotetores , Síndromes Neurotóxicas/etiologia , Síndromes Neurotóxicas/metabolismo , Síndromes Neurotóxicas/patologia , Transdução de Sinais
3.
Aerosp Med Hum Perform ; 90(9): 807-812, 2019 Sep 01.
Artigo em Inglês | MEDLINE | ID: mdl-31426897

RESUMO

INTRODUCTION: The previous Spacecraft Maximal Allowable Concentrations (SMACs) for methanol were established by characterizing minor effects upon cognitive functions as a no-observable adverse effects level (NOAEL). However, an increasing awareness of the risk posed by Space-Associated Neuro-ocular Syndrome (SANS) has caused NASA Toxicology to reexamine SMACs for methanol because exposure to it can also adversely affect ocular health. An updated review of the literature indicates that no adjustments to the SMACs due to SANS complications were required, while confirming that effects upon the central nervous system remain the appropriate basis for the SMACs for methanol. Our review, however, identified several issues that provide justification for modest SMAC reductions. It has recently been recognized that inhaled methanol may reach the brain via the olfactory system and be absorbed there into the highly toxic metabolite formaldehyde. A benchmark dose (BMD) for an extra risk of 10%, derived from an analysis of the incidences of neurological lesions in monkeys chronically exposed to methanol, is an order of magnitude less than the Environmental Protection Agency's (EPA's) reference concentration for chronic inhalation of methanol. Reports calling attention to the relative insensitivity of traditional methods of assessing cognitive function erode confidence that adverse effects at the concentration reported as a NOAEL would have been recognizable. Therefore, an additional modest safety factor of three is applied to SMACs for methanol.Scully RR, Garcia H, McCoy JT, Ryder VE. Revisions to limits for methanol in the air of spacecraft. Aerosp Med Hum Perform. 2019; 90(9):807-812.


Assuntos
Cognição/efeitos dos fármacos , Metanol/toxicidade , Síndromes Neurotóxicas/prevenção & controle , Astronave/normas , Níveis Máximos Permitidos , Animais , Astronautas , Modelos Animais de Doenças , Haplorrinos , Humanos , Incidência , Concentração Máxima Permitida , Síndromes Neurotóxicas/epidemiologia , Síndromes Neurotóxicas/etiologia , Nível de Efeito Adverso não Observado , Exposição Ocupacional/normas , Testes de Toxicidade Crônica
4.
Environ Sci Pollut Res Int ; 26(30): 31254-31262, 2019 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-31468353

RESUMO

Cadmium (Cd) has long been noted to induce neurodegenerative disorders. Therefore, this study aimed to assess the toxicological impact of Cd on rat brains and evaluate the possible ameliorative impact of omega-3 fatty acids as a protective agent of nervous system. Rats were divided into four groups: group I supplemented orally with saline; group II intoxicated with CdCl2 (5 mg/kg b.w. orally), and groups III and VI supplemented with omega-3 (100 mg/kg b.w. orally) simultaneously or before CdCl2 administration, respectively. Cd intoxication induced biochemical and histopathological disturbances in treated rats. Omega-3 fatty acid considerably improved the Cd-associated biochemical changes, reduced the elevation of lipid peroxidation, and normalized the Cd impact on the levels of superoxide dismutase, catalase, glutathione-S-transferases, 8-hydroxydeoxyguanosine, heatshock protein70, nuclear factor-κB, and interferon-γ as well as of neuronal enzymes such as acetylecholinesterase and monoamine oxidase within the brains of treated rats. Additionally, histological findings supported the results that Cd treatment-induced neurodegenerative changes and that polyunsaturated fatty acids act as antioxidants and neuroprotective agents against Cd toxicity. Co-treatment with omega-3 fatty acid was more beneficial than pretreatment. Thus, omega-3 fatty acid should be included in diet to prevent or suppress neurodegenerative disorders caused by continuous exposure to Cd.


Assuntos
Cádmio/toxicidade , Ácidos Graxos Ômega-3/farmacologia , Fármacos Neuroprotetores/farmacologia , Síndromes Neurotóxicas/patologia , Síndromes Neurotóxicas/prevenção & controle , Animais , Antioxidantes/farmacologia , Encéfalo/efeitos dos fármacos , Encéfalo/patologia , Cloreto de Cádmio/toxicidade , Intoxicação por Cádmio/prevenção & controle , Suplementos Nutricionais , Enzimas/metabolismo , Peroxidação de Lipídeos/efeitos dos fármacos , Masculino , Neurônios/efeitos dos fármacos , Neurônios/metabolismo , Síndromes Neurotóxicas/etiologia , Ratos
5.
Neurochem Res ; 44(8): 2020-2029, 2019 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-31264110

