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1.
Artigo em Russo | MEDLINE | ID: mdl-32929923

RESUMO

OBJECTIVE: Optimization of the choice of neuroprotective treatment regimens in patients with chronic cerebral ischemia that takes into account the synergy of drug interactions gives the doctor an opportunity for personalized approach that increases the effectiveness of treatment. MATERIAL AND METHODS: Differential chemoreactomic analysis of the synergism of ethyl methyl hydroxypyridine succinate (EMHPS) and a number of monocomponent neuroprotective agents (piracetam, vinpocetine, citicoline, choline alfoscerate); proteomic analysis of polypeptide neuroprotectors (cerebrolysin, etc.); an expert analysis of multicomponent neuroprotector Cytoflavin. RESULTS: Piracetam, citicoline (Neupilept) and choline alfoscerate (Cereton) effectively enhance the pharmacological properties of EMHPS and vice versa. Expert assessments of the synergism between the properties of EMHPS, polypeptide neuroprotectors (cerebrolysin) and other multicomponent drugs (cytoflavin), which are also used in adjuvant therapy with EMHPS, are presented. CONCLUSION: In real clinical practice, of particular interest is the objectification of the appointment of combined therapy regimens. This study indicates that EMHPS can provide a favorable background for maximizing the effectiveness of therapy when used with other drugs.


Assuntos
Isquemia Encefálica , Fármacos Neuroprotetores , Citidina Difosfato Colina , Interações Medicamentosas , Humanos , Proteômica
2.
Khirurgiia (Mosk) ; (8): 69-74, 2020.
Artigo em Russo | MEDLINE | ID: mdl-32869618

RESUMO

OBJECTIVE: To substantiate the advisability of using cytoflavin to correct postoperative cognitive dysfunction (POCD) in patients undergoing video laparoscopic cholecystectomy (VLCE) under conditions of inhalation anesthesia with sevoflurane. MATERIAL AND METHODS: The data of two representative groups of patients (n=60) who underwent video-laparoscopic cholecystectomy under the conditions of inhalation anesthesia with sevoflurane were analyzed. At the stages of the perioperative period, in order to monitor the state of higher mental functions, neuropsychological testing was performed: anxiety and depression scales (HADS), the Montreal scale of cognitive dysfunction (MoCA), and frontal dysfunction batteries (FAB). Patients of the first group (n=19) were not corrected for POKD. For the correction of cognitive impairment, patients of the second group (n=41) were treated with Cytoflavin according to the 20 ml regimen per 250 ml of 0.9% sodium chloride solution intravenously once before the operation, then within 4 days of the postoperative period. RESULTS: Neuropsychological testing in group I patients revealed the development of moderate POCD. The inclusion of Cytoflavin in the treatment regimen in the II group of patients contributed to an improvement in the state of HMF, accompanied by a decrease in the level of anxiety and depression. CONCLUSION: The inclusion of Cytoflavin in treatment regimens helps prevent the development of POKD and is accompanied by an improvement in the state of higher mental functions, which is manifested by a decrease in the level of anxiety and depression, favorably affecting the emotional background of patients.


Assuntos
Anestésicos Inalatórios/efeitos adversos , Colecistectomia Laparoscópica , Transtornos Cognitivos/terapia , Mononucleotídeo de Flavina/administração & dosagem , Inosina Difosfato/administração & dosagem , Fármacos Neuroprotetores/administração & dosagem , Niacinamida/administração & dosagem , Sevoflurano/efeitos adversos , Succinatos/administração & dosagem , Anestesia por Inalação/efeitos adversos , Anestesia por Inalação/métodos , Colecistectomia Laparoscópica/efeitos adversos , Colecistectomia Laparoscópica/métodos , Transtornos Cognitivos/induzido quimicamente , Transtornos Cognitivos/diagnóstico , Transtornos Cognitivos/etiologia , Combinação de Medicamentos , Humanos , Cirurgia Vídeoassistida
3.
J Transl Med ; 18(1): 322, 2020 08 26.
Artigo em Inglês | MEDLINE | ID: mdl-32847594

