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Organoselenium compounds modulate the metabolism by regulating carbohydrate and lipid syntheses and degradation in the liver, muscle, and adipose tissue. Notably, p-chloro-diphenyl diselenide (p-ClPhSe)2 can directly regulate the activities of enzymes involved in glucose metabolism, suggesting an insulin-like effect in rodents; however, there is still a lack of scientific evidence to confirm this hypothesis. The objective of this study was to investigate (p-ClPhSe)2 effects on glucose and lipid metabolism in Caenorhabditis elegans. The contribution of AGE-1/PI3K, AKT-1, AKT-2, PFK-1, DAF-16, and DAF-2 in the (p-ClPhSe)2 effects were also investigated. Our results demonstrate that (p-ClPhSe)2 acute exposure presented some toxicity to the worms, and therefore, lower concentrations were further used. (p-ClPhSe)2 reduced glucose and triglyceride levels to the baseline levels, after induction with glucose or fructose, in wild-type worms. This effect required proteins involved in the insulin/IGF-1 like signaling, such as the DAF-2, AGE-1, AKT-1 and AKT-2, PFK-1, but also DAF-16, which would be negatively regulated by DAF-2 activation. Moreover, the reduction in glucose and triglyceride levels, caused by (p-ClPhSe)2per se was lost in age-1/daf-16 worms, suggesting that insulin/IGF-1-like signaling in a DAF-2 and AGE-1/DAF-16 dependent-manner in C. elegans are necessary to effects of (p-ClPhSe)2. In conclusion, (p-ClPhSe)2 requires proteins involved in the IIS pathway to modulate carbohydrate and lipid metabolism.
Assuntos
Proteínas de Caenorhabditis elegans , Compostos Organosselênicos , Animais , Caenorhabditis elegans/metabolismo , Insulina/metabolismo , Fator de Crescimento Insulin-Like I/metabolismo , Proteínas Proto-Oncogênicas c-akt/metabolismo , Metabolismo dos Lipídeos , Compostos Organosselênicos/farmacologia , Proteínas de Caenorhabditis elegans/metabolismo , Glucose/metabolismo , Triglicerídeos/metabolismo , Longevidade , Fatores de Transcrição Forkhead/metabolismoRESUMO
In this study, we evaluated the toxicological and antiproliferative effects of B.â glabra Choisy bract extract (BGCE) in its free and loaded into liposomes forms administered to C.â elegans mutants with let-60 gain-of-function (gf). Our results demonstrated that the concentration up to 75â µg CAE/mL of BGCE was safe for the worms. Notably, we developed BGCE-loaded liposomes to extend the pharmacological window up to 100â µg CAE/mL without toxicity. In addition, the extract and liposomes reduced the number and area of the multivulva formed in let-60 gf mutants. There was also an increase in the apoptotic signaling in the germline cells and increased longevity mediated through DAF-16 nuclear translocation with GST-4 activation in the treated animals. Our findings demonstrated that the BGCE-loaded liposomes possess antitumoral effects due to the activation of the apoptotic signaling and DAF-16 nuclear translocation.
Assuntos
Proteínas de Caenorhabditis elegans , Nyctaginaceae , Animais , Caenorhabditis elegans/fisiologia , Hiperplasia , LipossomosRESUMO
1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) has been widely used due to its specific and reproducible neurotoxic effect on the nigrostriatal system, being considered a convenient model of dopaminergic neurodegeneration to study interventions therapeutics. The purple pitanga (Eugenia uniflora) is a polyphenol-rich fruit with antioxidant and antidepressant properties, among others. Therefore, this study investigated the effect of purple pitanga extract (PPE) on acute early oxidative stress induced by intranasal 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) administration in rats. Male Wistar rats were pre-treated orally with PPE (1000 mg/kg) or vehicle. After 24 h, MPTP (0.1 mg/10µL/nostril) or vehicle was administered bilaterally into the animal's nostrils, and 6 h later, the olfactory bulb (OB), striatum (ST), and substantia nigra (SN) were collected to evaluate the oxidative stress parameters. Our findings revealed that OB and SN were the most affected areas after 6 h of MPTP infusion; an early increase in reactive oxygen species (ROS) levels was observed, while pretreatment with a single dose of PPE prevented this increment. No differences in thiobarbituric acid reactive species (TBARS) and 3-nitrotyrosine (3-NT) formation were observed, although 4-hydroxy-2-nonenal (4-HNE) levels increased, which is the most toxic form of lipid peroxidation, in the MPTP group. The PPE pretreatment could prevent this increase by increasing the NPSH levels previously decreased by MPTP. Furthermore, PPE prevents the Na+/K + ATPase strongly inhibited by MPTP, showing the neuroprotective capacity of the PPE by inhibiting the MPTP-generated oxidation. Thus, we demonstrated for the first time the antioxidant and neuroprotective effects of PPE against the early MPTP neurotoxicity.