RESUMO

The neurotoxic effects of aluminum are generally associated with reduced antioxidant capacity, increased oxidative stress and apoptosis, which lead to the induction of neurodegenerative processes. Curcumin has a lipophilic polyphenol character and effects of antioxidant and anti-apoptotic. The present study was undertaken to examine possible aluminum exposure in rats brain synaptosomes and to investigate whether protective and therapeutic effects of curcumin on biochemical and morphological changes in both pre- and post-treated groups. Aluminum chloride (AlCl3) at 50 µM concentration and curcumin at 5 and 10 µg/mL doses were applied to hippocampal synaptosomes of rats according to experimental design. Biochemical effects were evaluated by MTT cytotoxicity, malondialdehyde (MDA) levels, nitric oxide (NO) levels, glutathione (GSH) levels, caspase 3 activities, cytochrome c levels, DNA fragmentation values and protein levels. Morphological examinations were done by TEM analysis. AlCI3 exposure in the synaptosomes enhanced oxidative stress, triggered apoptosis and caused ultrastructural alterations which were well reflected in the TEM images. Curcumin pre-treatment slightly ameliorated the MDA levels, NO levels, cytochrome c levels and caspase 3 activities in AlCI3-exposed synaptosomes, but these results were not statistically significant. Furthermore, curcumin post-treatment significantly improved oxidative damage and morphological alterations, and suppressed cytochrome c and caspase 3 activities. Taken together, our data showed that curcumin had more therapeutic effects than protective effects in AlCI3-induced neurotoxicity. Nevertheless, the therapeutic (post-protective) effects of curcumin should be further investigated in in vivo neurodegenerative models involving behavioral tests.


Assuntos
Alumínio/efeitos adversos , Curcumina/uso terapêutico , Hipocampo/efeitos dos fármacos , Síndromes Neurotóxicas/tratamento farmacológico , Sinaptossomos/efeitos dos fármacos , Animais , Apoptose/efeitos dos fármacos , Caspase 3/metabolismo , Citocromos c/metabolismo , Fragmentação do DNA/efeitos dos fármacos , Glutationa/metabolismo , Peroxidação de Lipídeos/efeitos dos fármacos , Masculino , Malondialdeído/metabolismo , Fármacos Neuroprotetores/uso terapêutico , Síndromes Neurotóxicas/prevenção & controle , Óxido Nítrico/metabolismo , Estresse Oxidativo/efeitos dos fármacos , Ratos Wistar
7.
Environ Sci Pollut Res Int ; 26(20): 20731-20741, 2019 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-31104238

RESUMO

Chlorpyrifos (CPF) is a widely used organophosphate insecticide with several harmful effects. N-acetylcysteine (NAC) represents an ideal antixenobiotic; it can directly enter endogenous biochemical processes and is used as adjunctive treatment for psychiatric disorders. We aimed to evaluate the neuroprotective effect of NAC as an antioxidant drug against CPF-induced neurotoxicity in adult male albino rat brains. Twenty-eight male Wister rats were allocated into four groups (n = 7) and were administered the following for 28 days: group I (control group), physiological saline (0.9% NaCl); group II (CPF group), 10 mg/kg body weight (BW) CPF; group III (NAC group), 100 mg/kg BW NAC; and group VI (CPF+NAC group), NAC 1 h before CPF. CPF intoxication resulted in acetylcholinesterase inhibition, reduced glutathione content, and elevated levels of malondialdehyde and nitric oxide, which are oxidative stress biomarkers. CPF also depleted the activity of antioxidant enzymes, superoxide dismutase and catalase, and levels of inflammatory mediators, tumor necrosis factor-α, interleukin (IL)-6, and IL-1ß. Levels of vascular endothelial growth factor, Bax, and the proapoptotic caspases-3 also increased, while brain-derived neurotrophic factor level decreased. Additionally, CPF significantly diminished Bcl-2 (an antiapoptotic protein) in rat brain cortical tissue. NAC treatment was found to protect brain tissue by reversing the CPF-induced neurotoxicity. Our results show the antioxidant, antiinflammatory, and antiapoptotic effects of NAC on CPF-induced neurotoxicity in rat brain tissue.


Assuntos
Acetilcisteína/uso terapêutico , Antioxidantes/uso terapêutico , Clorpirifos/toxicidade , Inseticidas/toxicidade , Síndromes Neurotóxicas/prevenção & controle , Acetilcisteína/farmacologia , Animais , Antioxidantes/farmacologia , Encéfalo/efeitos dos fármacos , Encéfalo/metabolismo , Encéfalo/patologia , Masculino , Síndromes Neurotóxicas/metabolismo , Síndromes Neurotóxicas/patologia , Estresse Oxidativo/efeitos dos fármacos , Ratos Wistar
8.
Curr Drug Saf ; 14(3): 209-216, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31057112

