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1.
Minerva Med ; 110(5): 455-463, 2019 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-31368292

RESUMO

Peripheral neuropathies are frequently encountered in clinical practice and are associated with a major impairment in quality of life. However, their management remains poor, and current therapies are often burdened with major side effects and can present poor efficacy on pain and functionality. Therefore, it has been suggested that the combination of two or more different drugs may improve analgesic efficacy and reduce side effects. Tricortin® 1000 is formulated with 12 mg of Brain cortex phospholipid liposomes + 1000 µg of Cyanocobalamin injectable solution (PL+CNCbl) for intramuscular use and is indicated in the treatment of poly-algo-neuropathic syndromes. This combination exerts a marked neurotrophic action by promoting the synthesis of endogenous phospholipids; moreover, the peculiar formulation optimizes the delivery of CNCbl which has analgesic and neurotrophic action. This paper discusses the pharmacotherapy of peripheral neuropathies, including low-back pain, neck pain, postherpetic neuropathy (PHN) and focuses on the fixed dose combination PL+CNCbl clinical efficacy in association with other treatments or in monotherapy.


Assuntos
Analgésicos/uso terapêutico , Fármacos Neuroprotetores/uso terapêutico , Doenças do Sistema Nervoso Periférico/tratamento farmacológico , Fosfolipídeos/uso terapêutico , Vitamina B 12/uso terapêutico , Analgésicos/administração & dosagem , Analgésicos/efeitos adversos , Córtex Cerebral/química , Ensaios Clínicos como Assunto , Combinação de Medicamentos , Humanos , Injeções Intramusculares , Lipossomos , Fármacos Neuroprotetores/administração & dosagem , Fármacos Neuroprotetores/efeitos adversos , Doenças do Sistema Nervoso Periférico/etiologia , Doenças do Sistema Nervoso Periférico/fisiopatologia , Fosfolipídeos/administração & dosagem , Fosfolipídeos/efeitos adversos , Vitamina B 12/administração & dosagem , Vitamina B 12/efeitos adversos
2.
J Stroke Cerebrovasc Dis ; 28(9): 2496-2505, 2019 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-31279697

RESUMO

BACKGROUND: Nicotine may have neuroprotective effects on the injured brain through modulation of the cholinergic anti-inflammatory pathway. AIMS: This study aimed to evaluate the relationship between cigarette smoking and outcomes in patients with spontaneous intracerebral hemorrhage (ICH). METHODS: This was a retrospective review of consecutive ICH patients enrolled in the ICH Outcomes Project from 2009 to 2017. Patients with age ≥18 years and baseline modified Rankin Scale (mRS) score 0-2 were included. Smoking patterns were categorized as recent smoker (≤30 days prior to ICH) and not recent smoker (>30 days prior to ICH). Not recent smokers were further categorized into former smokers and nonsmokers. The primary outcome was good outcome (90-day mRS ≤ 2). Secondary outcomes were excellent outcome (90-day mRS 0-1), 90-day Barthel Index, and in-hospital and 90-day mortality. RESULTS: The study cohort comprised 545 patients, including 60 recent smokers and 485 not recent smokers. Recent smokers had higher rates of good (35% versus 23%; odds ratio [OR] = 1.787, P = .047) and excellent (25% versus 13%; OR = 2.220, P = .015) outcomes compared to not recent smokers. These differences were not significant after baseline adjustments. Recent smokers had higher rates of good (36% versus 24%; OR = 1.732, P = .063) and excellent (25% versus 13%; OR = 2.203, P = .018) outcomes compared to nonsmokers. These differences were not significant after baseline adjustments. A 90-day Barthel Index, in-hospital, and 90-day mortality were comparable between recent and not recent smokers, recent and nonsmokers, and former and nonsmokers. CONCLUSIONS: Despite potential neuroprotective effects of nicotine found in cigarettes, these may be outweighed by the detrimental effects of cigarette smoking on health outcomes.


Assuntos
Encéfalo/fisiopatologia , Hemorragia Cerebral/fisiopatologia , não Fumantes , Fumantes , Fumar/efeitos adversos , Adulto , Idoso , Encéfalo/efeitos dos fármacos , Hemorragia Cerebral/diagnóstico , Hemorragia Cerebral/mortalidade , Bases de Dados Factuais , Avaliação da Deficiência , Feminino , Nível de Saúde , Mortalidade Hospitalar , Humanos , Masculino , Pessoa de Meia-Idade , Fármacos Neuroprotetores/administração & dosagem , Fármacos Neuroprotetores/efeitos adversos , Nicotina/administração & dosagem , Nicotina/efeitos adversos , Agonistas Nicotínicos/administração & dosagem , Agonistas Nicotínicos/efeitos adversos , Valor Preditivo dos Testes , Prognóstico , Fatores de Proteção , Recuperação de Função Fisiológica , Estudos Retrospectivos , Medição de Risco , Fatores de Risco , Fumar/mortalidade , Abandono do Hábito de Fumar , Fatores de Tempo
3.
J Agric Food Chem ; 67(30): 8348-8360, 2019 Jul 31.
Artigo em Inglês | MEDLINE | ID: mdl-31304751

RESUMO

We have recently demonstrated that tau hyperphosphorylation causes diabetic synaptic neurodegeneration of retinal ganglion cells (RGCs), which might be the earliest affair during the pathogenesis of diabetic retinopathy (DR). Thus, there is a pressing need to seek therapeutic agents possessing neuroprotective effects against tau hyperphosphorylation in RGCs for arresting the progression of DR. Here, using a well-characterized diabetes model of db/db mouse, we discovered that topical ocular application of 10 mg/kg/day of ginsenoside Rg1 (GRg1), one of the major active ingredients extracted from Panax ginseng and Panax notoginseng, ameliorated hyperphosphorylated tau-triggered RGCs synaptic neurodegeneration in diabetic mice. The neuroprotective effects of GRg1 on diabetic retinae were abrogated when retinal IRS-1 or Akt was suppressed by intravitreal injection with si-IRS-1 or topically coadministered with a specific inhibitor of Akt, respectively. However, selective repression of retinal GSK3ß by intravitreal administration of si-GSK3ß rescued the neuroprotective properties of GRg1 when Akt was inactivated. Therefore, the present study showed for the first time that GRg1 can prevent hyperphosphorylated tau-induced synaptic neurodegeneration of RGCs via activation of IRS-1/Akt/GSK3ß signaling in the early phase of DR. Moreover, our data clarify the potential therapeutic significance of GRg1 for neuroprotective intervention strategies of DR.