Assuntos
Eugenia , Fármacos Neuroprotetores , Ratos , Masculino , Animais , Camundongos , Antioxidantes/farmacologia , Antioxidantes/metabolismo , 1-Metil-4-Fenil-1,2,3,6-Tetra-Hidropiridina/farmacologia , Eugenia/metabolismo , Ratos Wistar , Estresse Oxidativo , Fármacos Neuroprotetores/farmacologia , Fármacos Neuroprotetores/uso terapêutico , Substância Negra/metabolismo , Extratos Vegetais/farmacologia , Extratos Vegetais/uso terapêutico , Camundongos Endogâmicos C57BL , Modelos Animais de DoençasRESUMO
BACKGROUND: Studies comparing the effects of phytochemicals under different regimens of exposure are necessary to give a better indication about their mechanism(s) of protection. Hence, in the present study, we investigated the preventive (pre-incubation), protective (co-incubation) and/or remediative (post-incubation) activity of chlorogenic acid and caffeic acids, in comparison with Ilex paraguariensis crude extract, against t-butyl hydroperoxide (t-BHP)-induced damage to human erythrocytes. RESULTS: We found that both caffeic and chlorogenic acids were able to prevent and revert the hemolysis associated with t-BHP exposure. By contrast, isolated compounds (alone or in combination) presented no effect on basal and/or t-BHP-induced non-protein thiol (NPSH) oxidation or production of thiobarbituric acid reactive substances (TBBARS). In turn, I. paraguariensis extract was effective to prevent, protect and revert the hemolysis associated with t-BHP exposure. Moreover, I. paraguariensis significantly protects and reverts t-BHP-induced NPSH oxidation and TBARS production. CONCLUSIONS: We have found that I. paraguariensis extract acts better with respect to the protection and reversion of t-BHP-associated changes, whereas isolated compounds are more active in preventing and reverting t-BHP pro-hemolytic action. Moreover, our data suggest that the pro-hemolytic activity of t-BHP may occur via mechanism(s) other(s) than lipid peroxidation and/or NPSH oxidation. © 2016 Society of Chemical Industry.
Assuntos
Ácidos Cafeicos/farmacologia , Ácido Clorogênico/farmacologia , Eritrócitos/efeitos dos fármacos , Ilex paraguariensis/química , Extratos Vegetais/farmacologia , terc-Butil Hidroperóxido/toxicidade , Ácidos Cafeicos/isolamento & purificação , Ácido Clorogênico/isolamento & purificação , Eritrócitos/citologia , Hemólise/efeitos dos fármacos , Humanos , Extratos Vegetais/isolamento & purificaçãoRESUMO
The present study investigated whether a p,p'-methoxyl-diphenyl diselenide (MeOPhSe)2-supplemented diet causes toxicity in rats. A second aim of this study was to determine whether a 10 ppm (MeOPhSe)2-supplemented diet has hypolipidemic effect on Triton WR-1339-induced hyperlipidemia in rats. To rule out the antioxidant property of (MeOPhSe)2 in its hypolipidemic action, parameters of oxidative stress were carried out. Wistar rats were fed with 3, 10, or 30 ppm of (MeOPhSe)2-supplemented diet for 30 days. None of (MeOPhSe)2-supplemented diets caused alteration in general parameters of toxicity and lipid profile of rats. The hypolipidemic effect of 10 ppm of (MeOPhSe)2-supplemented diet on rats treated with Triton WR-1339 (400 mg/kg, intraperitoneal) was investigated. The (MeOPhSe)2-supplemented diet partially protected against the levels of total cholesterol (TC) and non-HDL-C and reduced the atherogenic index (AI) increased by Triton WR-1339 in rats. A positive correlation between TC and triglyceride levels (r = 0.679) and non-HDL-C levels (r = 0.929) and AI (r = 0.889) was demonstrated. Triton WR-1339 altered parameters of oxidative stress in livers of rats but (MeOPhSe)2-supplemented diet did not protect against these alterations. The results demonstrated that the hypolipidemic action of (MeOPhSe)2-supplemented diet is not directly related to its antioxidant property and devoid of systemic toxicity in rats at the parameters analyzed.