RESUMO

BACKGROUND: Cyclophosphamide (CPA) is the most widely prescribed cancer chemotherapeutic agent which shows serious neurotoxic side effect. Generation of reactive oxygen species at the cellular level is the basic mechanism of cyclophosphamide induced neurotoxicity. Edaravone is the synthetic drug used for brain stroke and has potent antioxidant property. OBJECTIVE: This study aimed to investigate the effect of edaravone on neurobehavioral and neuropathological alteration induced by cyclophosphamide in male rats. METHODS: Twenty eight Sprague-Dawley rats were equally divided into four groups of seven rats in each. The control group received saline, and other groups were given CPA intraperitoneally (100 mg/kg), CPA (100 mg/kg) intraperitoneally + Edaravone (10 mg/kg) orally, or Edaravone (10 mg/kg) orally for one month. RESULTS: Our data showed that CPA significantly elevated brain AChE activity in the hippocampal region. A decrease in the total antioxidant capacity and a reduction in the CAT, SOD, and GPX activity occurred in the brains of the rats exposed to CPA. CPA-treated rats showed a significant impairment in long-termmemory and motor coordination. These results were supported by histopathological observations of the brain. Results revealed that administration of edaravone reversed AChE activity alternation and ameliorated behavioral and histopathological changes induced by CPA. CONCLUSION: This study suggests that co-administration of edaravone with cyclophosphamide may be a useful intriguing therapeutic approach to overcome cyclophosphamide induced neurotoxicity.


Assuntos
Ciclofosfamida/toxicidade , Edaravone/farmacologia , Síndromes Neurotóxicas/prevenção & controle , Estresse Oxidativo/efeitos dos fármacos , Acetilcolinesterase/metabolismo , Animais , Proteínas Ligadas por GPI/metabolismo , Masculino , Síndromes Neurotóxicas/enzimologia , Ratos Sprague-Dawley
9.
Anticancer Res ; 39(3): 1347-1353, 2019 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-30842168

RESUMO

BACKGROUND/AIM: Chemotherapy dose adjustments in colorectal cancer are usually based on body surface area (BSA). The goal of this study was to investigate patients with nutritional disorder who developed early peripheral neuropathy due to inappropriate dose adjustment of oxaliplatin. PATIENTS AND METHODS: The study subjects were 88 patients with advanced or recurrent colorectal cancer who underwent chemotherapy with oxaliplatin. The psoas muscle area (PMA) was used as a nutritional index. Mild (grades 0-1, MN group) and severe (grades 2-3, SN group) peripheral neuropathy was defined using neurotoxicity criteria of Debiopharm. RESULTS: Severe peripheral neuropathy developed in 29 patients (33.0%). The total oxaliplatin dose/PMA was significantly higher for the SN group (107.6±8.5 mg/cm2) and compared with the MN group (53.8±6.0 mg/cm2) in univariate (p<0.0001) and multivariate (p=0.012) analyses. CONCLUSION: In order to prevent peripheral neuropathy from chemotherapy for colorectal cancer, dose adjustment of oxaliplatin should be based on PMA, in addition to BSA.


Assuntos
Antineoplásicos/efeitos adversos , Neoplasias Colorretais/tratamento farmacológico , Síndromes Neurotóxicas , Oxaliplatina/efeitos adversos , Doenças do Sistema Nervoso Periférico/induzido quimicamente , Idoso , Antineoplásicos/administração & dosagem , Superfície Corporal , Neoplasias Colorretais/diagnóstico por imagem , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Músculo Esquelético/diagnóstico por imagem , Recidiva Local de Neoplasia , Síndromes Neurotóxicas/diagnóstico por imagem , Síndromes Neurotóxicas/prevenção & controle , Oxaliplatina/administração & dosagem , Doenças do Sistema Nervoso Periférico/diagnóstico por imagem , Doenças do Sistema Nervoso Periférico/prevenção & controle
10.
Basic Clin Pharmacol Toxicol ; 125(2): 142-151, 2019 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-30793490

RESUMO

High-dose cyclophosphamide (HD-CTX) treatment often leads to severe nephrotoxicity and neurotoxicity, which are mainly caused by one of its metabolites, chloroacetaldehyde (CAA). However, there are no effective antidotes to prevent these side effects. The objective of this study was to evaluate the effect of Wuzhi Capsule (WZC) on the pharmacokinetics of CTX and its metabolites in rats, and the attenuation of CAA induced kidney and brain injuries, which was produced at equimolar with 2-dechloroethylcyclophosphamide. Rats were treated with single- or multiple-dose of WZC when giving HD-CTX, and the plasma concentration of CTX and its metabolites were quantitated by UHPLC-MS/MS Single-dose, not multiple-dose of WZC co-administration (300 mg/kg) significantly reduced Cmax and AUC0→24 h of DC-CTX by 33.10% and 35.51%, respectively. Biochemical assay suggested oxidative stress was involved in kidney and brain injuries by HD-CTX, which were attenuated by single-dose WZC (300 mg/kg) pre-treatment, with increased glutathione, glutathione peroxidase and superoxide dismutase contents/or activities in both tissues and plasma (P < 0.05). Meanwhile, WZC pre-treatment could also significantly decrease the plasma levels of creatinine, blood urea nitrogen and malondialdehyde (P < 0.05). Additionally, WZC treatment improved the morphology and pathology condition of the kidneys and brains in rats. In conclusion, single-dose WZC co-administration decreased CAA production and exerted protective effect on CTX-induced oxidative stress in kidney and brain, whereas repetitive WZC co-administration with CTX was probably not recommended.


