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1.
Molecules ; 26(10)2021 May 12.
Artigo em Inglês | MEDLINE | ID: mdl-34066108

RESUMO

Lindera obtusiloba Blume (family, Lauraceae), native to Northeast Asia, has been used traditionally in the treatment of trauma and neuralgia. In this study, we investigated the neuroinflammatory effect of methanol extract of L. obtusiloba stem (LOS-ME) in a scopolamine-induced amnesia model and lipopolysaccharide (LPS)-stimulated BV2 microglia cells. LOS-ME downregulated the expression of inducible nitric oxide synthase (iNOS), cyclooxygenase (COX)-2, inflammatory cytokines, and inhibited the phosphorylation of nuclear factor kappa-B (NF-ĸB) and extracellular signal-regulated kinase (ERK) in LPS-stimulated BV2 cells. Male C57/BL6 mice were orally administered 20 and 200 mg/kg of LOS-ME for one week, and 2 mg/kg of scopolamine was administered intraperitoneally on the 8th day. In vivo behavioral experiments (Y-maze and Morris water maze test) confirmed that LOS-ME alleviated cognitive impairments induced by scopolamine and the amount of iNOS expression decreased in the hippocampus of the mouse brain. Microglial hyper-activation was also reduced by LOS-ME pretreatment. These findings suggest that LOS-ME might have potential in the treatment for cognitive improvement by regulating neuroinflammation.


Assuntos
Amnésia/induzido quimicamente , Amnésia/tratamento farmacológico , Anti-Inflamatórios/administração & dosagem , Lindera/química , Microglia/efeitos dos fármacos , Fármacos Neuroprotetores/administração & dosagem , Fitoterapia/métodos , Extratos Vegetais/administração & dosagem , Escopolamina/efeitos adversos , Animais , Células Cultivadas , Ciclo-Oxigenase 2/metabolismo , Citocinas/metabolismo , Modelos Animais de Doenças , Regulação para Baixo/efeitos dos fármacos , Hipocampo/metabolismo , Lipopolissacarídeos/farmacologia , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Óxido Nítrico Sintase Tipo II/metabolismo , Transdução de Sinais/efeitos dos fármacos , Resultado do Tratamento
2.
Nutrients ; 13(4)2021 Apr 14.
Artigo em Inglês | MEDLINE | ID: mdl-33919810

RESUMO

Although l-carnitine alleviated white-matter lesions in an experimental study, the treatment effects of l-carnitine on white-matter microstructural damage and cognitive decline in hemodialysis patients are unknown. Using novel diffusion magnetic resonance imaging (dMRI) techniques, white-matter microstructural changes together with cognitive decline in hemodialysis patients and the effects of l-carnitine on such disorders were investigated. Fourteen hemodialysis patients underwent dMRI and laboratory and neuropsychological tests, which were compared across seven patients each in two groups according to duration of l-carnitine treatment: (1) no or short-term l-carnitine treatment (NSTLC), and (2) long-term l-carnitine treatment (LTLC). Ten age- and sex-matched controls were enrolled. Compared to controls, microstructural disorders of white matter were widely detected on dMRI of patients. An autopsy study of one patient in the NSTLC group showed rarefaction of myelinated fibers in white matter. With LTLC, microstructural damage on dMRI was alleviated along with lower levels of high-sensitivity C-reactive protein and substantial increases in carnitine levels. The LTLC group showed better achievement on trail making test A, which was correlated with amelioration of disorders in some white-matter tracts. Novel dMRI tractography detected abnormalities of white-matter tracts after hemodialysis. Long-term treatment with l-carnitine might alleviate white-matter microstructural damage and cognitive impairment in hemodialysis patients.


Assuntos
Carnitina/administração & dosagem , Disfunção Cognitiva/prevenção & controle , Demência Vascular/prevenção & controle , Falência Renal Crônica/terapia , Fármacos Neuroprotetores/administração & dosagem , Diálise Renal/efeitos adversos , Administração Oral , Idoso , Idoso de 80 Anos ou mais , Disfunção Cognitiva/diagnóstico , Disfunção Cognitiva/etiologia , Estudos Transversais , Demência Vascular/diagnóstico , Demência Vascular/etiologia , Demência Vascular/patologia , Imagem de Tensor de Difusão , Esquema de Medicação , Feminino , Humanos , Falência Renal Crônica/complicações , Masculino , Pessoa de Meia-Idade , Testes Neuropsicológicos , Fatores de Tempo , Resultado do Tratamento , Substância Branca/diagnóstico por imagem , Substância Branca/efeitos dos fármacos , Substância Branca/patologia
3.
Toxicol Appl Pharmacol ; 419: 115515, 2021 05 15.
Artigo em Inglês | MEDLINE | ID: mdl-33798593

RESUMO

Exposure to organophosphorus nerve agents (NAs) like sarin (GB) and soman (GD) can lead to sustained seizure activity, or status epilepticus (SE). Previous research has shown that activation of A1 adenosine receptors (A1ARs) can inhibit neuronal excitability, which could aid in SE termination. Two A1AR agonists, 2-Chloro-N6-cyclopentyladenosine (CCPA) and N-Bicyclo(2.2.1)hept-2-yl-5'-chloro-5'-deoxyadenosine (ENBA), were effective in terminating GD-induced SE in rats when administered via intraperitoneal (IP) injection. However, IP injection is not a clinically relevant route of administration. This study evaluated the efficacy of these agonists in terminating NA-induced SE when administered via intramuscular (IM) route. Adult male rats were exposed subcutaneously (SC) to either GB (150 µg/kg) or GD (90 µg/kg) and were treated with ENBA or CCPA at 15, 30, or 60 min after seizure onset or left untreated. Up to 7 days after exposure, deeply anesthetized rats were euthanized and perfused brains were removed for histologic assessment of neuropathology (i.e., neuronal damage) in six brain regions (amygdala, cerebral cortex, piriform cortex, thalamus, dorsal hippocampus, and ventral hippocampus). A total neuropathy score (0-24) was determined for each rat by adding the scores from each of the six regions. The higher the total score the more severe the neuropathology. With the GB model and 60 min treatment delay, ENBA-treated rats experienced 78.6% seizure termination (N = 14) and reduced neuropathology (11.6 ± 2.6, N = 5), CCPA-treated rats experienced 85.7% seizure termination (N = 14) and slightly reduced neuropathology (20.7 ± 1.8, N = 6), and untreated rats experienced no seizure termination (N = 13) and severe neuropathology (22.3 ± 1.0, N = 4). With the GD model and 60 min treatment delay, ENBA-treated rats experienced 92.9% seizure termination (N = 14) and reduced neuropathology (13.96 ± 1.8, N = 9), CCPA-treated rats experienced 78.6% seizure termination (N = 14) and slightly reduced neuropathology (22.0 ± 0.9, N = 10); and untreated rats experienced 16.7% seizure termination (N = 12) and severe neuropathology (22.0 ± 1.8, N = 5). While ENBA and CCPA both demonstrate a clear ability to terminate SE when administered up to 60 min after seizure onset, ENBA offers more neuroprotection, making it a promising candidate for NA-induced SE.