Assuntos
Antioxidantes/administração & dosagem , Derivados de Benzeno/administração & dosagem , Suplementos Nutricionais , Hiperlipidemias/sangue , Hiperlipidemias/tratamento farmacológico , Hipolipemiantes/administração & dosagem , Compostos Organosselênicos/administração & dosagem , Animais , Colesterol/sangue , Feminino , Estresse Oxidativo/efeitos dos fármacos , Estresse Oxidativo/fisiologia , Distribuição Aleatória , Ratos , Ratos WistarRESUMO
Investigating new drugs or formulations that target Alzheimer disease (AD) is critical for advancing therapeutic interventions. Therefore, this study aimed to assess the effectiveness of nanoencapsulated curcumin (NC Curc) in alleviating memory impairment, oxidative stress, and neuroinflammation in a validated AD model. Male Wistar rats were given bilateral intracerebroventricular injections of either saline or streptozotocin (STZ) (3 mg/3 µL/site) to establish the AD model (day 0). On day 22, daily oral administrations of curcumin (6 mg/kg), NC Curc (6 mg/kg), or a vehicle (unloaded NC) were initiated and continued for 14 days. NC Curc significantly reversed memory deficits in object recognition and inhibitory avoidance tests induced by STZ. Both formulations of curcumin attenuated elevated acetylcholinesterase activity caused by STZ. Importantly, NC Curc alone effectively mitigated STZ-induced oxidative stress. Additionally, NC Curc treatment normalized GFAP levels, suggesting a potential reduction in neuroinflammation in STZ-treated rats. Our findings indicate that NC Curc improves memory in an AD rat model, highlighting its enhanced therapeutic effects compared to unencapsulated curcumin. This research significantly contributes to understanding the therapeutic and neurorestorative potential of NC Curc in AD, particularly in reversing pathophysiological changes.
RESUMO
Our previous study demonstrated that 2-phenylethynyl-butyltellurium (PEBT), an organotellurium compound, enhances memory in mice. In this study, the effects of PEBT on cognitive impairment induced by Aß25-35 were assessed by Morris water maze and step-down inhibitory avoidance tasks. Mice received a single intracerebroventricular injection of Aß25-35 (3 nmol/3 µl/per site) and a daily oral administration of PEBT (1 mg/kg, for 10 days). PEBT significantly improved Aß-induced learning deficits on the training session in the Morris water maze. At the probe trial session, PEBT significantly decreased the escape latency and increased the number of crossings in the platform local compared with the Aß-treated group. PEBT significantly improved Aß-induced memory impairment in the step-down inhibitory avoidance task. General locomotor activity was similar in all groups. This study showed that PEBT ameliorated the impairments of spatial and nonspatial long-term memory evaluated on Morris water maze and step-down inhibitory avoidance tasks, respectively. The results suggest that PEBT could be considered a candidate for the prevention of memory deficits such as those observed in Alzheimer's disease.
Assuntos
Doença de Alzheimer/fisiopatologia , Aprendizagem em Labirinto/efeitos dos fármacos , Fármacos Neuroprotetores/farmacologia , Compostos Organometálicos/farmacologia , Peptídeos beta-Amiloides/toxicidade , Animais , Modelos Animais de Doenças , Masculino , Camundongos , Fragmentos de Peptídeos/toxicidadeRESUMO
A growing body of evidence indicates that creatine (Cr) exerts beneficial effects on a variety of pathologies where energy metabolism and oxidative stress play an etiological role. However, the benefits of Cr treatment for epileptics are still shrouded in controversy. In the present study, we found that acute Cr treatment (300 mg/kg, p.o.) prevented the increase in electroencephalographic wave amplitude typically elicited by PTZ (30, 45 or 60 mg/kg, i.p.). Cr treatment also increased the latency periods of first myoclonic jerks, lengthened the latency periods of the generalized tonic-clonic seizures and reduced the time spent in the generalized tonic-clonic seizures induced by PTZ (60 mg/kg). Administration of PTZ (all doses) decreased Na(+), K(+)-ATPase activity as well as adenosine triphosphate (ATP) and adenosine diphosphate levels in the cerebral cortex, but Cr treatment prevented these effects. Cr administration also prevented increases in xanthine oxidase activity, adenosine monophosphate levels, adenosine levels, inosine levels and uric acid levels that normally occur after PTZ treatment (60 mg/kg, i.p.). We also showed that Cr treatment increased the total Cr (Cr + PCr) content, creatine kinase activity and the mitochondrial membrane potential (ΔΨ) in the cerebral cortex. In addition, Cr prevented PTZ-induced mitochondrial dysfunction characterized by decreasing ΔΨ, increasing thiobarbituric acid-reactive substance levels and increasing protein carbonylation. These experimental findings reinforce the idea that mitochondrial dysfunction plays a critical role in models of epileptic seizures and suggest that buffering brain energy levels through Cr treatment may be a promising therapeutic approach for the treatment of this neurological disease.