Assuntos
Acetaldeído/análogos & derivados , Ciclofosfamida/toxicidade , Medicamentos de Ervas Chinesas/uso terapêutico , Síndromes Neurotóxicas/prevenção & controle , Insuficiência Renal/prevenção & controle , Acetaldeído/farmacocinética , Acetaldeído/toxicidade , Animais , Encéfalo/efeitos dos fármacos , Encéfalo/patologia , Ciclofosfamida/administração & dosagem , Ciclofosfamida/farmacocinética , Modelos Animais de Doenças , Relação Dose-Resposta a Droga , Humanos , Rim/efeitos dos fármacos , Rim/patologia , Masculino , Síndromes Neurotóxicas/etiologia , Síndromes Neurotóxicas/patologia , Estresse Oxidativo/efeitos dos fármacos , Ratos , Insuficiência Renal/induzido quimicamente , Insuficiência Renal/patologia
11.
Biosci Rep ; 39(3)2019 03 29.
Artigo em Inglês | MEDLINE | ID: mdl-30777931

RESUMO

The extensive use of fipronil (FPN) may trigger hazards to more than insects. The present investigation was carried out to evaluate the abrogating role of Terminalia laxiflora (TL) methanol extract (TLE) against the neurotoxic effects provoked by FPN. Fourty male albino rats were assigned into four equal groups. The first group served as control, the second one was orally administered FPN (10.5 mg/kg BW), the third group was given combination of FPN and TLE) (100 mg/kg BW), and the fourth one was orally given TLE. Our findings highlighted the efficacy of TLE as a neuroprotectant through a significant reduction in malondialdehyde (MDA) content by 25.8%, elevations of the reduced glutathione (GSH) level, catalase (CAT,) and superoxide dismutase (SOD) activities by 30.9, 41.2, and 48.2% respectively. Consequently, the relative mRNA levels of both Bax and caspase-3 were down-regulated by 40.54% and caspase-3 by 30.35% compared with the control group. Moreover, restoration of the pathological tissue injuries were detected. In conclusion, TLE proved to be a potent neuroprotective agent against the FPN-induced toxicity.


Assuntos
Síndromes Neurotóxicas/prevenção & controle , Extratos Vegetais/farmacologia , Pirazóis/toxicidade , Terminalia/química , Animais , Caspase 3/genética , Caspase 3/metabolismo , Catalase/metabolismo , Glutationa/metabolismo , Inseticidas/toxicidade , Masculino , Malondialdeído/metabolismo , Metanol/química , Fármacos Neuroprotetores/química , Fármacos Neuroprotetores/farmacologia , Síndromes Neurotóxicas/etiologia , Síndromes Neurotóxicas/metabolismo , Extratos Vegetais/química , Ratos , Superóxido Dismutase/metabolismo
12.
Toxicology ; 414: 1-13, 2019 02 15.
Artigo em Inglês | MEDLINE | ID: mdl-30605698

RESUMO

The heavy metal cadmium (Cd) is well known to be neurotoxic. Studies have shown that apoptosis plays an essential role in Cd-induced brain injury; however, the mechanisms underlying this injury accompanied by apoptosis have yet to be elucidated. The endoplasmic reticulum (ER) stress plays a key part in the regulation of apoptosis. ER stress is defined as accumulation of unfolded or misfolded proteins in the ER. Here, we demonstrated the role of ER stress on Cd-evoked apoptosis in neuronal cells, as well as the neuroprotective effects of the antioxidant alpha-lipoic acid (α-LA) on Cd-induced ER stress and neuronal injury. In vitro, we observed that Cd activated ER associated proteins via the eIF2α-ATF4 pathway in primary rat cerebral cortical neurons. Furthermore, the ER-stress inhibitor salubrinal blocked the dephosphorylation of eukaryotic translation initiation factor 2α (eIF2α) and significantly reduced the induction of ER stress marker CHOP, the increase of the B-cell lymphoma-2 associate X protein (Bax)/B-cell lymphoma-2 (Bcl-2) ratio, and apoptosis induced by Cd. In addition, Z-ATAD-FMK (a caspase-12 inhibitor) counteracted the Cd-induced activation of caspase-12 and -3, and apoptosis. These in vitro results collectively suggested that ER stress was required for Cd-induced neuronal apoptosis. Importantly, α-LA inhibited the activation of the ER stress eIF2α-ATF4 pathway, the increase of the Bax/Bcl-2 ratio, the activation of caspase-12 and -3, and the apoptosis induced by Cd. In vivo, we also found that the administration of α-LA alleviated Cd-induced neuronal injury, inhibited the activation of the ER stress eIF2α-ATF4 pathway, restored the Bax/Bcl-2 ratio, and prevented the activation of caspase-12 and -3. Taken together, our results demonstrated that Cd triggered protein changes in the ER accompanied by apoptosis via the eIF2α-ATF4 signaling pathway in the neuronal cells of rats, both in vitro and in vivo. Furthermore, we demonstrated for the first time that α-LA protected neurons from Cd-induced injury partly by inhibiting ER stress in rat cerebral cortical neurons.