Assuntos
Retinopatia Diabética/tratamento farmacológico , Ginsenosídeos/administração & dosagem , Glicogênio Sintase Quinase 3 beta/metabolismo , Proteínas Substratos do Receptor de Insulina/metabolismo , Fármacos Neuroprotetores/administração & dosagem , Proteínas Proto-Oncogênicas c-akt/metabolismo , Células Ganglionares da Retina/efeitos dos fármacos , Proteínas tau/metabolismo , Animais , Retinopatia Diabética/genética , Retinopatia Diabética/metabolismo , Glicogênio Sintase Quinase 3 beta/genética , Humanos , Proteínas Substratos do Receptor de Insulina/genética , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Degeneração Neural/tratamento farmacológico , Degeneração Neural/genética , Degeneração Neural/metabolismo , Panax notoginseng/química , Fosforilação , Extratos Vegetais/administração & dosagem , Proteínas Proto-Oncogênicas c-akt/genética , Retina/patologia , Células Ganglionares da Retina/metabolismo , Transdução de Sinais/efeitos dos fármacos , Proteínas tau/genética
4.
Life Sci ; 232: 116647, 2019 Sep 01.
Artigo em Inglês | MEDLINE | ID: mdl-31301416

RESUMO

AIM: Brain injury after sepsis leads to high mortality and long-term brain dysfunction in patients. Previous studies revealed that borneol has a protective effect on the brain, but its function on sepsis associated encephalopathy (SAE) remains unknown. Herein, we investigated the protective effect of borneol against sepsis-related brain injury. MAIN METHODS: Lipopolysaccharide (LPS)-induced sepsis mice and cells were treated with borneol at the dose of 100 mg/kg by gavage or 10 µg/ml in culture, respectively. The protective effect of borneol on neurons and the microglia were assessed in vivo and in vitro. KEY FINDINGS: We observed that borneol attenuated brain neuronal and microglial inflammation in LPS-induced sepsis mice with a suppression of p-p65 and p38 signaling that were initially activated by LPS in the brain. In vitro examination confirmed that the protective effect of borneol on both neurons and microglia, and its suppressive effect on p-p65 and p38 pathways were, at least in part, direct. SIGNIFICANCE: An early protection of neurons and microglia from bacterial endotoxin during sepsis is beneficial, and borneol has the potential to protect these cells.


Assuntos
Bornanos/uso terapêutico , Lesões Encefálicas/tratamento farmacológico , Lesões Encefálicas/etiologia , Endotoxinas/toxicidade , Neurônios/efeitos dos fármacos , Fármacos Neuroprotetores/uso terapêutico , Sepse/complicações , Animais , Bornanos/administração & dosagem , Bornanos/farmacologia , Células Cultivadas , Relação Dose-Resposta a Droga , Lipopolissacarídeos/toxicidade , Sistema de Sinalização das MAP Quinases/efeitos dos fármacos , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Microglia/efeitos dos fármacos , Fármacos Neuroprotetores/administração & dosagem , Fármacos Neuroprotetores/farmacologia
5.
Khirurgiia (Mosk) ; (5): 57-63, 2019.
Artigo em Russo | MEDLINE | ID: mdl-31169820

RESUMO

AIM: To study the effectiveness of intraoperative administration of Cytoflavine for the prevention of ischemic brain injury during cerebral aneurysm (CA) clipping with temporary occlusion of the leading artery under general anesthesia. MATERIAL AND METHODS: The prospective cohort single-center study included 40 patients with CA ( the main group - 27 patients with intraoperative administration of cytoflavine; the comparison group -13 patients without use of cytoflavine), who underwent aneurism clipping with temporary occlusion of the afferent artery. We assesed the intraoperative state of the brain, the time of awakening and extubation of patients after surgery, neurological deficit and local ischemic changes in the area of surgery according to the CT of the brain in the early postoperative period, resuscitation bed-day and the relationship of these indicators with the duration of temporary occlusion of the afferent artery in the selected groups of patients. RESULTS: In intergroup comparison, patients of the main group treated with intraoperative cytoflavin showed a reduction in the time of awakening (p=0.013) and the time of extubation (p=0.01) both with temporary occlusion of the afferent artery and in patients without temporary occlusion (p<0.05). The duration of resuscitation bed-day decreased in the main group of patients receiving intraoperatively cytoflavine (p=0.01), as well as in patients in the comparison group without temporary occlusion (p<0.05). CONCLUSION: Temporary occlusion of the afferent artery with short intervals of vessel occlusion in combination with intraoperative intravenous administration of cytoflavine expands the tolerability to artery occlusion in patients operated in the 'cold' period, reduces the possibility of neurological deficit, reduces the recovery period and resuscitation bed-day after surgical clipping CA.