Assuntos
Agonistas do Receptor A1 de Adenosina/administração & dosagem , Adenosina/análogos & derivados , Anticonvulsivantes/administração & dosagem , Encéfalo/efeitos dos fármacos , Desoxiadenosinas/administração & dosagem , Fármacos Neuroprotetores/administração & dosagem , Norbornanos/administração & dosagem , Sarina , Soman , Estado Epiléptico/prevenção & controle , Adenosina/administração & dosagem , Animais , Encéfalo/metabolismo , Encéfalo/patologia , Encéfalo/fisiopatologia , Modelos Animais de Doenças , Esquema de Medicação , Injeções Intramusculares , Masculino , Ratos Sprague-Dawley , Estado Epiléptico/induzido quimicamente , Estado Epiléptico/metabolismo , Estado Epiléptico/patologia , Fatores de Tempo
4.
Int Immunopharmacol ; 94: 107494, 2021 May.
Artigo em Inglês | MEDLINE | ID: mdl-33676175

RESUMO

Resveratrol is a nutraceutical compound that has exciting pharmacological potential in different diseases, including stroke. Due to its low bioavailability, the efficacy of resveratrol is minimal. Hence, the present study is aimed to synthesize and characterize nanoparticles of resveratrol (NR) followed by evaluating the neuroprotective role and elucidate the mechanism of NR in a rat model of middle cerebral artery occlusion (MCAO). Male Wistar rats (280-300 g) were pretreated with various doses (125 µg, 250 µg, and NR 500 µg; once daily, i.p.) of NR or vehicle (nanostructured lipid carriers) for 10 days. MCAO was performed for 2 h followed by reperfusion of 22 h. After 24 h of MCAO, animals were tested for the neurological outcome and were sacrificed for the analysis of infarct volume, oxidative, inflammatory, and apoptotic markers. NR-treated rats showed a substantial reduction in infarction compared to saline controls in parallel with improved motor and cognitive function. Further, NR pretreatment ameliorated oxidative stress markers and attenuated activities of antioxidant enzymes and Na+ K+ ATPase. The enhanced activities of caspases -3 and -9 and cytokines: interleukin-1ß, and -6, and tumor necrosis factor-ɑ) in the MCAO group were significantly protected with the treatment of 500 µg of NR. Taken together, these data indicate that inhibition by NR has therapeutic potential in the ischemic stroke model. Further investigations into the therapeutic efficacy and post-treatment protocols are needed to confirm whether NR treatment could be a promising candidate for a stroke.


Assuntos
Anti-Inflamatórios/administração & dosagem , Antioxidantes/administração & dosagem , AVC Isquêmico/tratamento farmacológico , Nanopartículas/administração & dosagem , Fármacos Neuroprotetores/administração & dosagem , Resveratrol/administração & dosagem , Animais , Citocinas/imunologia , AVC Isquêmico/imunologia , Masculino , Ratos Wistar
5.
Clin Interv Aging ; 16: 301-309, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-33642856

RESUMO

Background: Rivastigmine is used to treat cognitive impairment in Alzheimer's disease (AD); however, the efficacy of Rivastigmine in patients with AD and concomitant small vessel cerebrovascular disease (svCVD) remains unclear. We investigated the effectiveness of Rivastigmine Patch in patients with AD and svCVD. Methods: In this open-label study, 100 patients with AD and MRI confirmed svCVD received 9.5mg/24 hours Rivastigmine transdermal treatment for 24 weeks. The primary outcome was global cognition indexed using the ADAS-Cog. Secondary outcomes included clinical-rated impression of change (indexed using (ADCS-CGIC), activities of daily living (indexed using ADCS-ADL) and side effects. Results: Overall, performance on the ADAS-Cog after 24 weeks deteriorated by 1.78 (SD = 5.29) points. Fifty-two percent of the sample demonstrated improvement or remained stable, while 48% demonstrated worsening of ADAS-Cog scores. Of the 52%, significant improvement (2 or more-point decline) on the ADAS-Cog was observed in 25% of the sample, with a mean change of -5.08 (SD = 3.11). A decline on the ADAS-Cog was observed in 48% of the sample, with a mean change of 6 (SD = 2.98) points. Cognitive outcome did not interact with severity of svCVD. ADCS-ADL scores remained stable from baseline to week 24 and ADCS-CGIC reports indicated that 81% of the patients remained stable after treatment. Side effects were reported by 16% of the patients, with contact dermatitis being the most common. Conclusion: Our findings suggest that Rivastigmine may have a role in the management of patients having AD and concomitant mild-severe svCVD, with minimal side effects.