RESUMO

The coronavirus disease 2019 (COVID-19) pandemic has led to a declaration of a Public Health Emergency of International Concern by the World Health Organization. As of May 18, 2020, there have been more than 4.7 million cases and over 316,000 deaths worldwide. COVID-19 is caused by a highly infectious novel coronavirus known as severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2), leading to an acute infectious disease with mild-to-severe clinical symptoms such as flu-like symptoms, fever, headache, dry cough, muscle pain, loss of smell and taste, increased shortness of breath, bilateral viral pneumonia, conjunctivitis, acute respiratory distress syndromes, respiratory failure, cytokine release syndrome (CRS), sepsis, etc. While physicians and scientists have yet to discover a treatment, it is imperative that we urgently address 2 questions: how to prevent infection in immunologically naive individuals and how to treat severe symptoms such as CRS, acute respiratory failure, and the loss of somatosensation. Previous studies from the 1918 influenza pandemic have suggested vitamin D's non-classical role in reducing lethal pneumonia and case fatality rates. Recent clinical trials also reported that vitamin D supplementation can reduce incidence of acute respiratory infection and the severity of respiratory tract diseases in adults and children. According to our literature search, there are no similar findings of clinical trials that have been published as of July 1st, 2020, in relation to the supplementation of vitamin D in the potential prevention and treatment for COVID-19. In this review, we summarize the potential role of vitamin D extra-renal metabolism in the prevention and treatment of the SARS-CoV-2 infection, helping to bring us slightly closer to fulfilling that goal. We will focus on 3 major topics here: 1. Vitamin D might aid in preventing SARS-CoV-2 infection: Vitamin D: Overview of Renal and Extra-renal metabolism and regulation. Vitamin D: Overview of molecular mechanism and multifaceted functions beyond skeletal homeostasis. Vitamin D: Overview of local immunomodulation in human infectious diseases. Anti-viral infection. Anti-malaria and anti-systemic lupus erythematosus (SLE). 2. Vitamin D might act as a strong immunosuppressant inhibiting cytokine release syndrome in COVID-19: Vitamin D: Suppression of key pro-inflammatory pathways including nuclear factor kappa B (NF-kB), interleukin-6 (IL-6), and tumor necrosis factor (TNF). 3. Vitamin D might prevent loss of neural sensation in COVID-19 by stimulating expression of neurotrophins like Nerve Growth Factor (NGF): Vitamin D: Induction of key neurotrophic factors. .


Assuntos
Quimioprevenção/métodos , Infecções por Coronavirus/prevenção & controle , Infecções por Coronavirus/terapia , Imunomodulação/efeitos dos fármacos , Fármacos Neuroprotetores/uso terapêutico , Pandemias/prevenção & controle , Pneumonia Viral/prevenção & controle , Pneumonia Viral/terapia , Vitamina D/uso terapêutico , Betacoronavirus/efeitos dos fármacos , Betacoronavirus/fisiologia , Encéfalo/efeitos dos fármacos , Encéfalo/fisiologia , Infecções por Coronavirus/epidemiologia , Infecções por Coronavirus/fisiopatologia , Suplementos Nutricionais , Humanos , Sistema Imunitário/efeitos dos fármacos , Sistema Imunitário/fisiologia , Neuroproteção/efeitos dos fármacos , Pneumonia Viral/epidemiologia , Pneumonia Viral/fisiopatologia , Vitamina D/metabolismo , Vitamina D/farmacologia , Deficiência de Vitamina D/dietoterapia , Deficiência de Vitamina D/epidemiologia , Deficiência de Vitamina D/metabolismo , Deficiência de Vitamina D/virologia
4.
Nat Commun ; 11(1): 3848, 2020 07 31.
Artigo em Inglês | MEDLINE | ID: mdl-32737286