Assuntos
Lesões Encefálicas/prevenção & controle , Isquemia Encefálica/fisiopatologia , Encéfalo/irrigação sanguínea , Mononucleotídeo de Flavina/administração & dosagem , Inosina Difosfato/administração & dosagem , Aneurisma Intracraniano/fisiopatologia , Fármacos Neuroprotetores/administração & dosagem , Procedimentos Neurocirúrgicos/efeitos adversos , Niacinamida/administração & dosagem , Succinatos/administração & dosagem , Encéfalo/efeitos dos fármacos , Encéfalo/fisiopatologia , Encéfalo/cirurgia , Lesões Encefálicas/etiologia , Lesões Encefálicas/fisiopatologia , Lesões Encefálicas/cirurgia , Isquemia Encefálica/etiologia , Isquemia Encefálica/cirurgia , Combinação de Medicamentos , Mononucleotídeo de Flavina/farmacologia , Humanos , Inosina Difosfato/farmacologia , Aneurisma Intracraniano/complicações , Aneurisma Intracraniano/cirurgia , Cuidados Intraoperatórios , Fármacos Neuroprotetores/farmacologia , Procedimentos Neurocirúrgicos/métodos , Niacinamida/farmacologia , Estudos Prospectivos , Succinatos/farmacologia , Técnicas de Sutura
6.
J Agric Food Chem ; 67(22): 6190-6201, 2019 Jun 05.
Artigo em Inglês | MEDLINE | ID: mdl-31117496

RESUMO

Sesamol, an antioxidant lignan from sesame oil, possesses neuroprotective bioactivities. The present work was aimed to elucidate the systemic protective effects of sesamol on cognitive deficits and to determine the possible link between gut and brain. Wildtype and ApoE-/- mice were treated with a high-fat diet and sesamol (0.05%, w/v, in drinking water) for 10 weeks. Behavioral tests including Morris-water maze, Y-maze, and elevated plus maze tests indicated that sesamol could only improve cognitive deficits and anxiety behaviors in wildtype. Consistently, sesamol improved synapse ultrastructure and inhibited Aß accumulation in an ApoE-dependent manner. Moreover, sesamol prevented dietary-induced gut barrier damages and systemic inflammation. Sesamol also reshaped gut microbiome and improved the generation of microbial metabolites short-chain fatty acids. To summarize, this study revealed that the possible mechanism of neuroprotective effects of sesamol might be ApoE-dependent, and its beneficial effects on gut microbiota/metabolites could be translated into neurodegenerative diseases treatment.


Assuntos
Apolipoproteínas E/metabolismo , Benzodioxóis/administração & dosagem , Encéfalo/efeitos dos fármacos , Disfunção Cognitiva/tratamento farmacológico , Dieta Hiperlipídica/efeitos adversos , Microbioma Gastrointestinal/efeitos dos fármacos , Fármacos Neuroprotetores/administração & dosagem , Fenóis/administração & dosagem , Óleo de Gergelim/química , Animais , Apolipoproteínas E/genética , Bactérias/classificação , Bactérias/efeitos dos fármacos , Bactérias/isolamento & purificação , Bactérias/metabolismo , Comportamento Animal/efeitos dos fármacos , Encéfalo/metabolismo , Disfunção Cognitiva/genética , Disfunção Cognitiva/metabolismo , Disfunção Cognitiva/microbiologia , Ácidos Graxos Voláteis/metabolismo , Humanos , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout
7.
Acta Neurol Scand ; 140(3): 212-218, 2019 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-31141159

RESUMO

OBJECTIVES: Intravenous glibenclamide (GBC) exerts neuroprotection in both preclinical and preliminary clinical studies. This study explored the safety and potential efficacy of oral GBC in patients with acute hemispheric infarction. MATERIALS & METHODS: During January 2017 and August 2017, adult volunteers were recruited to receive oral GBC treatment, if they presented with an acute anterior ischemic stroke and a National Institute of Health Stroke Score of ≥8. Controls were those who met the above inclusion criteria and had not been on GBC or other sulfonylureas prior to stroke or after hospitalization. Propensity score matching (PSM) was performed to balance baseline characteristics. The primary endpoint was the score on the modified Rankin Scale (mRS) at 6 months. RESULTS: We included 213 patients in the unmatched cohort (20 in the GBC group and 193 in the control group) and 40 patients (20 in each group) in the matched cohort. In both cohorts, GBC treatment did not increase the risks of early death, hypoglycemia, and early neurological deterioration. Although GBC did not substantially improve 6-month functional outcome that measured in shift analysis of mRS, a slight trend toward less severe disability and death (mRS 5-6) was observed. In the matched cohort, GBC treatment was associated with lighter brain edema, when CED score was used for evaluation. CONCLUSIONS: In this study, oral GBC is safe in treating acute hemispheric infarction and might have potential in preventing brain edema and consequential severe disability and death. An adequately powered and randomized trial is warranted.


Assuntos
Isquemia Encefálica/tratamento farmacológico , Glibureto/uso terapêutico , Fármacos Neuroprotetores/uso terapêutico , Acidente Vascular Cerebral/tratamento farmacológico , Administração Oral , Adulto , Idoso , Estudos de Casos e Controles , Feminino , Glibureto/administração & dosagem , Glibureto/efeitos adversos , Humanos , Masculino , Pessoa de Meia-Idade , Fármacos Neuroprotetores/administração & dosagem , Fármacos Neuroprotetores/efeitos adversos
8.
Molecules ; 24(9)2019 May 03.
Artigo em Inglês | MEDLINE | ID: mdl-31058815