Assuntos
Atividades Cotidianas , Doença de Alzheimer , Doenças de Pequenos Vasos Cerebrais , Rivastigmina , Administração Cutânea , Idoso , Doença de Alzheimer/complicações , Doença de Alzheimer/diagnóstico , Doença de Alzheimer/tratamento farmacológico , Doença de Alzheimer/psicologia , Doenças de Pequenos Vasos Cerebrais/complicações , Doenças de Pequenos Vasos Cerebrais/diagnóstico , Cognição/efeitos dos fármacos , Feminino , Humanos , Masculino , Fármacos Neuroprotetores/administração & dosagem , Fármacos Neuroprotetores/efeitos adversos , Rivastigmina/administração & dosagem , Rivastigmina/efeitos adversos , Resultado do Tratamento
6.
Nutrients ; 13(3)2021 Feb 28.
Artigo em Inglês | MEDLINE | ID: mdl-33671099

RESUMO

Methylxanthines (MTX) are purine derived xanthine derivatives. Whereas naturally occurring methylxanthines like caffeine, theophylline or theobromine are widely consumed in food, several synthetic but also non-synthetic methylxanthines are used as pharmaceuticals, in particular in treating airway constrictions. Besides the well-established bronchoprotective effects, methylxanthines are also known to have anti-inflammatory and anti-oxidative properties, mediate changes in lipid homeostasis and have neuroprotective effects. Known molecular mechanisms include adenosine receptor antagonism, phosphodiesterase inhibition, effects on the cholinergic system, wnt signaling, histone deacetylase activation and gene regulation. By affecting several pathways associated with neurodegenerative diseases via different pleiotropic mechanisms and due to its moderate side effects, intake of methylxanthines have been suggested to be an interesting approach in dealing with neurodegeneration. Especially in the past years, the impact of methylxanthines in neurodegenerative diseases has been extensively studied and several new aspects have been elucidated. In this review we summarize the findings of methylxanthines linked to Alzheimer´s disease, Parkinson's disease and Multiple Sclerosis since 2017, focusing on epidemiological and clinical studies and addressing the underlying molecular mechanisms in cell culture experiments and animal studies in order to assess the neuroprotective potential of methylxanthines in these diseases.


Assuntos
Doenças Neurodegenerativas/tratamento farmacológico , Fármacos Neuroprotetores/administração & dosagem , Xantinas/administração & dosagem , Doença de Alzheimer/tratamento farmacológico , Doença de Alzheimer/epidemiologia , Animais , Cafeína/administração & dosagem , Café/química , Humanos , Esclerose Múltipla/tratamento farmacológico , Esclerose Múltipla/epidemiologia , Doença de Parkinson/tratamento farmacológico , Doença de Parkinson/epidemiologia , Teobromina/administração & dosagem , Teofilina/administração & dosagem
7.
Expert Opin Investig Drugs ; 30(5): 571-577, 2021 May.
Artigo em Inglês | MEDLINE | ID: mdl-33641585

RESUMO

INTRODUCTION: Retinal neurodegeneration causes irreversible vision loss, impairing quality of life. By targeting neurotoxic conditions, such as oxidative stress and ischemia, neuroprotectants can slow or stop sight loss resulting from eye disease. Despite limimted clinical use of neuroprotectants, there are several promising compounds in early clinical trials (pre-phase III) which may fulfil new therapeutic roles. Search terms relating to neuroprotection and eye disease were used on ClinicalTrials.gov to identify neuroprotective candidates. AREAS COVERED: Research supporting neuroprotection in eye diseases is focused on, ranging from preclinical to phase II, according to the ClinicalTrials.gov database. The compounds discussed are explored in terms of future clinical applications. EXPERT OPINION: The major challenge in neuroprotection research is translation from basic research to the clinic. A number of potential neuroprotectants have progressed to ophthalmology clinical trials in recent years, with defined mechanisms of action - saffron and CoQ10 - targeting mitochondria, and both CNTF and NGF showing anti-apoptotic effects. Enhancements in trial design and patient cohorts in proof-of-concept trials with enriched patient populations and surrogate endpoints should accelerate drug development. A further important consideration is optimising drug delivery to improve individualised management and patient compliance. Progress in these areas means that neuroprotective strategies have a much improved chance of translational success.


Assuntos
Desenvolvimento de Medicamentos , Fármacos Neuroprotetores/farmacologia , Doenças Retinianas/tratamento farmacológico , Animais , Sistemas de Liberação de Medicamentos , Drogas em Investigação/administração & dosagem , Drogas em Investigação/farmacologia , Humanos , Fármacos Neuroprotetores/administração & dosagem , Qualidade de Vida , Projetos de Pesquisa , Doenças Retinianas/fisiopatologia
8.
Br J Anaesth ; 126(5): 1009-1021, 2021 May.
Artigo em Inglês | MEDLINE | ID: mdl-33722372

RESUMO

BACKGROUND: Structural brain abnormalities in newborn animals after prolonged exposure to all routinely used general anaesthetics have raised substantial concerns for similar effects occurring in millions of children undergoing surgeries annually. Combining a general anaesthetic with non-injurious sedatives may provide a safer anaesthetic technique. We tested dexmedetomidine as a mitigating therapy in a sevoflurane dose-sparing approach. METHODS: Neonatal rats were randomised to 6 h of sevoflurane 2.5%, sevoflurane 1% with or without three injections of dexmedetomidine every 2 h (resulting in 2.5, 5, 10, 25, 37.5, or 50 µg kg-1 h-1), or fasting in room air. Heart rate, oxygen saturation, level of hypnosis, and response to pain were measured during exposure. Neuronal cell death was quantified histologically after exposure. RESULTS: Sevoflurane at 2.5% was more injurious than at 1% in the hippocampal cornu ammonis (CA)1 and CA2/3 subfields; ventral posterior and lateral dorsal thalamic nuclei; prefrontal, retrosplenial, and somatosensory cortices; and subiculum. Although sevoflurane 1% did not provide complete anaesthesia, supplementation with dexmedetomidine dose dependently increased depth of anaesthesia and diminished responses to pain. The combination of sevoflurane 1% and dexmedetomidine did not reliably reduce neuronal apoptosis relative to an equianaesthetic dose of sevoflurane 2.5%. CONCLUSIONS: A sub-anaesthetic dose of sevoflurane combined with dexmedetomidine achieved a level of anaesthesia comparable with that of sevoflurane 2.5%. Similar levels of anaesthesia caused comparable programmed cell death in several developing brain regions. Depth of anaesthesia may be an important factor when comparing the neurotoxic effects of different anaesthetic regimens.