Assuntos
Creatina/administração & dosagem , Potencial da Membrana Mitocondrial/efeitos dos fármacos , Convulsões/metabolismo , Convulsões/prevenção & controle , Animais , Humanos , Masculino , Mitocôndrias/efeitos dos fármacos , Mitocôndrias/metabolismo , Estresse Oxidativo , Pentilenotetrazol/efeitos adversos , Carbonilação Proteica , Ratos , Ratos Wistar , Convulsões/induzido quimicamente , Convulsões/tratamento farmacológicoRESUMO
Alzheimer's disease (AD) is the most common form of dementia in older people, and available treatments are palliative and produce undesirable side effects. The 4-phenyltellanyl-7-chloroquinoline (TQ) is an organochalcogen compound studied due to its pharmacological properties, particularly its antioxidant potential. However, TQ possesses some drawbacks such as low aqueous solubility and high toxicity, thus warranting the search for tools that improve the safety and effectiveness of new compounds. Here, we developed and investigated the biological effects of TQ-loaded polymeric nanocapsules (NCTQ) in an AD model in transgenic Caenorhabditis elegans expressing human Aß1-42 in their body-wall muscles and Swiss mice injected with Aß25-35. The NCTQ displayed good physicochemical properties, including nanometer size and maximum encapsulation capacity. The treatment showed low toxicity, reduced Aß peptide-induced paralysis, and activated an endoplasmic reticulum chaperone in the C. elegans model. The Aß injection in mice caused memory impairment, which NCTQ mitigated by improving working, long-term, and aversive memory. Additionally, no changes in biochemical markers were evidenced in mice, demonstrating that there was no hepatotoxicity in the tested doses. Altogether, these findings provide insights into the neuroprotective effects of TQ and indicate that NCTQ is a promising candidate for AD treatment.
RESUMO
Parkinson's disease is a multisystemic neurodegenerative disorder that includes motor and non-motor symptoms, and common symptoms include memory loss and learning difficulties. Thus, we investigated the neuroprotective potential of a hydroalcoholic extract of Brazilian purple cherry (Eugenia uniflora) (HAE-BC) on memory impairments induced by intranasal 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) administration in rats and the involvement of hippocampal BDNF/TrkB/p75NTR pathway in its effects. Adult male Wistar rats were exposed to MPTP (1 mg/nostril) or vehicle. Twenty-four hours later, the HAE-BC treatments began at doses of 300 or 2000 mg/kg/day or vehicle for 14 days. From 7 days after the MPTP induction, the animals were subjected to behavioral tests to evaluate several cognitive paradigms. HAE-BC treatments, at both doses, blocked the MPTP-caused disruption in the social recognition memory, short- and long-term object recognition memories, and working memory. Furthermore, MPTP-induced motor deficit linked to striatal tyrosine hydroxylase levels decreased, which was blocked by HAE-BC. Our findings demonstrated that HAE-BC blocked the MPTP-induced increase in the hippocampal pro-BDNF, TrkB.t1, and p75NTR levels. The pro-BDNF/p75NTR interaction negatively regulates synaptic transmission and plasticity, and the neuroprotective effect of HAE-BC was related, at least partly, to the modulation of this hippocampal signaling pathway. Thus, our study reports the first evidence of the potential therapeutic of E. uniflora in a Parkinson's disease model in rodents.