RESUMO

c-Jun N-terminal kinase (JNK) is activated by various brain insults and is implicated in neuronal injury triggered by reperfusion-induced oxidative stress. Some JNK inhibitors demonstrated neuroprotective potential in various models, including cerebral ischemia/reperfusion injury. The objective of the present work was to study the neuroprotective activity of a new specific JNK inhibitor, IQ-1S (11H-indeno[1,2-b]quinoxalin-11-one oxime sodium salt), in the model of global cerebral ischemia (GCI) in rats compared with citicoline (cytidine-5'-diphosphocholine), a drug approved for the treatment of acute ischemic stroke and to search for pleiotropic mechanisms of neuroprotective effects of IQ-1S. The experiments were performed in a rat model of ischemic stroke with three-vessel occlusion (model of 3VO) affecting the brachiocephalic artery, the left subclavian artery, and the left common carotid artery. After 7-min episode of GCI in rats, 25% of animals died, whereas survived animals had severe neurological deficit at days 1, 3, and 5 after GCI. At day 5 after GCI, we observing massive loss of pyramidal neurons in the hippocampal CA1 area, increase in lipid peroxidation products in the brain tissue, and decrease in local cerebral blood flow (LCBF) in the parietal cortex. Moreover, blood hyperviscosity syndrome and endothelial dysfunction were found after GCI. Administration of IQ-1S (intragastrically at a dose 50 mg/kg daily for 5 days) was associated with neuroprotective effect comparable with the effect of citicoline (intraperitoneal at a dose of 500 mg/kg, daily for 5 days).The neuroprotective effect was accompanied by a decrease in the number of animals with severe neurological deficit, an increase in the number of animals with moderate degree of neurological deficit compared with control GCI group, and an increase in the number of unaltered neurons in the hippocampal CA1 area along with a significant decrease in the number of neurons with irreversible morphological damage. In rats with IQ-1S administration, the LCBF was significantly higher (by 60%) compared with that in the GCI control. Treatment with IQ-1S also decreases blood viscosity and endothelial dysfunction. A concentration-dependent decrease (IC50 = 0.8 ± 0.3 µM) of tone in isolated carotid arterial rings constricted with phenylephrine was observed after IQ-1S application in vitro. We also found that IQ-1S decreased the intensity of the lipid peroxidation in the brain tissue in rats with GCI. 2.2-Diphenyl-1-picrylhydrazyl scavenging for IQ-1S in acetonitrile and acetone exceeded the corresponding values for ionol, a known antioxidant. Overall, these results suggest that the neuroprotective properties of IQ-1S may be mediated by improvement of cerebral microcirculation due to the enhanced vasorelaxation, beneficial effects on blood viscosity, attenuation of the endothelial dysfunction, and antioxidant/antiradical IQ-1S activity.


Assuntos
Isquemia Encefálica/prevenção & controle , Citidina Difosfato Colina/administração & dosagem , Fármacos Neuroprotetores/administração & dosagem , Oximas/administração & dosagem , Quinoxalinas/administração & dosagem , Traumatismo por Reperfusão/prevenção & controle , Animais , Isquemia Encefálica/metabolismo , Circulação Cerebrovascular , Citidina Difosfato Colina/farmacologia , Modelos Animais de Doenças , Relação Dose-Resposta a Droga , Humanos , Peroxidação de Lipídeos/efeitos dos fármacos , Masculino , Fármacos Neuroprotetores/farmacologia , Oximas/farmacologia , Quinoxalinas/farmacologia , Ratos , Ratos Wistar , Resultado do Tratamento
9.
Acta Neurobiol Exp (Wars) ; 79(1): 73-85, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31038486

RESUMO

Preconditioning with lipopolysaccharide (LPS) or opioid antagonists has a neuroprotective effect in ischemic insults. However, the co­preconditioning effect of toll­like receptor ligands and opioid antagonists has not been investigated. In this study we examined the neuroprotective effect of LPS and naltrexone (NTX) preconditioning and co­preconditioning in unilateral selective hippocampal ischemia in rats to assess for possible synergistic protective effects. LPS and NTX were injected unilaterally into the left cerebral ventricle of male rats. Forty­eight hours after LPS and twenty­four hours after NTX injection, ipsilateral selective hippocampal ischemia was induced using a modified version of the photothrombotic method. Protective effects for LPS and NTX were assessed by evaluating infarct volume (using 2,3,5­triphenyltetrazolium chloride staining), and cognitive function (using radial arm water maze and passive avoidance tests). Animals in the ischemic group had an infarct lesion and considerable cognitive impairment, compared with the sham group. LPS or NTX preconditioning significantly reduced the infarct size and improved cognitive function. Moreover, co­preconditioning with LPS and NTX increased the protective effect compared with preconditioning with LPS or NTX alone. Our data showed that LPS and NTX preconditioning resulted in a neuroprotective effect in hippocampal ischemia. Furthermore, co­preconditioning with LPS and NTX resulted in a synergistic protective effect.


Assuntos
Isquemia Encefálica/tratamento farmacológico , Lateralidade Funcional/fisiologia , Hipocampo/patologia , Precondicionamento Isquêmico/métodos , Lipopolissacarídeos/administração & dosagem , Naltrexona/administração & dosagem , Fármacos Neuroprotetores/administração & dosagem , Animais , Aprendizagem da Esquiva/efeitos dos fármacos , Isquemia Encefálica/complicações , Isquemia Encefálica/etiologia , Modelos Animais de Doenças , Hipocampo/irrigação sanguínea , Injeções Intraventriculares , Transtornos de Aprendizagem/etiologia , Transtornos de Aprendizagem/prevenção & controle , Masculino , Aprendizagem em Labirinto/efeitos dos fármacos , Estimulação Luminosa/efeitos adversos , Distribuição Aleatória , Ratos , Ratos Wistar , Tempo de Reação/efeitos dos fármacos , Resultado do Tratamento
10.
J Neurosurg Sci ; 63(3): 265-269, 2019 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-31096724