Assuntos
Anestésicos Inalatórios/toxicidade , Dexmedetomidina/farmacologia , Hipnóticos e Sedativos/farmacologia , Sevoflurano/toxicidade , Anestésicos Inalatórios/administração & dosagem , Animais , Animais Recém-Nascidos , Apoptose/efeitos dos fármacos , Encéfalo/efeitos dos fármacos , Encéfalo/fisiopatologia , Morte Celular/efeitos dos fármacos , Dexmedetomidina/administração & dosagem , Relação Dose-Resposta a Droga , Hipnóticos e Sedativos/administração & dosagem , Fármacos Neuroprotetores/administração & dosagem , Fármacos Neuroprotetores/farmacologia , Síndromes Neurotóxicas/etiologia , Síndromes Neurotóxicas/prevenção & controle , Ratos , Ratos Wistar , Sevoflurano/administração & dosagem
9.
Eur Rev Med Pharmacol Sci ; 25(2): 1016-1023, 2021 01.
Artigo em Inglês | MEDLINE | ID: mdl-33577057

RESUMO

OBJECTIVE: Colistin is a potent antibiotic which is mainly preferred in the treatment of multidrug-resistant (MDR) gram-negative bacilli. However, due to the increased risk of acute kidney injury following its use, the clinical application is limited. This nephrotoxicity is known to be induced by oxidative stress and related inflammation. In this study on rats, potent antioxidants Dexpanthenol (DEX) and Ascorbic acid (Vit C) have been administered in combination with Colistin to find out whether they would weaken Colistin's nephrotoxic effects. MATERIALS AND METHODS: Inflammation biomarkers were studied with enzyme-linked immunosorbent assay (ELISA) kits, and oxidative stress biomarkers were studied with different photometric methods in blood and tissue samples taken after treatment with DEX and Vit C in rats with colistin nephrotoxicity. In addition, inflammation and necrosis in the kidney tissues were examined pathologically. RESULTS: It has been observed in the serum and tissue samples that DEX and Vit C decrease oxidative stress and inflammation biomarkers, therefore acting as nephroprotective agents. CONCLUSIONS: These compounds have been found to ameliorate the nephrotoxic effects of Colistin, which were demonstrated in the rats treated with Colistin, as well as the combinations.


Assuntos
Injúria Renal Aguda/tratamento farmacológico , Ácido Ascórbico/farmacologia , Inflamação/tratamento farmacológico , Fármacos Neuroprotetores/farmacologia , Ácido Pantotênico/análogos & derivados , Injúria Renal Aguda/induzido quimicamente , Injúria Renal Aguda/metabolismo , Animais , Ácido Ascórbico/administração & dosagem , Colistina/administração & dosagem , Modelos Animais de Doenças , Inflamação/induzido quimicamente , Inflamação/metabolismo , Injeções Intraperitoneais , Masculino , Fármacos Neuroprotetores/administração & dosagem , Estresse Oxidativo/efeitos dos fármacos , Ácido Pantotênico/administração & dosagem , Ácido Pantotênico/farmacologia , Ratos , Ratos Sprague-Dawley
10.
Biochem Pharmacol ; 186: 114486, 2021 04.
Artigo em Inglês | MEDLINE | ID: mdl-33631189

RESUMO

Ferroptosis is a recently defined form of programmed cell death that is different from apoptosis. It is an iron-dependent programmed cell death and the accumulation of lipid hydroperoxides to lethal levels make ferroptosis distinct. Ferroptosis can be effectively regulated by a number of cellular variables including iron content, amino acid uptake, polyunsaturated fatty acid incorporation, glutathione biosynthesis, and NADPH levels. A number of severe and common degenerative diseases in humans such as Parkinson's disease and Huntington's disease, as well as several acute injury scenarios, such as stroke, intracerebral hemorrhage, traumatic brain injury, and ischemia-reperfusion injury are likely to be linked to ferroptosis. Ferroptosis may play a critical role in tumor-suppression and has been proposed as a potential target for cancer therapy. However, regulating ferroptosis in vivo remains difficult due to a lack of compounds that can effectively activate or repress ferroptosis. Here we review the cellular mechanisms underlying ferroptosis and the pathophysiological circumstances where its regulation could be beneficial.


Assuntos
Sistemas de Liberação de Medicamentos/métodos , Ferroptose/efeitos dos fármacos , Ferroptose/fisiologia , Peroxidação de Lipídeos/efeitos dos fármacos , Peroxidação de Lipídeos/fisiologia , Animais , Antineoplásicos/administração & dosagem , Apoptose/efeitos dos fármacos , Apoptose/fisiologia , Transtornos Cerebrovasculares/tratamento farmacológico , Transtornos Cerebrovasculares/metabolismo , Humanos , Doenças do Sistema Nervoso/tratamento farmacológico , Doenças do Sistema Nervoso/metabolismo , Fármacos Neuroprotetores/administração & dosagem , Espécies Reativas de Oxigênio/antagonistas & inibidores , Espécies Reativas de Oxigênio/metabolismo
11.
Prostaglandins Other Lipid Mediat ; 154: 106540, 2021 06.
Artigo em Inglês | MEDLINE | ID: covidwho-1096205

RESUMO

Coronavirus Disease 2019 (COVID-19) is upsetting the world and innovative therapeutic solutions are needed in an attempt to counter this new pandemic. Great hope lies in vaccines, but drugs to cure the infected patient are just as necessary. In the most severe forms of the disease, a cytokine storm with neuroinflammation occurs, putting the patient's life at serious risk, with sometimes long-lasting sequelae. Palmitoylethanolamide (PEA) is known to possess anti-inflammatory and neuroprotective properties, which make it an ideal candidate to be assumed in the earliest stage of the disease. Here, we provide a mini-review on the topic, pointing out phospholipids consumption in COVID-19, the possible development of an antiphospholipid syndrome secondary to SARS-CoV-2 infection, and reporting our preliminary single-case experience concerning to a 45-year-old COVID-19 female patient recently treated with success by micronized / ultramicronized PEA.