RESUMO

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


Assuntos
Esclerose Amiotrófica Lateral/tratamento farmacológico , Hidrazonas/farmacologia , Neurônios Motores/efeitos dos fármacos , Fármacos Neuroprotetores/farmacologia , Proteínas de Transporte Vesicular/genética , Esclerose Amiotrófica Lateral/genética , Esclerose Amiotrófica Lateral/metabolismo , Esclerose Amiotrófica Lateral/patologia , Animais , Encéfalo/efeitos dos fármacos , Encéfalo/metabolismo , Encéfalo/patologia , Diferenciação Celular , Sobrevivência Celular/efeitos dos fármacos , Modelos Animais de Doenças , Humanos , Hidrazonas/síntese química , Células-Tronco Pluripotentes Induzidas/citologia , Células-Tronco Pluripotentes Induzidas/efeitos dos fármacos , Células-Tronco Pluripotentes Induzidas/metabolismo , Locomoção/efeitos dos fármacos , Locomoção/fisiologia , Masculino , Camundongos , Camundongos Transgênicos , Neurônios Motores/metabolismo , Neurônios Motores/patologia , Neuroproteção/efeitos dos fármacos , Fármacos Neuroprotetores/síntese química , Ligação Proteica/efeitos dos fármacos , Multimerização Proteica , Relação Estrutura-Atividade , Superóxido Dismutase-1/genética , Superóxido Dismutase-1/metabolismo , Proteínas de Transporte Vesicular/metabolismo
5.
Curr Opin Anaesthesiol ; 33(5): 655-660, 2020 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-32826628

RESUMO

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


Assuntos
Hidrogênio/farmacologia , Doenças do Sistema Nervoso/tratamento farmacológico , Neuroproteção , Fármacos Neuroprotetores/farmacologia , Assistência Perioperatória/métodos , Humanos , Período Perioperatório , Complicações Pós-Operatórias/prevenção & controle
6.
Yakugaku Zasshi ; 140(8): 1007-1012, 2020.
Artigo em Japonês | MEDLINE | ID: mdl-32741858

RESUMO

We previously showed that increased permeability of the blood-brain barrier (BBB) after ischemic stroke enables extravasation of nano-sized liposomes and accumulation in the ischemic region, and that delivery of neuroprotective agents using liposomal drug delivery systems (DDS) is applicable for treating cerebral ischemia/reperfusion (I/R) injury. However, entry of liposomes into the brain parenchyma was limited in the early stages after I/R possibly due to microvascular dysfunction induced by pathological progression. As such, new approaches to overcome the BBB are needed. Leukocytes can pass through inflamed BBB in I/R region due to membrane proteins displayed on their surface. We thus hypothesized that incorporation of leukocyte membrane proteins onto liposomal membranes would impart leukocyte-mimicking functions to liposomes and that leukocyte-mimetic liposomes (LM-Lipo) may pass through inflamed endothelial cells and BBB, similar to leukocytes. LM-Lipo prepared using intermembrane protein transfer from human leukemia cells showed significantly increased association to inflamed human umbilical vein endothelial cells relative to plain liposomes. Moreover, LM-Lipo passed through inflamed endothelial cell layer by regulating intercellular junctions. These results suggest that imparting leukocyte-like properties to liposomes via intermembrane protein transfer would be an effective strategy to overcome inflamed endothelial barriers. In this review, we describe our findings on ischemic stroke treatment using liposomal DDS and the potential of LM-Lipo to overcome inflamed endothelial barriers.


Assuntos
Barreira Hematoencefálica/metabolismo , Sistemas de Liberação de Medicamentos , Desenvolvimento de Medicamentos , Leucócitos , Lipossomos/metabolismo , Proteínas de Membrana/metabolismo , Fármacos Neuroprotetores/administração & dosagem , Acidente Vascular Cerebral/tratamento farmacológico , Acidente Vascular Cerebral/metabolismo , Humanos , Permeabilidade , Transporte Proteico , Traumatismo por Reperfusão/tratamento farmacológico , Traumatismo por Reperfusão/metabolismo
7.
Zhonghua Yi Xue Za Zhi ; 100(31): 2462-2466, 2020 Aug 18.
Artigo em Chinês | MEDLINE | ID: mdl-32819064