Assuntos
Acetatos/toxicidade , Fator 4 Ativador da Transcrição/metabolismo , Apoptose/efeitos dos fármacos , Cádmio/toxicidade , Córtex Cerebral/efeitos dos fármacos , Estresse do Retículo Endoplasmático/efeitos dos fármacos , Fator de Iniciação 2 em Eucariotos/metabolismo , Neurônios/efeitos dos fármacos , Fármacos Neuroprotetores/farmacologia , Síndromes Neurotóxicas/prevenção & controle , Ácido Tióctico/farmacologia , Animais , Proteínas Reguladoras de Apoptose/metabolismo , Células Cultivadas , Córtex Cerebral/metabolismo , Córtex Cerebral/patologia , Citoproteção , Feminino , Neurônios/metabolismo , Neurônios/patologia , Síndromes Neurotóxicas/metabolismo , Síndromes Neurotóxicas/patologia , Ratos Sprague-Dawley , Transdução de Sinais/efeitos dos fármacos
13.
Mol Neurobiol ; 56(5): 3326-3340, 2019 May.
Artigo em Inglês | MEDLINE | ID: mdl-30120732

RESUMO

Tissue acidosis is a common feature of brain ischemia which causes neuronal injury. Activation of acid-sensing ion channel 1a (ASIC1a) plays an important role in acidosis-mediated neurotoxicity. Acute ethanol administration has been shown to provide neuroprotective effects during ischemic stroke, but the precise mechanisms have yet to be determined. In this study, we investigated the effect of ethanol on the activity/expression of ASIC1a channels and acidosis-induced neurotoxicity. We showed that acute treatment of neuronal cells with ethanol for more than 3 h could reduce ASIC1a protein expression, ASIC currents, and acid-induced [Ca2+]i elevation. We further demonstrated that ethanol-induced reduction of ASIC1a expression is mediated by autophagy-lysosome pathway (ALP)-dependent protein degradation. Finally, we showed that ethanol protected neuronal cells against acidosis-induced cytotoxicity, which effect was mimicked by autophagy activator rapamycin and abolished by autophagy inhibitor CQ. Together, these results indicate that moderate acute ethanol exposure can promote autophagy-lysosome pathway-dependent ASIC1a protein degradation and protect against acidosis-induced neurotoxicity.


Assuntos
Canais Iônicos Sensíveis a Ácido/metabolismo , Acidose/complicações , Autofagia , Etanol/efeitos adversos , Lisossomos/metabolismo , Síndromes Neurotóxicas/etiologia , Síndromes Neurotóxicas/prevenção & controle , Proteólise , Animais , Apoptose/efeitos dos fármacos , Autofagia/efeitos dos fármacos , Cálcio/metabolismo , Proteínas Quinases Dependentes de AMP Cíclico/metabolismo , Ativação Enzimática/efeitos dos fármacos , Ativação do Canal Iônico/efeitos dos fármacos , Lisossomos/efeitos dos fármacos , Sistema de Sinalização das MAP Quinases/efeitos dos fármacos , Camundongos , Neurônios/efeitos dos fármacos , Neurônios/metabolismo , Proteólise/efeitos dos fármacos , Canais de Sódio/metabolismo
14.
J Matern Fetal Neonatal Med ; 32(11): 1813-1819, 2019 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-29295636

RESUMO

OBJECTIVE: Unconjugated bilirubin (UCB) may cause neurotoxicity in preterm neonates due to immaturity of UGT1A1 leading to bilirubin accumulation in the brain. Caffeine used in the treatment of apnea of prematurity was reported to decrease mechanical ventilation requirement, the frequencies of bronchopulmonary dysplasia, patent ductus arteriosus, cerebral palsy and neurodevelopmental disorders in very low birth weight infants. However, the effect of caffeine on hyperbilirubinemia was not yet clarified. METHODS: We used astrocyte cell cultures obtained from 2-day-old Wistar albino rats via modified Cole and de Vellis method. UCB concentration toxic to 50% of astrocytes, and caffeine concentration increasing cell viability 100% were used in experiments. While no medication was applied to the control group, UCB (50 µM) and caffeine (100 µM) were applied to the bilirubin and caffeine groups for 24 h. Prophylactic and therapeutic caffeine groups were treated with caffeine 4 h before and after UCB exposure. The effects of caffeine were investigated in rat astrocytes exposed to UCB in terms of cell viability, apoptosis, antioxidant defense, proinflammatory cytokines, and Toll-like receptor (TLR)s. RESULTS: Compared to the control group, UCB increased apoptosis, malondialdehyde (MDA), tumor necrosis factor-α (TNF-α), interleukin (IL)-1ß, IL-6, total nitrate/nitrite, and TLR4 levels, and decreased cell viability, catalase (CAT), glutathione peroxidase (GPx), superoxide dismutase (SOD) activities, glutathione, and TLR9 levels (for all p < .001). Conversely, prophylactic and therapeutic caffeine improved the detrimental effects of UCB. CONCLUSIONS: Caffeine seems encouraging for the prevention and treatment of bilirubin neurotoxicity in rats by means of its antiapoptotic, antioxidant, anti-inflammatory, anti-nitrosative, and anti-TLR-4 properties.