Assuntos
Amidas/administração & dosagem , Anti-Inflamatórios/administração & dosagem , Síndrome Antifosfolipídica/tratamento farmacológico , COVID-19/tratamento farmacológico , Etanolaminas/administração & dosagem , Fármacos Neuroprotetores/administração & dosagem , Ácidos Palmíticos/administração & dosagem , SARS-CoV-2/metabolismo , Síndrome Antifosfolipídica/etiologia , Síndrome Antifosfolipídica/metabolismo , Síndrome Antifosfolipídica/patologia , COVID-19/complicações , COVID-19/metabolismo , COVID-19/patologia , Feminino , Humanos , Pessoa de Meia-Idade
12.
Prostaglandins Other Lipid Mediat ; 154: 106540, 2021 06.
Artigo em Inglês | MEDLINE | ID: mdl-33636368

RESUMO

Coronavirus Disease 2019 (COVID-19) is upsetting the world and innovative therapeutic solutions are needed in an attempt to counter this new pandemic. Great hope lies in vaccines, but drugs to cure the infected patient are just as necessary. In the most severe forms of the disease, a cytokine storm with neuroinflammation occurs, putting the patient's life at serious risk, with sometimes long-lasting sequelae. Palmitoylethanolamide (PEA) is known to possess anti-inflammatory and neuroprotective properties, which make it an ideal candidate to be assumed in the earliest stage of the disease. Here, we provide a mini-review on the topic, pointing out phospholipids consumption in COVID-19, the possible development of an antiphospholipid syndrome secondary to SARS-CoV-2 infection, and reporting our preliminary single-case experience concerning to a 45-year-old COVID-19 female patient recently treated with success by micronized / ultramicronized PEA.


Assuntos
Amidas/administração & dosagem , Anti-Inflamatórios/administração & dosagem , Síndrome Antifosfolipídica/tratamento farmacológico , COVID-19/tratamento farmacológico , Etanolaminas/administração & dosagem , Fármacos Neuroprotetores/administração & dosagem , Ácidos Palmíticos/administração & dosagem , SARS-CoV-2/metabolismo , Síndrome Antifosfolipídica/etiologia , Síndrome Antifosfolipídica/metabolismo , Síndrome Antifosfolipídica/patologia , COVID-19/complicações , COVID-19/metabolismo , COVID-19/patologia , Feminino , Humanos , Pessoa de Meia-Idade
13.
Mol Med Rep ; 23(4)2021 04.
Artigo em Inglês | MEDLINE | ID: mdl-33576468

RESUMO

Orexin­A (OXA) protects neurons against cerebral ischemia­reperfusion injury (CIRI). Endoplasmic reticulum stress (ERS) induces apoptosis after CIRI by activating caspase­12 and the CHOP pathway. The present study aimed to determine whether OXA mitigates CIRI by inhibiting ERS­induced neuronal apoptosis. A model of CIRI was established, in which rats were subjected to middle cerebral artery occlusion with ischemic intervention for 2 h, followed by reperfusion for 24 h. Neurological deficit examination and 2,3,5­triphenyltetrazolium chloride staining were performed to assess the level of CIRI and neuroprotection by OXA. Expression levels of ERS­related proteins and cleaved caspase­3 were measured via western blotting, while the rate of neuronal apoptosis in the cortex was determined using a TUNEL assay. OXA treatment decreased the infarct volume of rats after CIRI and attenuated neuron apoptosis. Furthermore, administration of OXA decreased the expression levels of GRP78, phosphorylated (p)­PERK, p­eukaryotic initiation factor­2α, p­inositol requiring enzyme 1α, p­JNK, cleaved caspase­12, CHOP and cleaved caspase­3, all of which were induced by CIRI. Collectively, these findings suggested that OXA attenuated CIRI by inhibiting ERS­mediated apoptosis, thus clarifying the mechanism underlying its neuroprotective effect and providing a novel therapeutic direction for the treatment of CIRI.


Assuntos
Apoptose/efeitos dos fármacos , Estresse do Retículo Endoplasmático/efeitos dos fármacos , Neurônios/efeitos dos fármacos , Orexinas/farmacologia , Traumatismo por Reperfusão/prevenção & controle , Animais , Encéfalo/efeitos dos fármacos , Encéfalo/metabolismo , Caspase 12/metabolismo , Caspase 3/metabolismo , Proteínas de Choque Térmico/metabolismo , Infarto da Artéria Cerebral Média/complicações , Injeções Intraventriculares , Masculino , Neurônios/citologia , Neurônios/metabolismo , Fármacos Neuroprotetores/administração & dosagem , Fármacos Neuroprotetores/farmacologia , Orexinas/administração & dosagem , Fosfoproteínas/metabolismo , Ratos Sprague-Dawley , Traumatismo por Reperfusão/etiologia , Traumatismo por Reperfusão/fisiopatologia , Fator de Transcrição CHOP/metabolismo
14.
Microbiome ; 9(1): 34, 2021 01 31.
Artigo em Inglês | MEDLINE | ID: mdl-33517890

RESUMO

BACKGROUND: Parkinson's disease (PD) is a neurodegenerative disorder with no absolute cure. The evidence of the involvement of gut microbiota in PD pathogenesis suggests the need to identify certain molecule(s) derived from the gut microbiota, which has the potential to manage PD. Osteocalcin (OCN), an osteoblast-secreted protein, has been shown to modulate brain function. Thus, it is of interest to investigate whether OCN could exert protective effect on PD and, if yes, whether the underlying mechanism lies in the subsequent changes in gut microbiota. RESULTS: The intraperitoneal injection of OCN can effectively ameliorate the motor deficits and dopaminergic neuronal loss in a 6-hydroxydopamine-induced PD mouse model. The further antibiotics treatment and fecal microbiota transplantation experiments confirmed that the gut microbiota was required for OCN-induced protection in PD mice. OCN elevated Bacteroidetes and depleted Firmicutes phyla in the gut microbiota of PD mice with elevated potential of microbial propionate production and was confirmed by fecal propionate levels. Two months of orally administered propionate successfully rescued motor deficits and dopaminergic neuronal loss in PD mice. Furthermore, AR420626, the agonist of FFAR3, which is the receptor of propionate, mimicked the neuroprotective effects of propionate and the ablation of enteric neurons blocked the prevention of dopaminergic neuronal loss by propionate in PD mice. CONCLUSIONS: Together, our results demonstrate that OCN ameliorates motor deficits and dopaminergic neuronal loss in PD mice, modulating gut microbiome and increasing propionate level might be an underlying mechanism responsible for the neuroprotective effects of OCN on PD, and the FFAR3, expressed in enteric nervous system, might be the main action site of propionate. Video abstract.