Assuntos
Eugenia , Fármacos Neuroprotetores , Doença de Parkinson , Ratos , Animais , Masculino , Camundongos , Fármacos Neuroprotetores/farmacologia , Fármacos Neuroprotetores/uso terapêutico , Fator Neurotrófico Derivado do Encéfalo/metabolismo , Doença de Parkinson/tratamento farmacológico , Ratos Wistar , Eugenia/metabolismo , Transtornos da Memória/tratamento farmacológico , Transtornos da Memória/prevenção & controle , Transtornos da Memória/metabolismo , 1-Metil-4-Fenil-1,2,3,6-Tetra-Hidropiridina , Modelos Animais de Doenças , Camundongos Endogâmicos C57BLRESUMO
In the present study, the effect of 6-((4-fluorophenyl) selanyl)-9H-purine (FSP) was tested against memory impairment and sensitivity to nociception induced by intracerebroventricular injection of amyloid-beta peptide (Aß) (25-35 fragment), 3 nmol/3 µl/per site in mice. Memory impairment was determined by the object recognition task (ORT) and nociception by the Von-Frey test (VFT). Aß caused neuroinflammation with upregulation of glial fibrillary acidic protein (GFAP) (in hippocampus), nuclear factor-κB (NF-κB), and the proinflammatory cytokines interferon-γ (IFN-γ) and tumor necrosis factor-α (TNF-α) in cerebral cortex and hippocampus. Additionally, Aß increased oxidant levels and lipid peroxidation in cerebral cortex and hippocampus, but decreased heme oxygenase-1 (HO-1) and peroxiredoxin-1 (Prdx1) expression in the hippocampus. Anti-neuroinflammatory effects of FSP were demonstrated by a decrease in the expression of GFAP and NF-κB in the hippocampus, as well as a decrease in proinflammatory cytokines in both the hippocampus and cerebral cortex FSP protected against oxidative stress by decreasing oxidant levels and lipid peroxidation and by increasing HO-1 and Prdx1 expressions in the hippocampus of mice. Moreover, FSP prevented the activation of nuclear factor erythroid 2-related factor 2 (Nrf-2) in the hippocampus of mice induced by Aß. In conclusion, treatment with FSP attenuated memory impairment, nociception sensitivity by decreasing oxidative stress, and neuroinflammation in a mouse model of Alzheimer's disease.
Assuntos
Doença de Alzheimer , Camundongos , Animais , Doença de Alzheimer/complicações , Doença de Alzheimer/tratamento farmacológico , Doença de Alzheimer/metabolismo , NF-kappa B/metabolismo , Doenças Neuroinflamatórias , Nociceptividade , Peptídeos beta-Amiloides/toxicidade , Peptídeos beta-Amiloides/metabolismo , Transtornos da Memória/complicações , Transtornos da Memória/tratamento farmacológico , Transtornos da Memória/induzido quimicamente , Estresse Oxidativo , Hipocampo/metabolismo , Citocinas/metabolismo , Oxidantes , Purinas/farmacologia , Modelos Animais de Doenças , Fragmentos de Peptídeos/metabolismoRESUMO
Ovarian hormone loss contributes to cognitive decline in postmenopausal women. Studies have demonstrated a positive role of the level of the element selenium in cognitive performance. The present study investigated the effects of the synthetic organoselenium compound diphenyl diselenide (PhSe)2 on cognitive functions in ovariectomized rats. Ninety-day-old female Wistar rats were subjected to ovariectomy (OVX) or Sham operation. One week after surgery, rats were orally treated with (PhSe)2 (5 mg/kg, per oral route) or vehicle once a day for 30 days. Next, the rats were evaluated in behavioral tests [Morris water maze (MWM) and open-field tests] and biochemical [cerebral acetylcholinesterase (AChE)] analyses were carried out. In MWM probe trial, (PhSe)2 decreased the latency to reach the platform location and increased the number of crossings over the platform location, protecting against cognitive impairment induced by OVX. Furthermore, (PhSe)2 prevented the stimulation of AChE activity caused by OVX. In conclusion, the present study showed a cognition-enhancing effect of (PhSe)2 treatment for 30 days in ovariectomized rats in the MWM test, which could be related to its ability to prevent the stimulation of AChE activity caused by OVX in rats. These findings suggest that (PhSe)2 might have a promising role in preventing the cognitive decline related to menopause.