Assuntos
Astrócitos/efeitos dos fármacos , Cafeína/uso terapêutico , Hiperbilirrubinemia/complicações , Síndromes Neurotóxicas/prevenção & controle , Antagonistas de Receptores Purinérgicos P1/uso terapêutico , Animais , Animais Recém-Nascidos , Células Cultivadas , Avaliação Pré-Clínica de Medicamentos , Síndromes Neurotóxicas/etiologia , Ratos Wistar
15.
Toxicol Sci ; 167(2): 397-407, 2019 02 01.
Artigo em Inglês | MEDLINE | ID: mdl-30247689

RESUMO

Chronic exposure to 1-bromopropane (1-BP), an alternative to ozone-depleting solvents, produces potential neurotoxicity in occupational populations. However, no therapeutic strategy is available currently. Accumulating evidence suggests that cytochrome P4502E1 (CYP2E1) is critical for the active metabolism of 1-BP. The purpose of this study is aimed to test whether inhibition of CYP2E1 by allyl sulfide, a specific inhibitor of CYP2E1, could be able to protect against 1-BP-induced neurotoxicity. Male Wistar rats were intoxicated with 1-BP for 9 continuous weeks with or without allyl sulfide pretreatment. Results clearly demonstrated that 1-BP exposure induced decrease in NeuN+ cells and increase in cleaved caspase-3 expression and TUNEL+ cells in motor cortex of rats, which was significantly ameliorated by allyl sulfide. Allyl sulfide treatment also recovered the motor performance of rats treated with 1-BP. Mechanistically, allyl sulfide-inhibited 1-BP-induced expression of CYP2E1 in microglia, which was associated with suppression of microglial activation and M1 polarization in motor cortex of rats. Reduced oxidative stress was also observed in rats treated with combined allyl sulfide and 1-BP compared with 1-BP alone group. Furthermore, we found that allyl sulfide abrogated 1-BP-induced activation of Nuclear factor(NF)-κB and GSH/Thioredoxin/ASK1 pathways, the key factor for the maintenance of M1 microglial inflammatory response and oxidative stress-related neuronal apoptosis, respectively. Thus, our results showed that allyl sulfide exerted neuroprotective effects in combating 1-BP-induced neurotoxicity through inhibition of neuroinflammation and oxidative stress. Blocking CYP2E1 activity by allyl sulfide might be a promising avenue for the treatment of neurotoxicity elicited by 1-BP and other related neurotoxicants.


Assuntos
Compostos Alílicos/farmacologia , Córtex Motor/efeitos dos fármacos , Fármacos Neuroprotetores/farmacologia , Síndromes Neurotóxicas/prevenção & controle , Sulfetos/farmacologia , Animais , Apoptose/efeitos dos fármacos , Citocromo P-450 CYP2E1/metabolismo , Hidrocarbonetos Bromados/toxicidade , Inflamação , Masculino , Córtex Motor/imunologia , Córtex Motor/patologia , NF-kappa B/metabolismo , Neurônios/efeitos dos fármacos , Neurônios/patologia , Síndromes Neurotóxicas/imunologia , Síndromes Neurotóxicas/metabolismo , Síndromes Neurotóxicas/patologia , Estresse Oxidativo/efeitos dos fármacos , Ratos Wistar
16.
Wien Med Wochenschr ; 169(3-4): 56-60, 2019 Mar.
Artigo em Alemão | MEDLINE | ID: mdl-30229333

RESUMO

Pediatric anesthesia has always been conjuncted with higher risk than anesthesia for adults (JP Morray; Pediatric Anesthesia 2011;21:722-9). Not only the imminent critical events, but also, caused by recently published data, the theoretical neurotoxicity of anesthetic agents and a potencial negative influence of anesthetics on braindevelopement, are in the spotlight.Concerns about the neurodevelopement and the general warnings from the U.S. Food and Drug Administration (FDA) for anesthesia in young children led to a worldwide discussion about safety in pediatric anesthesia (FDA Safety Anouncement 2017).Beside these theoretical risks, which are based only on animal research, we have to pay much more attention to the widely spread out poor quality of anesthesia in children.The following article should summarize the state of science about the risks and the opportunities to minimize them.