Assuntos
Microbioma Gastrointestinal/fisiologia , Fármacos Neuroprotetores/farmacologia , Osteocalcina/farmacologia , Doença de Parkinson/tratamento farmacológico , Doença de Parkinson/metabolismo , Propionatos/metabolismo , Animais , Antibacterianos/farmacologia , Modelos Animais de Doenças , Progressão da Doença , Neurônios Dopaminérgicos/efeitos dos fármacos , Transplante de Microbiota Fecal , Microbioma Gastrointestinal/efeitos dos fármacos , Infusões Parenterais , Masculino , Camundongos , Fármacos Neuroprotetores/administração & dosagem , Osteocalcina/administração & dosagem , Oxidopamina , Doença de Parkinson/microbiologia , Doença de Parkinson/fisiopatologia , Receptores Acoplados a Proteínas G/agonistas , Receptores Acoplados a Proteínas G/metabolismo
15.
J Nutr Biochem ; 90: 108579, 2021 04.
Artigo em Inglês | MEDLINE | ID: mdl-33388350

RESUMO

Sevoflurane, the most commonly used inhaled anesthetic in pediatric anesthesia, has been reported to induce cognitive impairment in developing brain in preclinical and clinical settings. However, the mechanism and therapeutic measures of this developmental neurotoxicity need to be further investigated. Resveratrol, a natural polyphenolic agent, has been reported to improve cognitive function in neurological disorders and aging models through anti-inflammatory activity. However, its effect on sevoflurane-induced cognitive impairment in developing mice remains unknown. The present study was designed to investigate the therapeutic potential of resveratrol on sevoflurane-induced cognitive impairment. Six-day-old mice received anesthesia with 3% sevoflurane 2 h daily on postnatal days (P) 6, P7 and P8. About 100 mg/kg resveratrol were intraperitoneally administered for 6 consecutive days to neonatal mice before anesthesia. Sevoflurane exposure significantly suppressed the expression of Sirtuin 1 (SIRT1) and activated microglia in hippocampi. Furthermore, the levels of interleukin-6 (IL-6) and tumor necrosis factor-α (TNF-α) were markedly increased after sevoflurane exposure. Strikingly, resveratrol pretreatment ameliorated sevoflurane-induced SIRT1 inhibition and microglial activation. Of note, resveratrol reversed sevoflurane-induced imbalance of M1/M2 microglia ratio revealed by increasing mRNA level of clusters of differentiation 206 (CD206) and decreasing mRNA levels of clusters of differentiation 86 (CD86) and suppressor of cytokine signaling 3 (SOCS3). Consequently, sevoflurane-induced cognitive impairment in developing mice was ameliorated by resveratrol pretreatment. Taken together, repeated sevoflurane exposure to the developing brain resulted in SIRT1 inhibition, NF-κB acetylation, and microglial activation. Resveratrol pretreatment ameliorated cognitive impairment in developing mice received sevoflurane exposure by modulating SIRT1-NF-κB pathway in microglia. In this regard, our findings open novel directions to explore promising therapeutic targets for preventing the developmental neurotoxicity of sevoflurane.


Assuntos
Disfunção Cognitiva/tratamento farmacológico , NF-kappa B/metabolismo , Fármacos Neuroprotetores/farmacologia , Resveratrol/farmacologia , Sevoflurano/efeitos adversos , Sirtuína 1/metabolismo , Anestésicos Inalatórios/efeitos adversos , Animais , Animais Recém-Nascidos , Anti-Inflamatórios/farmacologia , Disfunção Cognitiva/induzido quimicamente , Disfunção Cognitiva/metabolismo , Feminino , Hipocampo/efeitos dos fármacos , Hipocampo/metabolismo , Interleucina-6/metabolismo , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Microglia/efeitos dos fármacos , Fármacos Neuroprotetores/administração & dosagem , Síndromes Neurotóxicas/metabolismo , Resveratrol/administração & dosagem , Fator de Necrose Tumoral alfa/metabolismo
16.
J Pharmacol Exp Ther ; 377(1): 1-10, 2021 04.
Artigo em Inglês | MEDLINE | ID: mdl-33500265

RESUMO

Oxidative stress plays a crucial role in the pathogenesis of Parkinson disease (PD), and one strategy for neuroprotective therapy for PD is to scavenge reactive species using a catalytic antioxidant. Previous studies in our laboratory revealed that pretreatment of lipophilic metalloporphyrins showed protective effects in a mouse PD model. In this study, we optimized the formulations of these metalloporphyrins to deliver them orally and tested their efficacy on disease outcomes in a second species after initiation of an insult (i.e., disease modification). In this study, a pharmaceutical formulation of two metalloporphyrin catalytic antioxidants, AEOL11207 and AEOL11114, was tested for oral drug delivery. Both compounds showed gastrointestinal absorption, achieved high plasma concentrations, and readily penetrated the blood-brain barrier after intravenous or oral delivery. AEOL11207 and AEOL11114 bioavailabilities were calculated to be 24% and 25%, respectively, at a dose of 10 mg/kg via the oral route. In addition, both compounds significantly attenuated 6-hydroxydopamine (6-OHDA)-induced neurotoxic damage, including dopamine depletion, cytokine production, and microglial activation in the striata; dopaminergic neuronal loss in the substantia nigra; oxidative/nitrative stress indices (glutathione disulfide and 3-nitrotyrosine) in the ventral midbrain; and rotation behavioral abnormality in rats. These results indicate that AEOL11207 and AEOL11114 are orally active metalloporphyrins and protect against 6-OHDA neurotoxicity 1-3 days postlesioning, suggesting disease-modifying properties and translational potential for PD. SIGNIFICANCE STATEMENT: Two catalytic antioxidants showed gastrointestinal absorption, achieved high plasma concentrations, and readily penetrated the blood-brain barrier. Both compounds significantly attenuated dopamine depletion, cytokine production, microglial activation, dopaminergic neuronal loss, oxidative/nitrative stress indices, and behavioral abnormality in a Parkinson disease rat model. The results suggest that both metalloporphyrins possess disease-modifying properties that may be useful in treating Parkinson disease.