Assuntos
Derivados de Benzeno/uso terapêutico , Transtornos Cognitivos/tratamento farmacológico , Menopausa/psicologia , Compostos Organosselênicos/uso terapêutico , Acetilcolinesterase/metabolismo , Animais , Feminino , Aprendizagem em Labirinto , Modelos Animais , Ovariectomia , Ratos , Ratos WistarRESUMO
Propolis has been highlighted for its antioxidant, anti-inflammatory and antiviral properties. The purpose of this study was to investigate if brown Brazilian hydroalcoholic propolis extract (HPE) protects against vaginal lesions caused by herpes simplex virus type 2 (HSV-2) in female BALB/c mice. The treatment was divided in 5 days of pre-treatment with HPE [50 mg · kg(-1), once a day, intragastric (i.g.)], HSV-2 infection [10 µl of a solution 1 × 10(2) plaque-forming unit (PFU · ml(-1) HSV-2), intravaginal inoculation at day 6] and post-treatment with HPE (50 mg · kg(-1)) for 5 days more. At day 11, the animals were killed, and the in vivo analysis (score of lesions) and ex vivo analysis [haematological and histological evaluation; superoxide dismutase (SOD), catalase (CAT) and myeloperoxidase (MPO) activities; reactive species (RS), tyrosine nitration levels, non-protein thiols (NPSH) and ascorbic acid (AA) levels] were carried out. HPE treatment reduced extravaginal lesions and the histological damage caused by HSV-2 infection in vaginal tissues of animals. HPE was able to decrease RS, tyrosine nitration, AA levels and MPO activity. Also, it protected against the inhibition of CAT activity in vaginal tissues of mice. HPE promoted protective effect on HSV-2 infected animals by acting on inflammatory and oxidative processes, and this effect probably is caused by its antioxidant and anti-inflammatory properties.
Assuntos
Anti-Inflamatórios/farmacologia , Antioxidantes/farmacologia , Antivirais/farmacologia , Herpes Genital/tratamento farmacológico , Herpesvirus Humano 2 , Própole/farmacologia , Vagina/efeitos dos fármacos , Animais , Anti-Inflamatórios/uso terapêutico , Antioxidantes/uso terapêutico , Antivirais/uso terapêutico , Misturas Complexas/farmacologia , Misturas Complexas/uso terapêutico , Feminino , Herpes Genital/metabolismo , Herpes Genital/patologia , Camundongos Endogâmicos BALB C , Própole/química , Vagina/patologia , Vagina/virologiaRESUMO
Human exposure to the natural environmental contaminant methylmercury (MeHg) has been associated to adverse health effects. Importantly, the mechanisms by which this organomercurial exerts its neurotoxicity have yet to be fully clarified. Therefore, the aim of this study was to evaluate whether exposure to MeHg alters dopamine (DA) and octopamine (OA) levels, acetylcholinesterase (AChE) activity and impacts both motor and non-motor behaviours. We studied the effect of MeHg by feeding 1-2 d old flies (male and females) with 25 and 50 µM MeHg for 4 d and determined effects on survival, motor and non-motor behaviours, oxidative stress, AChE and tyrosine hydroxylase (TH) activities, as well as DA and OA levels. We found that Drosophila melanogaster (D. melanogaster) exposed to MeHg showed a reduction in survival rate, associated with the inhibition of AChE and TH activities in head of flies and decreased DA and OA levels. These changes were accompanied by behavioural alterations, such as locomotor deficit and increased grooming behaviour, in addition to an increase in oxidative stress markers both in head and in body of flies, and an increase in glutathione-S-transferase (GST) activity in head of flies. Collectively, our data support the hypothesis that MeHg neurotoxicity is associated with altered OA and DA levels, AChE inhibition, which may serve, at least in part, as the underpinnings of both motor and non-motor behavioural changes.
Assuntos
Compostos de Metilmercúrio , Síndromes Neurotóxicas , Acetilcolinesterase/metabolismo , Animais , Colinérgicos/farmacologia , Dopamina , Drosophila melanogaster , Feminino , Humanos , Masculino , Compostos de Metilmercúrio/toxicidade , Estresse OxidativoRESUMO
In a previous in vitro study, dihydropyrimidinone-derived selenoesteres demonstrated antioxidant properties, metal chelators and inhibitory acetylcholinesterase (AChE) activity, making these compounds promising candidates for Alzheimer's Disease (AD) treatment. However, these effects have yet to be demonstrated in an in vivo animal model; therefore, this study aimed to evaluate the safety and efficacy of eight selenoester compounds in a Caenorhabditis elegans model using transgenic strains for amyloid-beta peptide (Aß) aggregation. The L1 stage worms were acutely exposed (30 min) to the compounds at concentrations ranging from 5 to 200 µM and after 48 h the maintenance temperature was increased to 25 ° C for Aß expression and aggregation. After 48 h, several parameters related to phenotypic manifestations of Aß toxicity and mechanistic elucidation were analyzed. At the concentrations tested no significant toxicity of the compounds was found. The selenoester compound FA90 significantly reduced the rate of paralyzed worms and increased the number of swimming movements compared to the untreated worms. In addition, FA90 and FA130 improved egg-laying induced by levamisole and positively modulated HSP-6 and HSP-4 expression, thereby increasing reticular and mitochondrial protein folding response in C. elegans, which could attenuate Aß aggregation in early exposure. Therefore, our initial screening using an alternative model demonstrated that FA90, among the eight selenoesters evaluated, was the most promising compound for AD evaluation screening in more complex animals.