Assuntos
Anestesia , Anestésicos , Síndromes Neurotóxicas , Anestesia/efeitos adversos , Anestesia/métodos , Anestesia/normas , Anestésicos/efeitos adversos , Anestésicos/metabolismo , Animais , Criança , Pré-Escolar , Humanos , Síndromes Neurotóxicas/etiologia , Síndromes Neurotóxicas/prevenção & controle , Segurança do Paciente , Segurança
17.
ACS Chem Neurosci ; 10(1): 120-131, 2019 01 16.
Artigo em Inglês | MEDLINE | ID: mdl-30362702

RESUMO

Neurotoxicity is one major unwanted side-effects associated with polymyxin (i.e., colistin and polymyxin B) therapy. Clinically, colistin neurotoxicity is characterized by neurological symptoms including dizziness, visual disturbances, vertigo, confusion, hallucinations, seizures, ataxia, and facial and peripheral paresthesias. Pathologically, colistin-induced neurotoxicity is characterized by cell injury and death in neuronal cell. This Review covers our current understanding of polymyxin-induced neurotoxicity, its underlying mechanisms, and the discovery of novel neuroprotective agents to limit this neurotoxicity. In recent years, an increasing body of literature supports the notion that polymyxin-induced nerve damage is largely related to oxidative stress and mitochondrial dysfunction. P53, PI3K/Akt, and MAPK pathways are also involved in colistin-induced neuronal cell death. The activation of the redox homeostasis pathways such as Nrf2/HO-1 and autophagy have also been shown to play protective roles against polymyxin-induced neurotoxicity. These pathways have been demonstrated to be upregulated by neuroprotective agents including curcumin, rapamycin and minocycline. Further research is needed toward the development of novel polymyxin formulations in combination with neuroprotective agents to ameliorate this unwanted adverse effect during polymyxins therapy in patients.


Assuntos
Quimioprevenção/métodos , Síndromes Neurotóxicas/prevenção & controle , Estresse Oxidativo/fisiologia , Polimixinas/toxicidade , Animais , Quimioprevenção/tendências , Humanos , Síndromes Neurotóxicas/metabolismo , Estresse Oxidativo/efeitos dos fármacos , Polimixinas/metabolismo , Espécies Reativas de Oxigênio/antagonistas & inibidores , Espécies Reativas de Oxigênio/metabolismo
18.
Neurosci Lett ; 690: 29-35, 2019 01 18.
Artigo em Inglês | MEDLINE | ID: mdl-30304707

RESUMO

Oxidative stress and mitochondrial dysfunction are two pathophysiological factors often associated with the neurodegenerative process involved in Parkinson's disease (PD). The aim of this study was to investigate the effects of a novel hybrid molecule, named JM-20, in different in vitro and in vivo models of PD induced by rotenone. To perform in vitro studies, SHSY-5Y cells were exposed to rotenone and/or treated with JM-20. To perform in vivo studies male Wistar rats were intoxicated with rotenone (2.5 mg/kg) via intraperitoneal injection and/or treated with JM-20 (40 mg/kg) administered via oral (for 25 days, both treatment). Rats were evaluated for global motor activity by measurement of locomotor activity. In addition, the effects on mortality, general behavior and redox parameters were also investigated. JM-20 protected SHSY-5Y cells against rotenone-induced cytotoxicity, evidenced by a significant diminution of cell death. In in vivo studies, JM-20 prevented rotenone-induced vertical exploration and locomotion frequency reductions, moreover prevented body weight loss and mortality induced by rotenone. It also improved the redox state of rotenone-exposured animals by increasing superoxide dismutase and catalase activities, total tissue-SH levels and decreasing malondialdehyde concentrations. Finally, JM-20 inhibited spontaneous mitochondrial swelling and membrane potential dissipation in isolated rats brain mitochondria. These results demonstrate that JM-20 is a potential neuroprotective agent against rotenone-induced damage in both in vitro and in vivo models, resulting in reduced neuronal oxidative injury and protection of mitochondria from impairment.


Assuntos
Benzodiazepinas/farmacologia , Fármacos Neuroprotetores/farmacologia , Síndromes Neurotóxicas/prevenção & controle , Niacina/análogos & derivados , Rotenona/toxicidade , Animais , Peso Corporal/efeitos dos fármacos , Encéfalo/metabolismo , Catalase/metabolismo , Morte Celular/efeitos dos fármacos , Células Cultivadas , Humanos , Masculino , Mitocôndrias/metabolismo , Atividade Motora/efeitos dos fármacos , Niacina/farmacologia , Estresse Oxidativo/efeitos dos fármacos , Ratos , Superóxido Dismutase/metabolismo
19.
Mol Cell Biochem ; 455(1-2): 91-97, 2019 May.
Artigo em Inglês | MEDLINE | ID: mdl-30446906