RESUMO

BACKGROUND: Acute ischemic stroke (AIS) is associated with significant morbidity and mortality and has a very narrow window of treatment with fibrinolytics. We investigated the safety and efficacy of combined chlorpromazine and promethazine (C+P) treatment in AIS. METHODS: A total of 64 consecutive patients diagnosed with AIS were selected and were randomly (double-blind) assigned into either the control group (standard of care [SOC] treatment) or the treatment group (SOC+C+P [12.5+12.5 mg BID or 25+25 mg BID]) which were treated for 2 weeks. The National Institutes of Health Stroke Scale (NIHSS) and Modified Rankin Scale (mRS) were computed prior to and after treatment to evaluate neurological deficits and daily functional status. RESULTS: In our study, 64 patients (males=81.3%) were divided into either the control (34 patients, 83.3% males, mean age=58.8±11.7 years) or the study group (30 patients, 79.4% males, mean age=62.3±9.1 years). While the NIHSS scores were not different between the control and treatment group at admission (P>0.05), a greater proportion of the cohort in both the groups (control group low NIHSS=79.4%, high NIHSS=20.6%, P<0.01) had a lower NIHSS at admission and (treatment group low NIHSS=83.3%, high NIHSS=16.7%, P<0.01). Interestingly, while both the control and treatment group had lower NIHSS and mRS scores at 90d post treatment compared to those at baseline, there were no significant differences in those scores between the two group (P>0.05) suggesting no improved benefit with C+P. Moreover, using C+P did not lead to any serious adverse effects when compared to the treatment group. CONCLUSIONS: While the addition of low dose chlorpromazine and promethazine to standard of care for acute ischemic stroke did not have any significant improvement in functional outcomes, there were no serious adverse effects. Thus, the use of chlorpromazine and promethazine in the acute ischemic stroke setting and future studies using higher doses of C+P are justified.


Assuntos
Clorpromazina/administração & dosagem , Fármacos Neuroprotetores/administração & dosagem , Prometazina/administração & dosagem , Acidente Vascular Cerebral/tratamento farmacológico , Adulto , Idoso , Aspirina/administração & dosagem , Atorvastatina/administração & dosagem , Método Duplo-Cego , Quimioterapia Combinada , Edaravone/administração & dosagem , Feminino , Humanos , Inibidores de Hidroximetilglutaril-CoA Redutases/administração & dosagem , Masculino , Pessoa de Meia-Idade , Inibidores da Agregação de Plaquetas/administração & dosagem , Alcaloides de Vinca/administração & dosagem
11.
Prog Brain Res ; 245: 145-200, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-30961867

RESUMO

Alzheimer's disease (AD) is estimated to be afflicting over 55 millions of individual worldwide in 2018-19 for which no suitable clinical therapeutic measures have been developed so far. Thus, there is an urgent need to explore novel therapeutic strategies using nanodelivery of drugs and agents either alone or in combination for superior neuroprotection in AD and enhanced quality of life of the affected individuals. There are reports that AD is often associated with diminished neurotrophic factors and neprilysin together with enhancement of phosphorylated Tau (p-Tau) within the brain and in the cerebrospinal fluid (CSF). Thus, studies aiming to enhance neurotrophic factors and neprilysin together with neutralizing p-Tau within the central nervous system (CNS) may alleviate brain pathology in AD. In this review these strategies are discussed using nanotechnological approaches largely based on our own investigations in relation to current literature in the field.


Assuntos
Doença de Alzheimer/tratamento farmacológico , Doença de Alzheimer/metabolismo , Aminoácidos/administração & dosagem , Anticorpos/administração & dosagem , Nanomedicina/métodos , Nanofios/uso terapêutico , Neprilisina/administração & dosagem , Fármacos Neuroprotetores/administração & dosagem , Proteínas tau/imunologia , Animais , Humanos
12.
Prog Brain Res ; 245: 201-246, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-30961868

RESUMO

Parkinson's disease (PD) is affecting >10 million people worldwide for which no suitable cure has been developed so far. Roughly, about two people per thousand populations are affected with PD like symptoms especially over the age of 50. About 1% of the populations above 60 years suffer from PD-like disease. The prevalence of the disease is increasing over the years, and future projections by 2020 could be 12-14 millions people affected by the disease. Thus, exploration of suitable therapeutic measures is the need of the hour to enhance quality of the life of PD patients. PD induced brain pathology includes loss of dopaminergic neurons in the substantia niagra that could later extends to other cortical regions causing loss of voluntary motor control. Deposition of α-synuclein in the brain further leads to neurodegeneration. However, the exact cause of PD is still unknown. It appears that breakdown of the blood-brain barrier (BBB) and leakage of serum component into the brain could lead to neurodegeneration in PD. Thus, novel treatment strategies that are able to restore BBB breakdown and enhance neuronal plasticity and neuroregeneration in PD could be effective in future therapy. With the advancement of nanotechnology, it is worthwhile to understand the role of nanodelivery of selected agents in PD to enhance neuroprotection. In this review new role of BBB, brain edema, and neuropathology in PD is discussed. In addition, superior neuroprotection induced by nanowired delivery of a multimodal drug cerebrolysin in PD is summarized based on our own investigations.