Assuntos
Peptídeos beta-Amiloides/antagonistas & inibidores , Fármacos Neuroprotetores/farmacologia , Compostos Organosselênicos/farmacologia , Pirimidinonas/farmacologia , Acetilcolinesterase/metabolismo , Peptídeos beta-Amiloides/metabolismo , Animais , Caenorhabditis elegans , Modelos Animais de Doenças , Levamisol/farmacologia , Fármacos Neuroprotetores/efeitos adversos , Organismos Geneticamente Modificados , Compostos Organosselênicos/efeitos adversos , Oviposição/efeitos dos fármacos , Pirimidinonas/efeitos adversosRESUMO
A series of 4-Se-(Te, S)-isochromenones and 3-substituted isochromenones were synthesized in good yields via FeCl(3)-mediated cyclization of alkynylaryl esters with different diorganyl dichalcogenides. This methodology was carried out at room temperature, using inexpensive and environmentally friendly iron salts as metallic source and under air atmosphere. The reaction showed to be tolerant to a range of substituents bonded into the aromatic ring of the diorganyl dichalcogenides as well as to alkyl groups directly bonded to the chalcogen atom. Alternatively, the cyclization reaction of 2-alkynylaryl esters with FeCl(3), in the absence of diorganyl dichalcogenide, gave the isochromenones without the chalcogen moiety in the structure. This approach proved to be highly regioselective, providing only six-membered ring products, once the possible five-membered products were not observed in any experiments.
Assuntos
Benzopiranos/síntese química , Calcogênios/química , Compostos Férricos/química , Ferro/química , Benzopiranos/química , Catálise , Ciclização , Ésteres , Estrutura MolecularRESUMO
The present study investigated whether the antioxidant activity of p,p'-methoxyl-diphenyl diselenide [(MeOPhSe)(2)] is involved in its protective effect against cognitive impairment induced by streptozotocin (STZ) in a model of sporadic dementia of Alzheimer's type (SDAT). Swiss mice were treated with STZ or vehicle [2 µl of 2·5 mg ml(-1) solution; intracerebroventricularly (i.c.v.)] twice, 48 h apart. (MeOPhSe)(2) (25 mg kg(-1)) or vehicle was orally administered 30 min prior to each STZ treatment. Neuroprotector effect of (MeOPhSe)(2) on the behavioral performance of mice on spatial recognition memory consolidation was investigated in the Y-maze test. After that, mouse brains were removed for measuring antioxidant parameters. (MeOPhSe)(2) protected against the impairment in learning and memory caused by i.c.v. administration of STZ in mice. (MeOPhSe)(2) protected against the increase in reactive species and the reduction of glutathione levels, as well as, the increase in superoxide dismutase and glutathione S-transferase activities caused by STZ in whole brain. These results suggest that antioxidant property is involved, at least in part, in the neuroprotective effect of (MeOPhSe)(2) on SDAT induced by STZ in mice.
Assuntos
Doença de Alzheimer/metabolismo , Derivados de Benzeno/farmacologia , Demência/metabolismo , Aprendizagem em Labirinto/efeitos dos fármacos , Memória/efeitos dos fármacos , Compostos Organosselênicos/farmacologia , Doença de Alzheimer/induzido quimicamente , Doença de Alzheimer/psicologia , Animais , Antioxidantes/síntese química , Antioxidantes/farmacologia , Aprendizagem da Esquiva/efeitos dos fármacos , Derivados de Benzeno/síntese química , Encéfalo/efeitos dos fármacos , Encéfalo/metabolismo , Catalase/metabolismo , Demência/induzido quimicamente , Demência/psicologia , Modelos Animais de Doenças , Glutationa/metabolismo , Glutationa Transferase/metabolismo , Infusões Intraventriculares , Masculino , Aprendizagem em Labirinto/fisiologia , Memória/fisiologia , Camundongos , Fármacos Neuroprotetores/farmacologia , Compostos Organosselênicos/síntese química , Estresse Oxidativo/efeitos dos fármacos , Espécies Reativas de Oxigênio/metabolismo , Estreptozocina/administração & dosagem , Estreptozocina/efeitos adversos , Superóxido Dismutase/metabolismoRESUMO
The present study evaluated the effect of acute exposure to diphenyl ditelluride [(PhTe)(2)] on oxidative status in lungs of rats. Rats were exposed to a single subcutaneous application of (PhTe)(2) at the doses of 0.3, 0.6, 0.9 µmol/kg or vehicle. After 72 h of exposure to (PhTe)(2), biochemical parameters of oxidative stress were carried out in lungs of rats. The lungs of rats exposed to (PhTe)(2) showed an increase in the levels of lipid peroxidation, reactive species and non-protein thiol. Alterations in superoxide dismutase activity were observed at all tested doses. (PhTe)(2) caused an increase in catalase activity and a reduction in ascorbic acid levels at the dose of 0.9 µmol/kg. The oxidative damage was more pronounced in animals treated with the highest dose of (PhTe)(2). Thus, this study demonstrated that acute exposure to (PhTe)(2) induced oxidative damage and an adaptive response of antioxidants in pulmonary tissue of rats.