RESUMO

Cisplatin has been extensively used as a chemotherapeutic agent since around 40 years, though its usage is limited due to severe adverse effects like neurotoxicity that might be because of oxidative stress. Hence, the present study was planned to investigate the possible protective role of sitagliptin against cisplatin-associated neurotoxic, biochemical, and behavioral alterations in male Wistar rats. Sitagliptin is a dipeptidyl peptidase-4 inhibitor that shows dual effects by improving the control on metabolism as well as decreasing the debility in cognitive function that is associated with increased insulin sensitivity and antioxidant property. For the in vitro assay, cultured rat pheochromocytoma (PC12) cells were exposed to different concentrations (10, 20, and 50 mM) of sitagliptin for 24 h. Cisplatin at 5 mM concentrations was added and cell viability was assessed using MTT assay. For in vivo study, animals were divided into four groups. Group I (Vehicle control): animals were administered 0.9% (w/v) of normal saline (1 mL/100 g; p.o.). Group II (Cisplatin): animals were treated with cisplatin (2 mg/kg; i.p.). Group III (Cisplatin + sitagliptin): animals were administered cisplatin along with sitagliptin. Group IV (Sitagliptin): animals were given sitagliptin (10 mg/kg; p.o.). All the treatments were administered for 8 weeks. On last day of treatment, behavioral evaluations including locomotor and rotarod studies were performed. In addition, several antioxidant enzymes were also estimated from cerebellum tissues; such as levels of thiobarbituric acid reactive substance (TBARS) were determined as a marker of lipid peroxidation, reduced glutathione (GSH) and catalase (CAT) were also estimated. Histological study of cerebellum tissue was also performed after performing the behavioral study. Exposure to cisplatin decreased cell viability in PC12 cells which were significantly increased by co-treatment with sitagliptin. In in vivo study, cisplatin significantly elevated the level of TBARS and reduced the level of antioxidant enzymes such as GSH and CAT which were significantly restored in sitagliptin + cisplatin group of rats. In addition, cisplatin impaired performance on the locomotor and rotarod activities, whereas sitagliptin significantly improved the performance of both activities. These results suggested the neuroprotective influence of sitagliptin by protecting cerebellum part of brain against cisplatin-induced toxicity.


Assuntos
Comportamento Animal/efeitos dos fármacos , Cisplatino/administração & dosagem , Fármacos Neuroprotetores/farmacologia , Síndromes Neurotóxicas/prevenção & controle , Fosfato de Sitagliptina/farmacologia , Animais , Cisplatino/farmacologia , Masculino , Síndromes Neurotóxicas/sangue , Células PC12 , Ratos , Ratos Wistar
20.
Phytother Res ; 33(3): 690-701, 2019 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-30556245

RESUMO

Loganin, a major iridoid glycoside obtained from fruits of Cornus officinalis, possesses anti-inflammatory, antitumor, antidiabetic, and osteoporosis prevention effects. Loganin has been linked to neuroprotection in several models of neurodegeneration, including Parkinson's disease (PD). However, mechanisms underlying the neuroprotective effects of loganin are still mostly unknown. Here, we demonstrated the protective effects of loganin against PD mimetic toxin 1-methyl-4-phenylpyridinium (MPP+ ) and the important roles of insulin-like growth factor 1 receptor (IGF-1R) and glucagon-like peptide 1 receptor (GLP-1R) in the neuroprotective mechanisms of loganin. In primary mesencephalic neuronal cultures treated with or without MPP+ , loganin up-regulated expressions of neurotrophic signals including IGF-1R, GLP-1R, p-Akt, BDNF, and tyrosine hydroxylase. Loganin protected against MPP+ -induced apoptosis by up-regulating antiapoptotic protein and down-regulating proapoptotic protein. Moreover, loganin attenuated MPP+ -induced neurite damage via up-regulation of GAP43 and down-regulation of membrane-RhoA/ROCK2/p-LIMK/p-cofilin. Loganin also attenuated MPP+ -induced reactive oxygen species (ROS) production. However, both AG1024, an IGF-1R antagonist, and exendin 9-39, a GLP-1R antagonist, attenuated the protective effects of loganin on MPP+ -induced cytotoxicity, apoptosis, neurite length decrease, and ROS production. Our results suggest that loganin attenuates MPP+ -induced apoptotic death, neurite damage, and oxidative stress through enhancement of neurotrophic signaling, activation of IGF-1R/GLP-1R, and inhibition of RhoA/ROCK pathway, providing the evidence that loganin possesses novel neuroprotective effects.


Assuntos
Receptor do Peptídeo Semelhante ao Glucagon 1/fisiologia , Iridoides/farmacologia , Fármacos Neuroprotetores/farmacologia , Síndromes Neurotóxicas/prevenção & controle , Receptor IGF Tipo 1/fisiologia , Transdução de Sinais/efeitos dos fármacos , Quinases Associadas a rho/antagonistas & inibidores , Proteína rhoA de Ligação ao GTP/antagonistas & inibidores , 1-Metil-4-fenilpiridínio/toxicidade , Animais , Células Cultivadas , Humanos , Estresse Oxidativo/efeitos dos fármacos , Ratos , Ratos Sprague-Dawley
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