RESUMO

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


Assuntos
Doença de Alzheimer , Ginsenosídeos/farmacologia , Fármacos Neuroprotetores/farmacologia , Animais , Masculino , Fator 2 Relacionado a NF-E2 , Estresse Oxidativo/efeitos dos fármacos , Ratos , Ratos Sprague-Dawley , Superóxido Dismutase
8.
Life Sci ; 257: 118070, 2020 Sep 15.
Artigo em Inglês | MEDLINE | ID: mdl-32668327

RESUMO

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


Assuntos
Glibureto/farmacologia , Canais KATP/antagonistas & inibidores , Fármacos Neuroprotetores/farmacologia , Transtornos Parkinsonianos/tratamento farmacológico , Bloqueadores dos Canais de Potássio/farmacologia , Animais , Apoptose/efeitos dos fármacos , Dopamina/metabolismo , Neurônios Dopaminérgicos/metabolismo , Canais KATP/metabolismo , Levodopa/farmacologia , Masculino , Camundongos , Nicorandil/farmacologia , Transtornos Parkinsonianos/fisiopatologia , Rotenona/toxicidade
9.
Life Sci ; 257: 118037, 2020 Sep 15.
Artigo em Inglês | MEDLINE | ID: mdl-32622942

RESUMO

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


Assuntos
Astrócitos/efeitos dos fármacos , Astrócitos/metabolismo , Etanolaminas/farmacologia , Ácidos Palmíticos/farmacologia , Doença de Alzheimer/tratamento farmacológico , Doença de Alzheimer/metabolismo , Peptídeos beta-Amiloides/metabolismo , Animais , Sobrevivência Celular/efeitos dos fármacos , Córtex Cerebral/metabolismo , Técnicas de Cocultura , Modelos Animais de Doenças , Etanolaminas/metabolismo , Gliose , Humanos , Masculino , Camundongos , Camundongos Transgênicos , Proteínas Associadas aos Microtúbulos , Neurônios/efeitos dos fármacos , Fármacos Neuroprotetores/farmacologia , Ácidos Palmíticos/metabolismo , Proteínas tau/metabolismo
10.
Life Sci ; 257: 118050, 2020 Sep 15.
Artigo em Inglês | MEDLINE | ID: mdl-32634425

RESUMO

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


Assuntos
Fosfolipídeo Hidroperóxido Glutationa Peroxidase/metabolismo , Fosfolipídeo Hidroperóxido Glutationa Peroxidase/uso terapêutico , Hemorragia Subaracnóidea/tratamento farmacológico , Animais , Antioxidantes/farmacologia , Encéfalo/metabolismo , Edema Encefálico/patologia , Lesões Encefálicas/etiologia , Morte Celular/efeitos dos fármacos , Modelos Animais de Doenças , Ferroptose/efeitos dos fármacos , Peroxidação de Lipídeos/efeitos dos fármacos , Masculino , Malondialdeído/metabolismo , Neurônios/efeitos dos fármacos , Fármacos Neuroprotetores/metabolismo , Fármacos Neuroprotetores/farmacologia , Ratos , Ratos Sprague-Dawley , Hemorragia Subaracnóidea/metabolismo
11.
Life Sci ; 257: 118049, 2020 Sep 15.
Artigo em Inglês | MEDLINE | ID: mdl-32634430

RESUMO

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


Assuntos
Concussão Encefálica/tratamento farmacológico , Cognição/efeitos dos fármacos , Silimarina/uso terapêutico , Animais , Animais não Endogâmicos , Concussão Encefálica/metabolismo , Lesões Encefálicas/tratamento farmacológico , Fator Neurotrófico Derivado do Encéfalo/metabolismo , Cognição/fisiologia , Disfunção Cognitiva/tratamento farmacológico , Modelos Animais de Doenças , Feminino , Ácido Glutâmico/metabolismo , Hipocampo/metabolismo , Masculino , Aprendizagem em Labirinto/efeitos dos fármacos , Memória/efeitos dos fármacos , Camundongos , Fármacos Neuroprotetores/farmacologia , Estresse Oxidativo/efeitos dos fármacos , Fatores Sexuais , Silimarina/metabolismo , Fator de Necrose Tumoral alfa/metabolismo
12.
Artigo em Russo | MEDLINE | ID: mdl-32678562