Assuntos
Aminoácidos/farmacologia , Nanomedicina/métodos , Nanofios/uso terapêutico , Fármacos Neuroprotetores/farmacologia , Doença de Parkinson/tratamento farmacológico , Doença de Parkinson/metabolismo , Aminoácidos/administração & dosagem , Animais , Humanos , Fármacos Neuroprotetores/administração & dosagem , Doença de Parkinson/patologia , Doença de Parkinson/fisiopatologia
13.
Prog Brain Res ; 245: 263-279, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-30961870

RESUMO

Parkinson's disease (PD) as a motor disorder is pathologically featured by the loss of dopaminergic neurons of the substantia nigra compacta (SNc) and the consequent depletion of dopamine in the striatum. However, motor signs are detectable when the loss of dopaminergic striatal terminals exceeds to the dopaminergic neuronal degeneration in SN. Hence, recent evidences about the topological organization of the nigrostriatal system could provide novel insights about the progression of the neurodegenerative process as well as the correct application of the novel therapeutic strategies. Though dopaminergic drugs and different routes of administration have been proposed to treat PD, most of the effects are symptomatic with temporary effects resorting to invasive procedures to ameliorate the side effects. Since the blood-brain barrier (BBB) is the main obstacle for most of molecules to access to the brain, ongoing research is focused on halting the progression of PD through the use of those technologies that allow the effective delivery and diffusion of therapeutic molecules to the central nervous system for bypassing BBB and avoiding the side effects. In this context, nanotechnology is emerging as a promising tool for drug delivery. In fact, nanodelivery of restorative treatments in PD, such as gene therapy increased the effectiveness of neurotrophic factors for restoring the dopamine deficit and improving motor deficit in rodent models. Therefore, the present review is focused on the description and identification of the available nanotherapies developed in experimental models of PD which could suppose an important advance for controlled delivery of nanobioactive components into the brain and one more step for the clinical projection.


Assuntos
Antioxidantes/administração & dosagem , Barreira Hematoencefálica , Dopaminérgicos/administração & dosagem , Nanomedicina/métodos , Fatores de Crescimento Neural/administração & dosagem , Fármacos Neuroprotetores/administração & dosagem , Doença de Parkinson/tratamento farmacológico , Animais , Humanos
14.
Prog Brain Res ; 245: 57-88, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-30961872

RESUMO

The treatment of Alzheimer's disease (AD) is up to today one of the most unsuccessful examples of biomedical science. Despite the high number of literature evidences detailing the multifactorial and complex etiopathology of AD, no cure is yet present on the market and the available treatments are only symptomatic. The reasons could be ascribed on two main factors: (i) lack of ability of the majority of drugs to cross the blood-brain barrier (BBB), thus excluding the brain for any successful therapy; (ii) lack of selectivity and specificity of drugs, decreasing the efficacy of even potent anti-AD drugs. The exploitation of specifically engineered nanomedicines planned to cross the BBB and to target the most "hot" site of action (i.e., ß-amyloid) is one of the most interesting innovations in drug delivery and could reasonably represent an promising choice for possible treatments and even early-diagnosis of AD. In this chapter, we therefore outline the most talented approaches in AD treatment with a specific focus on the main advantages/drawbacks and future possible translation to clinic application.


Assuntos
Doença de Alzheimer/tratamento farmacológico , Peptídeos beta-Amiloides/efeitos dos fármacos , Barreira Hematoencefálica , Nanomedicina/métodos , Fármacos Neuroprotetores/administração & dosagem , Nootrópicos/administração & dosagem , Animais , Humanos
15.
Prog Brain Res ; 245: 89-118, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-30961873

RESUMO

Concussive head injury (CHI) is quite prevalent in military personnel leading to lifetime disability in more than 85% of cases. Other reasons of CHI include motor vehicle accident, fall or blunt trauma under various conditions. In United States of America (USA) alone more than 150k cases of head injury are added every year for which no suitable therapeutic strategies are still available. Thus, there is a need to expand our knowledge in treating CHI cases with novel therapeutic measures to enhance the quality of life of head injury victims. With recent advancements in nanodelivery of drugs for superior neuroprotective effects in neurological diseases, our laboratory is engaged in understanding the role of nanowired delivery of suitable drugs in treating CHI and other neurodegenerative diseases. DL-3-n-butylphthalide (NBP) is an extract of Chinese celery and is able to induce profound neuroprotection following ischemic stroke and other related neurological dysfunction. Thus, it is quite likely that synthetic NBP could have pronounced neuroprotective effects in CHI as well. We believe that nanodelivery of NBP have superior neuroprotection in CHI. In this review neuroprotective effects of nanowired delivery of NBP in CHI induced brain pathology is described. Our experimental observations show that nanowired delivery of NBP results in superior neuroprotection than the regular NBP in CHI. The probable mechanisms and functional significance of our finding in relation to military medicine is discussed based on our own investigations.


Assuntos
Benzofuranos/administração & dosagem , Concussão Encefálica/tratamento farmacológico , Edema Encefálico/tratamento farmacológico , Nanomedicina/métodos , Nanofios/uso terapêutico , Fármacos Neuroprotetores/administração & dosagem , Animais , Concussão Encefálica/complicações , Concussão Encefálica/patologia , Edema Encefálico/etiologia , Edema Encefálico/patologia , Humanos
16.
Adv Mater ; 31(21): e1808361, 2019 May.
Artigo em Inglês | MEDLINE | ID: mdl-30957932

RESUMO

Reperfusion injury exists as the major obstacle to full recovery of neuron functions after ischemic stroke onset and clinical thrombolytic therapies. Complex cellular cascades including oxidative stress, neuroinflammation, and brain vascular impairment occur within neurovascular units, leading to microthrombus formation and ultimate neuron death. In this work, a multitarget micelle system is developed to simultaneously modulate various cell types involved in these events. Briefly, rapamycin is encapsulated in self-assembled micelles that are consisted of reactive oxygen species (ROS)-responsive and fibrin-binding polymers to achieve micelle retention and controlled drug release within the ischemic lesion. Neuron survival is reinforced by the combination of micelle facilitated ROS elimination and antistress signaling pathway interference under ischemia conditions. In vivo results demonstrate an overall remodeling of neurovascular unit through micelle polarized M2 microglia repair and blood-brain barrier preservation, leading to enhanced neuroprotection and blood perfusion. This strategy gives a proof of concept that neurovascular units can serve as an integrated target for ischemic stroke treatment with nanomedicines.