Assuntos
Derivados de Benzeno/toxicidade , Pulmão/efeitos dos fármacos , Compostos Organometálicos/toxicidade , Estresse Oxidativo/efeitos dos fármacos , Animais , Ácido Ascórbico/metabolismo , Derivados de Benzeno/administração & dosagem , Catalase/metabolismo , Relação Dose-Resposta a Droga , Feminino , Pulmão/enzimologia , Pulmão/metabolismo , Compostos Organometálicos/administração & dosagem , Sintase do Porfobilinogênio/metabolismo , Ratos , Ratos Wistar , Espécies Reativas de Oxigênio/metabolismo , Compostos de Sulfidrila/metabolismo , Superóxido Dismutase/metabolismo , Substâncias Reativas com Ácido Tiobarbitúrico/metabolismo , Testes de Toxicidade AgudaRESUMO
The present study evaluated if repeated malathion administration would cause behavioral impairment in rat pups. Na+K+ ATPase and acetylcholinesterase (AChE) activities were investigated in brains of rat pups. Malathion was administered (100 or 200 mg/kg) orally (p.o.), once a day for four consecutive days. Rat pups were submitted to behavioral tests on the 5th day, 24 h after the last malathion administration. Malathion at the dose of 200 mg/kg caused a significant increase in the negative geotaxis latency and a decrease in the rotarod latency of rat pups. Rat pups exposed to malathion at both doses showed a significant decrease in the forelimb support latency and an inhibition of brain AChE activity. Repeated exposure of rat pups to malathion caused a decrease in motor coordination, vestibular function and muscular strength/coordination. The brain activity of AChE is involved in the behavioral alterations caused by malathion in rat pups.
Assuntos
Acetilcolinesterase/metabolismo , Encéfalo/metabolismo , Inibidores da Colinesterase/toxicidade , Malation/toxicidade , Animais , Animais Recém-Nascidos/metabolismo , Encéfalo/efeitos dos fármacos , Feminino , Inseticidas/toxicidade , Masculino , Ratos , Ratos WistarRESUMO
AChE inhibition caused by exposure to organophosphate (OP) compounds is strongly related to behavioural disorders such as depression. Malathion is an OP that already has a relationship between its exposure and behavioural changes, although few data still have its effects in a longer exposure protocol. In addition, intoxication therapy is based on the use of atropine-oxime which still has its controversial efficacy depending on the type of compound. For this, (3Z)-5-Chloro-3-(hydroxyimino)indolin-2-one (Câ-HIN), a compound that has properties of isatin and oxime in its structure, have shown reactivating properties in the activity of AChE that have been added to antidepressant-like effects in rats exposed to malathion in acute protocol. In this sense, effects of Câ-HIN on the depressive-like behaviour and AChE activity were evaluated in a protocol of subchronic exposure to malathion in rats. Male wistar rats were co-treated with Câ-HIN [5 mg/kg, p.o.] and/or malathion [1 or 10 mg/kg, i.p] for 20 days. The exposure to both doses of malathion increased immobility time of rats on the forced swimming test (FST). Besides, malathion inhibited the AChE activity in the prefrontal cortex of rats, but any significant difference was observed in the hippocampus. Câ-HIN protected against increased immobility time in the FST of those rats exposed to a dose of 1 mg/kg of malathion. Similarly, Câ-HIN was able to reactivate AChE activity only in that group exposed to the lowest dose of malathion. Collectively, the results of this study suggest that Câ-HIN is an oxime capable of reactivating AChE inhibited and presents na antidepressant-like effect in cases of prolonged exposure to malathion.