RESUMO

The analysis of mechanisms of the neuroprotective effect of choline precursors reveals the primary effects of citicoline on the processes of repair of neuronal membranes, a decrease in the degeneration of free fatty acids, and choline alfoscerate, an increase in the production of the neurotransmitter acetylcholine. Although citicoline has a lesser effect on choline secretion than choline alfoscerate, the combination of choline and cytidine in its composition is a universal tool to reduce symptoms of cerebral ischemia, to stabilize cognitive status, superior to the standard benefits of choline. Various mechanisms of the action of citicoline enable to recommend it as a drug effective both in the acute phase of the disease and in the delayed period, giving it the status of a universal nootropic compound.


Assuntos
Colina/farmacologia , Isquemia Encefálica , Citidina Difosfato Colina , Humanos , Fármacos Neuroprotetores , Nootrópicos
13.
Life Sci ; 257: 118019, 2020 Sep 15.
Artigo em Inglês | MEDLINE | ID: mdl-32629002

RESUMO

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


Assuntos
Medicina Tradicional Chinesa/métodos , Doença de Parkinson/tratamento farmacológico , Doença de Parkinson/terapia , Animais , Encéfalo/metabolismo , Corpo Estriado/metabolismo , Modelos Animais de Doenças , Dopamina , Neurônios Dopaminérgicos/efeitos dos fármacos , Humanos , Camundongos , Camundongos Endogâmicos C57BL , Fármacos Neuroprotetores/farmacologia , Parte Compacta da Substância Negra/metabolismo , Substância Negra/efeitos dos fármacos , Tirosina 3-Mono-Oxigenase/metabolismo , alfa-Sinucleína/metabolismo
14.
Cochrane Database Syst Rev ; 7: CD007026, 2020 07 14.
Artigo em Inglês | MEDLINE | ID: mdl-32662068