Assuntos
Isquemia Encefálica/tratamento farmacológico , Circulação Cerebrovascular/efeitos dos fármacos , Microcirculação/efeitos dos fármacos , Fármacos Neuroprotetores/administração & dosagem , Sirolimo/administração & dosagem , Acidente Vascular Cerebral/tratamento farmacológico , Trombose/metabolismo , Apoptose/efeitos dos fármacos , Barreira Hematoencefálica/metabolismo , Encéfalo/irrigação sanguínea , Encéfalo/efeitos dos fármacos , Isquemia Encefálica/patologia , Isquemia Encefálica/fisiopatologia , Linhagem Celular , Humanos , Micelas , Microglia/efeitos dos fármacos , Microglia/patologia , Neurônios/metabolismo , Neurônios/patologia , Fármacos Neuroprotetores/química , Oligopeptídeos/química , Polietilenoglicóis/química , Espécies Reativas de Oxigênio/metabolismo , Sirolimo/química , Acidente Vascular Cerebral/patologia , Acidente Vascular Cerebral/fisiopatologia
17.
Int J Nanomedicine ; 14: 1979-1991, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-30936698

RESUMO

Background: Ischemic stroke is a devastating condition, with metabolic derangement and persistent inflammation enhancing the initial insult of ischaemia. Recombinant tissue plasminogen remains the only effective treatment but limited as therapy must commence soon after the onset of symptoms. Purpose: We investigated whether acetate, which modulates many pathways including inflammation, may attenuate brain injury in stroke. As acetate has a short blood half-life and high amounts irritate the gastrointestinal tract, acetate was administered encapsulated in a liposomal nanoparticle (liposomal-encapsulated acetate, LITA). Methods: Transient ischemia was induced by 90 mins middle-cerebral artery occlusion (MCAO) in Sprague-Dawley rats, and LITA or control liposomes given intraperitoneally at occlusion and daily for up to two weeks post-MCAO. Magnetic resonance imaging (MRI) was used to estimate lesion volume at 24 h, 1 and 2 weeks post-MCAO and anterior lateral ventricular volume (ALVv) at 2 weeks post-MCAO. Locomotive behaviour was tested prior to the final MRI scan. After the final scan, brains were collected, and immunohistochemistry was performed. Results: Lesion volumes were decreased by ~80% from 24 h to one-week post-MCAO, in both control and LITA groups (P⩽0.05). However, the lesion was increased by ~50% over the subsequent 1 to 2 weeks after MCAO in the control group (from 24.1±10.0 to 58.7±28.6 mm3; P⩽0.05) but remained unchanged in the LITA group. ALVv were also attenuated by LITA treatment at 2 weeks post-MCAO (177.2±11.9% and 135.3±10.9% of contralateral ALVv for control and LITA groups, respectively; P⩽0.05). LITA-treated animals also appeared to have improved motor activity, moving with greater average velocity than control animals. Microglial immunoreactivity was ~40% lower in the LITA group compared to the control group (P⩽0.05), but LITA did not modulate neurogenesis, apoptosis, histone acetylation and lipid peroxidation. Conclusion: LITA appears to attenuate the harmful chronic neuroinflammation observed during brain remodeling after a focal ischemic insult.


Assuntos
Acetatos/administração & dosagem , Isquemia Encefálica/tratamento farmacológico , Nanopartículas/administração & dosagem , Fármacos Neuroprotetores/administração & dosagem , Acetatos/química , Animais , Apoptose/efeitos dos fármacos , Encéfalo/diagnóstico por imagem , Encéfalo/efeitos dos fármacos , Encéfalo/patologia , Isquemia Encefálica/patologia , Modelos Animais de Doenças , Sistemas de Liberação de Medicamentos/métodos , Infarto da Artéria Cerebral Média , Lipossomos/química , Imagem por Ressonância Magnética , Masculino , Neurogênese/efeitos dos fármacos , Ratos Sprague-Dawley , Acidente Vascular Cerebral/tratamento farmacológico , Acidente Vascular Cerebral/patologia
18.
J Stroke Cerebrovasc Dis ; 28(6): 1500-1508, 2019 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-30935810

RESUMO

OBJECTIVE: The role of heparin in acute ischemic stroke is controversial. We investigated the effect of heparin on ischemic lesion growth. METHODS: Data were analyzed on nonthrombolyzed ischemic stroke patients in whom diffusion-weighted imaging (DWI)/perfusion-weighted imaging (PWI) MRI was performed less than 12 hours of last known well and showed a PWI-DWI lesion mismatch, and who underwent follow-up neuroimaging at least 4 days after admission. Lesion growth was assessed by (1) absolute lesion growth and (2) percentage mismatch lost (PML). Univariate and multivariate regression analysis, and propensity score matching, were used to determine the effects of heparin on ischemic lesion growth. RESULTS: Of the 113 patients meeting study criteria, 59 received heparin within 24 hours. Heparin use was associated with ∼5-fold reductions in PML (3.5% versus 19.2%, P = .002) and absolute lesion growth (4.7 versus 20.5 mL, P = .009). In multivariate regression models, heparin independently predicted reduced PML (P = .04) and absolute lesion growth (P = .04) in the entire cohort, and in multiple subgroups (patients with and without proximal artery occlusion; DWI volume greater than 5 mL; cardio-embolic mechanism; DEFUSE-3 target mismatch). In propensity score matching analysis where patients were matched by admission NIHSS, DWI volume and proximal artery occlusion, heparin remained an independent predictor of PML (P = .048) and tended to predict absolute lesion growth (P = .06). Heparin treatment did not predict functional outcome at discharge or 90 days. CONCLUSION: Early heparin treatment in acute ischemic stroke patients with PWI-DWI mismatch attenuates ischemic lesion growth. Clinical trials with careful patient selection are warranted to investigate the potential ischemic protective effects of heparin.