Assuntos
Antioxidantes/farmacocinética , Metaloporfirinas/farmacocinética , Fármacos Neuroprotetores/farmacocinética , Transtornos Parkinsonianos/tratamento farmacológico , Administração Oral , Animais , Antioxidantes/administração & dosagem , Antioxidantes/uso terapêutico , Barreira Hematoencefálica/metabolismo , Masculino , Metaloporfirinas/administração & dosagem , Metaloporfirinas/uso terapêutico , Fármacos Neuroprotetores/administração & dosagem , Fármacos Neuroprotetores/uso terapêutico , Ratos , Ratos Sprague-Dawley , Distribuição Tecidual
17.
Int J Mol Sci ; 22(2)2021 Jan 16.
Artigo em Inglês | MEDLINE | ID: mdl-33467075

RESUMO

Recent clinical and epidemiological studies support the contention that diabetes mellitus (DM) is a strong risk factor for the development of Alzheimer's disease (AD). The use of insulin cell toxin, streptozotocin (STZ), when injected into the lateral ventricles, develops an insulin resistant brain state (IRBS) and represents a non-transgenic, or sporadic AD model (SAD), with several AD-like neuropathological features. The present study explored the effects of an anti-diabetic drug, liraglutide (LIR), in reversing major pathological hallmarks in the prodromal disease stage of both the 5xFAD transgenic and SAD mouse models of AD. Three-month-old 5xFAD and age-matched wild type mice were given a single intracerebroventricular (i.c.v) injection of STZ or vehicle (saline) and were subsequently treated with LIR, intraperitoneally (IP), once a day for 30 days. The extent of neurodegeneration, Aß plaque load, and key proteins associated with the insulin signaling pathways were measured using Western blot and neuroinflammation (via immunohistological assays) in the cortical and hippocampal regions of the brain were assessed following a series of behavioral tests used to measure cognitive function after LIR or vehicle treatments. Our results indicated that STZ significantly increased neuroinflammation, Aß plaque deposition and disrupted insulin signaling pathway, while 25 nmol/kg LIR, when injected IP, significantly decreased neuroinflammatory responses in both SAD and 5xFAD mice before significant cognitive changes were observed, suggesting LIR can reduce early neuropathology markers prior to the emergence of overt memory deficits. Our results indicate that LIR has neuroprotective effects and has the potential to serve as an anti-inflammatory and anti-amyloid prophylactic therapy in the prodromal stages of AD.


Assuntos
Doença de Alzheimer/tratamento farmacológico , Anti-Inflamatórios/uso terapêutico , Liraglutida/uso terapêutico , Fármacos Neuroprotetores/uso terapêutico , Doença de Alzheimer/etiologia , Doença de Alzheimer/genética , Peptídeos beta-Amiloides/efeitos dos fármacos , Animais , Anti-Inflamatórios/administração & dosagem , Anti-Inflamatórios/farmacologia , Liraglutida/administração & dosagem , Liraglutida/farmacologia , Camundongos , Fármacos Neuroprotetores/administração & dosagem , Fármacos Neuroprotetores/farmacologia , Presenilinas/genética , Estreptozocina/toxicidade
18.
J Stroke Cerebrovasc Dis ; 30(3): 105595, 2021 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-33450605

RESUMO

BACKGROUND: Endovascular thrombectomy (EVT) is highly effective but may also lead to hemorrhagic transformation (HT) and edema, which may be more pronounced in severe ischemia. We sought to determine whether glibenclamide can attenuate HT and edema in a severe ischemia-reperfusion model that reflects EVT. METHODS: Using a transient middle cerebral artery occlusion (tMCAo) rodent model of stroke, we studied two rat cohorts, one without rt-PA and a second cohort treated with rt-PA. Glibenclamide or vehicle control was administered as an intravenous bolus at reperfusion, followed by continuous subcutaneous administration with an osmotic pump. RESULTS: Compared to vehicle control, glibenclamide improved neurological outcome (median 7, interquartile range [IQR 6-8] vs. control median 6 [IQR 0-6], p = 0.025), reduced stroke volume (323 ± 42 vs. 484 ± 60 mm3, p < 0.01), swelling volume (10 ± 4 vs. 28 ± 7%, p < 0.01) and water content (84 ± 1 vs. 85 ± 1%, p < 0.05). Glibenclamide administration also reduced HT based on ECASS criteria, densitometry (0.94 ± 0.1 vs. 1.15 ± 0.2, p < 0.01), and quantitative hemoglobin concentration (2.7 ± 1.5 vs. 6.2 ± 4.6 uL, p = 0.011). In the second cohort with rt-PA coadministration, concordant effects on HT were observed with glibenclamide. CONCLUSIONS: Taken together, these studies demonstrated that glibenclamide reduced the amount of edema and HT after severe ischemia. This study suggests that co-administration of glibenclamide may be worth further study in severe stroke patients treated with EVT with or without IV rt-PA.