RESUMO

BACKGROUND: Cerebrolysin is a mixture of low-molecular-weight peptides and amino acids derived from porcine brain that has potential neuroprotective properties. It is widely used in the treatment of acute ischaemic stroke in Russia, Eastern Europe, China, and other Asian and post-Soviet countries. This is an update of a review first published in 2010 and last updated in 2017. OBJECTIVES: To assess the benefits and harms of Cerebrolysin for treating acute ischaemic stroke. SEARCH METHODS: We searched the Cochrane Stroke Group Trials Register, CENTRAL, MEDLINE, Embase, Web of Science Core Collection, with Science Citation Index, LILACS, OpenGrey, and a number of Russian databases in October 2019. We also searched reference lists, ongoing trials registers, and conference proceedings. SELECTION CRITERIA: Randomised controlled trials (RCTs) comparing Cerebrolysin, started within 48 hours of stroke onset and continued for any length of time, with placebo or no treatment in people with acute ischaemic stroke. DATA COLLECTION AND ANALYSIS: Two review authors independently applied the inclusion criteria, assessed trial quality and risk of bias, extracted data, and applied GRADE criteria to the evidence. MAIN RESULTS: Seven RCTs (1601 participants) met the inclusion criteria of the review. In this update we re-evaluated risk of bias through identification, examination, and evaluation of study protocols and judged it to be low, unclear, or high across studies: unclear for all domains in one study, and unclear for selective outcome reporting across all studies; low for blinding of participants and personnel in four studies and unclear in the remaining three; low for blinding of outcome assessors in three studies and unclear in four studies. We judged risk of bias to be low in two studies and unclear in the remaining five studies for generation of allocation sequence; low in one study and unclear in six studies for allocation concealment; and low in one study, unclear in one study, and high in the remaining five studies for incomplete outcome data. The manufacturer of Cerebrolysin supported four multicentre studies, either totally, or by providing Cerebrolysin and placebo, randomisation codes, research grants, or statisticians. We judged three studies to be at high risk of other bias and the remaining four studies to be at unclear risk of other bias. All-cause death: we extracted data from six trials (1517 participants). Cerebrolysin probably results in little to no difference in all-cause death: risk ratio (RR) 0.90, 95% confidence interval (CI) 0.61 to 1.32 (6 trials, 1517 participants, moderate-quality evidence). None of the included trials reported on poor functional outcome defined as death or dependence at the end of the follow-up period or early death (within two weeks of stroke onset), or time to restoration of capacity for work and quality of life. Only one trial clearly reported on the cause of death: cerebral infarct (four in the Cerebrolysin and two in the placebo group), heart failure (two in the Cerebrolysin and one in the placebo group), pulmonary embolism (two in the placebo group), and pneumonia (one in the placebo group). Serious adverse events (SAEs): Cerebrolysin probably results in little to no difference in the total number of people with SAEs (RR 1.15, 95% CI 0.81 to 1.65, 4 RCTs, 1435 participants, moderate-quality evidence). This comprised fatal SAEs (RR 0.90, 95% CI 0.59 to 1.38) and an increase in the total number of people with non-fatal SAEs (RR 2.15, 95% CI 1.01 to 4.55, P = 0.047, 4 trials, 1435 participants, moderate-quality evidence). In the subgroup of dosing schedule 30 mL for 10 days (cumulative dose 300 mL), the increase was more prominent: RR 2.86, 95% CI 1.23 to 6.66, P = 0.01 (2 trials, 1189 participants). Total number of people with adverse events: four trials reported on this outcome. Cerebrolysin may result in little to no difference in the total number of people with adverse events: RR 0.97, 95% CI 0.85 to 1.10, P = 0.90, 4 trials, 1435 participants, low-quality evidence. Non-death attrition: evidence from six trials involving 1517 participants suggests that Cerebrolysin results in little to no difference in non-death attrition, with 96 out of 764 Cerebrolysin-treated participants and 117 out of 753 placebo-treated participants being lost to follow-up for reasons other than death (very low-quality evidence). AUTHORS' CONCLUSIONS: Moderate-quality evidence indicates that Cerebrolysin probably has little or no beneficial effect on preventing all-cause death in acute ischaemic stroke, or on the total number of people with serious adverse events. Moderate-quality evidence also indicates a potential increase in non-fatal serious adverse events with Cerebrolysin use.


Assuntos
Aminoácidos/uso terapêutico , Fármacos Neuroprotetores/uso terapêutico , Acidente Vascular Cerebral/tratamento farmacológico , Doença Aguda , Aminoácidos/efeitos adversos , Viés , Isquemia Encefálica/complicações , Causas de Morte , Humanos , Fármacos Neuroprotetores/efeitos adversos , Pacientes Desistentes do Tratamento/estatística & dados numéricos , Ensaios Clínicos Controlados Aleatórios como Assunto , Acidente Vascular Cerebral/etiologia , Acidente Vascular Cerebral/mortalidade
15.
Phytochemistry ; 178: 112461, 2020 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-32692660

RESUMO

Eight pairs of enantiomeric lignans and neolignans including thirteen undescribed compounds, along with an undescribed meso compound, were isolated from the herbs of Solanum lyratum Thunb.(Solanaceae). Their structures and relative configurations were determined by extensive spectroscopic analyses of HRESIMS and nuclear magnetic resonance. The absolute configurations of the pure isomers were established based on the cooperative comparison between the experimental and calculated electronic circular dichroism (ECD) and optical rotation (OR). It is interesting that we obtained several naturally occurring stereoisomers with the identical gross structure possessing several stereogenic carbons from S. lyratum. Additionally, all isolates were assessed for neuroprotective effects toward human neuroblastoma SH-SY5Y cells injury induced by H2O2.