Assuntos
Anticoagulantes/administração & dosagem , Isquemia Encefálica/tratamento farmacológico , Heparina/administração & dosagem , Fármacos Neuroprotetores/administração & dosagem , Acidente Vascular Cerebral/tratamento farmacológico , Idoso , Idoso de 80 Anos ou mais , Isquemia Encefálica/diagnóstico por imagem , Imagem de Difusão por Ressonância Magnética , Esquema de Medicação , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Estudos Prospectivos , Estudos Retrospectivos , Acidente Vascular Cerebral/diagnóstico por imagem , Fatores de Tempo , Tomografia Computadorizada por Raios X , Resultado do Tratamento
19.
J Therm Biol ; 81: 1-11, 2019 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-30975405

RESUMO

Heat-stress exposure increased the expression of heat-shock proteins (HSPs), B-cell lymphoma 2 (BCL-2) and anti-oxidative enzymes to maintain normal cellular function by attenuating the oxidative reaction and apoptosis. Reducing the stress response or enhancing anti-stress capability is an important goal in animal production. Our previous study indicated a protective role of flavangenol, a pine bark extract, in chicks after three hours of high-temperature exposure. However, the cellular mechanism of flavangenol was not clarified ex vivo. In the current study, we investigated the effect of flavangenol on cellular apoptosis and oxidation in heat-stressed treated chick brain cells (mixed neurons and glia cells). The primary brain cells were isolated from the diencephalon of 14-day-old chicks and cultured at 41.5 °C (to mimic the body temperature of young chicks), and were treated with flavangenol from day 3 of isolation to day 8. Cells were kept bathed in the cell culture dish under a high temperature (HT: 45 °C, 20 or 60 min) on day 8 and were then collected for analysis of cell viability as well as for HSP and other related gene expression. Flavangenol treatment significantly increased cell viability and BCL-2 mRNA expression, and attenuated HSP-70 and BCL-2-associated X protein mRNA expression. Moreover, flavangenol treatment elevated the mRNA expression of glutathione peroxidase in the HT group, which indicates that cellular anti-oxidative ability was strengthened by flavangenol. In conclusion, flavangenol may play a protective role in cells damaged or killed by heat stress by increasing cellular anti-oxidative pathways.


Assuntos
Antioxidantes/administração & dosagem , Apoptose/efeitos dos fármacos , Biflavonoides/administração & dosagem , Encéfalo/efeitos dos fármacos , Galinhas/genética , Regulação da Expressão Gênica/efeitos dos fármacos , Resposta ao Choque Térmico/efeitos dos fármacos , Fármacos Neuroprotetores/administração & dosagem , Proantocianidinas/administração & dosagem , Fenômenos Fisiológicos da Nutrição Animal , Animais , Proteínas Reguladoras de Apoptose/metabolismo , Proteínas Aviárias/metabolismo , Encéfalo/metabolismo , Sobrevivência Celular/efeitos dos fármacos , Galinhas/metabolismo , Proteínas de Choque Térmico/metabolismo , Resposta ao Choque Térmico/genética , Temperatura Alta , Masculino , Cultura Primária de Células , RNA Mensageiro/metabolismo
20.
Int J Mol Sci ; 20(7)2019 Apr 03.
Artigo em Inglês | MEDLINE | ID: mdl-30987181

RESUMO

(1) Background: Chemokine-like factor 1 (CKLF1) is a chemokine with potential to be a target for stroke therapy. Compound IMM-H004 is a novel coumarin derivative screened from a CKLF1/C-C chemokine receptor type 4 (CCR4) system and has been reported to improve cerebral ischemia/reperfusion injury. This study aims to investigate the protective effects of IMM-H004 on cerebral ischemia injury and its infectious cardiopulmonary complications in adult and aged rats from the CKLF1 perspective. (2) Methods: The effects of IMM-H004 on the protection was determined by 2,3,5-triphenyltetrazolium chloride (TTC) staining, behavior tests, magnetic resonance imaging (MRI) scans, enzyme-linked immunosorbent assay (ELISA), Nissl staining, histo-pathological examination, and cardiopulmonary function detection. Immunohistological staining, immunofluorescence staining, quantitative real-time PCR (qPCR), and western blotting were used to elucidate the underlying mechanisms. (3) Results: IMM-H004 protects against cerebral ischemia induced brain injury and its cardiopulmonary complications, inhibiting injury, and inflammation through CKLF1-dependent anti-inflammation pathway in adult and aged rats. IMM-H004 downregulates the amount of CKLF1, suppressing the followed inflammatory response, and further protects the damaged organs from ischemic injury. (4) Conclusions: The present study suggested that the protective mechanism of IMM-H004 is dependent on CKLF1, which will lead to excessive inflammatory response in cerebral ischemia. IMM-H004 could also be a therapeutic agent in therapy for ischemic stroke and cardiopulmonary complications in the aged population.


Assuntos
Envelhecimento/patologia , Isquemia Encefálica/tratamento farmacológico , Quimiocinas/metabolismo , Cumarínicos/uso terapêutico , Inflamação/patologia , Pulmão/patologia , Proteínas com Domínio MARVEL/metabolismo , Miocárdio/patologia , Fármacos Neuroprotetores/uso terapêutico , Animais , Lesões Encefálicas/tratamento farmacológico , Lesões Encefálicas/etiologia , Lesões Encefálicas/patologia , Isquemia Encefálica/complicações , Cumarínicos/administração & dosagem , Cumarínicos/química , Cumarínicos/farmacologia , Inflamação/metabolismo , Masculino , Fármacos Neuroprotetores/administração & dosagem , Fármacos Neuroprotetores/farmacologia , Ratos Sprague-Dawley , Acidente Vascular Cerebral/complicações
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