Assuntos
Edema Encefálico/prevenção & controle , Glibureto/administração & dosagem , Infarto da Artéria Cerebral Média/tratamento farmacológico , Hemorragias Intracranianas/prevenção & controle , Fármacos Neuroprotetores/administração & dosagem , Traumatismo por Reperfusão/tratamento farmacológico , Animais , Edema Encefálico/diagnóstico por imagem , Edema Encefálico/patologia , Modelos Animais de Doenças , Fibrinolíticos/farmacologia , Infarto da Artéria Cerebral Média/diagnóstico por imagem , Infarto da Artéria Cerebral Média/patologia , Infusões Subcutâneas , Injeções Intravenosas , Hemorragias Intracranianas/diagnóstico por imagem , Hemorragias Intracranianas/patologia , Masculino , Ratos Wistar , Traumatismo por Reperfusão/diagnóstico por imagem , Traumatismo por Reperfusão/patologia , Terapia Trombolítica , Ativador de Plasminogênio Tecidual/farmacologia
19.
Aging (Albany NY) ; 13(2): 1671-1685, 2021 01 20.
Artigo em Inglês | MEDLINE | ID: mdl-33471781

RESUMO

Cuminaldehyde (CA) is one of the major compounds of the essential oil of Cuminum cyminum. The aim of this study was to evaluate the effects of CA on aging, specifically on spatial learning and memory. To achieve our objective, an in vitro study on SH-SY5Y cells was performed to analyze the neuroprotective effect of CA against dexamethasone using the MTT assay. An in vivo study was performed for evaluation of the spatial learning and memory using Morris water maze (MWM). RT-PCR was performed to quantify the expression of specific genes (Bdnf, Icam and ApoE) in the mice brain. The results obtained showed a neuroprotective effect of CA against dexamethasone-induced neuronal toxicity. The escape latency of CA-treated aged mice was significantly decreased as compared to the water-treated aged mice after 4 days of training in MWM. Moreover, CA treatment up-regulated the gene expression of Bdnf, Icam and ApoE, while it down-regulated the gene expression of IL-6. These findings suggest that CA has a neuroprotective effect, as well as a spatial learning and memory enhancement potential through the modulation of genes coding for neurotrophic factors and/or those implicated in the imbalance of neural circuitry and impairment of synaptic plasticity. Cuminaldehyde (CA) is one of the major compound of the essential oil of Cuminum cyminum. The aim of this study was to evaluate the effects of CA on aging, specifically on spatial learning and memory. To achieve our objective, an in vitro study on SH-SY5Y cells was performed to analyze the neuroprotective effect of CA against dexamethasone using the MTT assay. An in vivo study was performed for evaluation of the spatial learning and memory using Morris water maze (MWM). RT-PCR was performed to quantify the expression of specific genes (Bdnf, Icam and ApoE) in the mice brain. The results obtained showed a neuroprotective effect of CA against dexamethasone-induced neuronal toxicity. The escape latency of CA-treated aged mice was significantly decreased as compared to the water-treated aged mice after 4 days of training in MWM. Moreover, CA treatment up-regulated the gene expression of Bdnf, Icam and ApoE, while it down-regulated the gene expression of IL-6. These findings suggest that CA has a neuroprotective effect, as well as a spatial learning and memory enhancement potential through the modulation of genes coding for neurotrophic factors and/or those implicated in the imbalance of neural circuitry and impairment of synaptic plasticity.


Assuntos
Envelhecimento/metabolismo , Benzaldeídos/administração & dosagem , Cimenos/administração & dosagem , Aprendizagem em Labirinto/efeitos dos fármacos , Memória/efeitos dos fármacos , Fármacos Neuroprotetores/administração & dosagem , Memória Espacial/efeitos dos fármacos , Animais , Encéfalo/efeitos dos fármacos , Encéfalo/metabolismo , Linhagem Celular Tumoral , Dieta , Dopamina/metabolismo , Epinefrina/metabolismo , Humanos , Interleucina-6/metabolismo , Camundongos , Atividade Motora/efeitos dos fármacos , Norepinefrina/metabolismo , Fator de Necrose Tumoral alfa/metabolismo
20.
J Sci Food Agric ; 101(6): 2256-2263, 2021 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-33006386

RESUMO

BACKGROUND: Stroke is a neurological disease caused by a sudden disturbance of cerebral blood flow to the brain, leading to loss of brain function. Recently, accumulating lines of evidence have suggested that dietary enrichment with nutritional antioxidants could reduce brain damage and improve cognitive function. In this study, we investigated the possible protective effects of Apium graveolens, a medicinal plant with putative neuroprotective activity, against oxidative-stress-related brain damage and brain damage due to inflammation induced by focal cerebral ischemia. METHODS: Male adult Wistar rats were administered with an extract of A. graveolens orally 14 days before permanent occlusion of their right middle cerebral artery. The brain infarct volumes of rats in each group were determined by 2,3,5-triphenyltetrazolium chloride staining, and the density of neurons in the cortex and hippocampus of rats was determined by cresyl violet staining. The levels of malondialdehyde, catalase, glutathione peroxidase, and superoxide dismutase in the cerebral cortex and hippocampus of the rats were also quantified at the end of the study period. RESULTS: Our results show that A. graveolens extract significantly decreased infarct volume and improved neuronal density in the cortex and hippocampus of rats receiving A. graveolens extract compared with those rats receiving no treatment. This neuroprotective effect was found to occur partly due to antioxidant, anti-inflammatory, and anti-apoptotic effects. CONCLUSION: Our study demonstrates that A. graveolens helps to reduce the severity of cognitive damage caused by focal cerebral ischemia. © 2020 Society of Chemical Industry.


Assuntos
Anti-Inflamatórios/administração & dosagem , Antioxidantes/administração & dosagem , Apium/química , Apoptose/efeitos dos fármacos , Isquemia Encefálica/prevenção & controle , Fármacos Neuroprotetores/administração & dosagem , Animais , Encéfalo/efeitos dos fármacos , Encéfalo/imunologia , Isquemia Encefálica/imunologia , Isquemia Encefálica/metabolismo , Isquemia Encefálica/fisiopatologia , Glutationa Peroxidase/metabolismo , Humanos , Masculino , Malondialdeído/metabolismo , Estresse Oxidativo/efeitos dos fármacos , Fitoterapia , Ratos , Ratos Wistar , Superóxido Dismutase/metabolismo
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