Assuntos
Lignanas , Fármacos Neuroprotetores , Solanum , Humanos , Peróxido de Hidrogênio , Estrutura Molecular
16.
PLoS One ; 15(7): e0223633, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32701951

RESUMO

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


Assuntos
Neurônios Dopaminérgicos/efeitos dos fármacos , Fármacos Neuroprotetores/farmacologia , Canais de Potássio Ativados por Cálcio de Condutância Baixa/agonistas , Animais , Benzimidazóis/farmacologia , Sobrevivência Celular/efeitos dos fármacos , Células Cultivadas , Neurônios Dopaminérgicos/metabolismo , Neurônios Dopaminérgicos/patologia , Embrião de Mamíferos/citologia , Desenvolvimento Embrionário/efeitos dos fármacos , Feminino , Mesencéfalo/citologia , Mesencéfalo/metabolismo , Ratos , Ratos Sprague-Dawley , Receptores de AMPA/metabolismo , Ácido alfa-Amino-3-hidroxi-5-metil-4-isoxazol Propiônico/toxicidade
17.
J Thorac Cardiovasc Surg ; 160(2): e55-e66, 2020 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-32689704

RESUMO

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


Assuntos
Encéfalo/efeitos dos fármacos , Hipóxia/tratamento farmacológico , Leucoencefalopatias/prevenção & controle , Fármacos Neuroprotetores/farmacologia , Progesterona/farmacologia , Substância Branca/efeitos dos fármacos , Animais , Animais Recém-Nascidos , Comportamento Animal/efeitos dos fármacos , Encéfalo/crescimento & desenvolvimento , Encéfalo/metabolismo , Plasticidade Celular/efeitos dos fármacos , Doença Crônica , Modelos Animais de Doenças , Feminino , Hipóxia/metabolismo , Hipóxia/patologia , Hipóxia/fisiopatologia , Leucoencefalopatias/metabolismo , Leucoencefalopatias/patologia , Leucoencefalopatias/fisiopatologia , Masculino , Microglia/efeitos dos fármacos , Microglia/metabolismo , Microglia/patologia , Atividade Motora/efeitos dos fármacos , Proteína Básica da Mielina/metabolismo , Oligodendroglia/efeitos dos fármacos , Oligodendroglia/metabolismo , Oligodendroglia/patologia , Ratos Sprague-Dawley , Substância Branca/metabolismo , Substância Branca/patologia , Substância Branca/fisiopatologia
18.
Toxicol Lett ; 331: 152-158, 2020 Oct 01.
Artigo em Inglês | MEDLINE | ID: mdl-32522579

RESUMO

Chronic exposure to n-hexane, a widely used solvent in industry, causes sensorimotor neuropathy, which is mainly mediated by its toxic metabolite, 2,5-hexanedione (HD). However, the mechanisms remain unclear. This study is designed to investigate whether nod-like receptor family pyrin domain-containing 3 (NLRP3) inflammasome is involved in HD-induced neurotoxicity. Results showed that HD intoxication significantly elevated NLRP3 expression, caspase-1 activation and interleukin-1ß (IL-1ß) maturation in the spinal cord of rats, indicating NLRP3 inflammasome activation. Glibenclamide, a sulfonylurea inhibitor of NLRP3 inflammasome, reduced HD-induced NLRP3 inflammasome activation, which was associated with mitigated gasdermin D (GSDMD) cleavage, neurofilament protein L (NF-L) reduction and demyelination as well as axon degeneration in the spinal cord of rats. Subsequently, we found that inhibition of NLRP3 inflammasome by glibenclamide suppressed microglial activation and M1 polarization and simultaneously recovered M2 polarization in HD-intoxicated rats. Furthermore, glibenclamide treatment reduced the contents of malondialdehyde (MDA) as well as elevated glutathione (GSH) levels and total-antioxidative capacity in the spinal cord of HD-intoxicated rats, indicating attenuated oxidative stress. Collectively, our findings suggested that NLRP3 inflammasome activation contributed to HD-induced neurotoxicity by enhancing microglial M1 polarization and oxidative damage. Inhibition of NLRP3 inflammasome by glibenclamide might a potential avenue to combat n-hexane-induced neuropathy.


Assuntos
Glibureto/farmacologia , Hexanonas/toxicidade , Inflamassomos/antagonistas & inibidores , Proteína 3 que Contém Domínio de Pirina da Família NLR/antagonistas & inibidores , Fármacos Neuroprotetores/farmacologia , Síndromes Neurotóxicas/prevenção & controle , Estresse Oxidativo/efeitos dos fármacos , Medula Espinal/efeitos dos fármacos , Animais , Antioxidantes/metabolismo , Masculino , Síndromes Neurotóxicas/imunologia , Síndromes Neurotóxicas/metabolismo , Estresse Oxidativo/imunologia , Ratos Sprague-Dawley , Medula Espinal/imunologia , Medula Espinal/metabolismo
19.
Adv Gerontol ; 33(2): 299-306, 2020.
Artigo em Russo | MEDLINE | ID: mdl-32593244

RESUMO

Neurodegenerative diseases are a heterogeneous group of nervous system pathologies. They are found mainly in people of an older age group. The incidence of neurodegenerative diseases is continuously growing due to an increase in the average life expectancy of the population. At the moment, there are no effective and safe treatments for neurodegenerative diseases, which are most often diagnosed at the stage of decompensation, when therapy is ineffective and does not bring positive outcomes. Most of the currently used drugs act only symptomatically. The review provides analyzed data and information about the prospects of using peptide bioregulators as neuroprotectors with high physiological activity and low immunogenicity.


Assuntos
Doenças Neurodegenerativas/prevenção & controle , Fármacos Neuroprotetores/farmacologia , Peptídeos/farmacologia , Idoso , Humanos , Doenças Neurodegenerativas/tratamento farmacológico , Fármacos Neuroprotetores/uso terapêutico , Peptídeos/uso terapêutico
20.
Georgian Med News ; (301): 159-165, 2020 Apr.
Artigo em Russo | MEDLINE | ID: mdl-32535582

RESUMO

The aim of the research was to investigate the effect of aminoguanidine on the content of autoantibodies in the serum, nitric oxide synthesis (NO), glial fibrillary acidic protein (GFAP) content and indicators of free radical oxidation in the cerebral hemispheres of BALB/c mice with antiphospholipid syndrome (APS) on the 18th day of pregnancy. An increase in the content of autoantibodies to brain proteins (120 kDa, 150 kDa, and >170 kDa) was detected in the serum of BALB/c mice with APS on the 18th day of pregnancy. An increase in the content of GFAP (total), GFAP (49-37 kDa), NO2¯, NO3¯ and prooxidant-antioxidant system imbalance in the cerebral hemispheres of pregnant mice with APS was established. With administration of aminoguanidine into the pregnant mice with APS, a decrease in the content of autoantibodies to brain proteins (120 kDa and 150 kDa) in serum was proved. With the introduction of aminoguanidine, a selective inhibitor of inducible NO synthase on the 18th day of pregnancy the increase in GFAP (49-37 kDa) in the cerebral hemispheres of APS mice was established, and the GFAP (total), NO2¯ and NO3¯ content did not change significantly, relative to the indicators of pregnant animals with APS. With introduction of aminoguanidine in cases of APS on the 18th day of pregnancy lesser manifestations of oxidative stress in the cerebral hemispheres, a decrease in the activity of lipid peroxidation processes, an increase in the activity and content of the antioxidant system components was evidenced. Thus, aminoguanidine has a neuroprotective effect in obstetric antiphospholipid syndrome in the BALB/c mice.


Assuntos
Síndrome Antifosfolipídica , Fármacos Neuroprotetores , Animais , Feminino , Guanidinas , Camundongos , Camundongos Endogâmicos BALB C , Gravidez
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