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1.
J Pharmacol Exp Ther ; 2024 May 22.
Artículo en Inglés | MEDLINE | ID: mdl-38777603

RESUMEN

Metformin's potential in treating ischemic stroke and neurodegenerative conditions is of growing interest. Yet, the absence of established systemic and brain pharmacokinetic (PK) parameters at relevant pre-clinical doses presents a significant knowledge gap. This study highlights these PK parameters and the importance of using pharmacologically relevant pre-clinical doses to study pharmacodynamics (PD) in stroke and related neurodegenerative diseases. An LC-MS/MS method to measure metformin levels in plasma, brain, and cerebrospinal fluid (CSF) was developed and validated. In vitro assays examined brain tissue binding and metabolic stability. Intravenous (IV) bolus administration of metformin to C57BL6 mice covered low to high dose range maintaining pharmacological relevance. Quantification of metformin in the brain was used to assess brain pharmacokinetic parameters, such as unidirectional blood-to-brain constant (Kin) and unbound brain-to-plasma ratio (Kp, uu, brain). Metformin exhibited no binding in the mouse plasma and brain and remained metabolically stable. It rapidly entered the brain, reaching detectable levels in as little as 5 minutes. A Kin value of 1.87 {plus minus} 0.27 µl/g/min was obtained. As the dose increased, Kp, uu, brain showed decreased value, implying saturation, but this did not affect an increase in absolute brain concentrations. Metformin was quantifiable in the CSF at 30 minutes but decreased over time, with concentrations lower than those in the brain across all doses. Our findings emphasize the importance of metformin dose selection based on pharmacokinetic parameters for pre-clinical pharmacological studies. We anticipate further investigations focusing on pharmacokinetics and pharmacodynamics (PKPD) in disease conditions, such as stroke. Significance Statement The study establishes crucial pharmacokinetic parameters of metformin for treating ischemic stroke and neurodegenerative diseases, addressing a significant knowledge gap. It further emphasizes the importance of selecting pharmacologically relevant pre-clinical doses. The findings highlight metformin's rapid brain entry, minimal binding, and metabolic stability. The necessity of considering pharmacokinetic parameters in pre-clinical studies provides a foundation for future investigations into metformin's efficacy for neurodegenerative disease (s).

2.
Int J Mol Sci ; 23(15)2022 Jul 31.
Artículo en Inglés | MEDLINE | ID: mdl-35955647

RESUMEN

Proper regulation of energy metabolism in the brain is crucial for maintaining brain activity in physiological and different pathophysiological conditions. Ischemic stroke has a complex pathophysiology which includes perturbations in the brain energy metabolism processes which can contribute to worsening of brain injury and stroke outcome. Smoking and diabetes are common risk factors and comorbid conditions for ischemic stroke which have also been associated with disruptions in brain energy metabolism. Simultaneous presence of these conditions may further alter energy metabolism in the brain leading to a poor clinical prognosis after an ischemic stroke event. In this review, we discuss the possible effects of smoking and/or diabetes on brain glucose utilization and mitochondrial energy metabolism which, when present concurrently, may exacerbate energy metabolism in the ischemic brain. More research is needed to investigate brain glucose utilization and mitochondrial oxidative metabolism in ischemic stroke in the presence of smoking and/or diabetes, which would provide further insights on the pathophysiology of these comorbid conditions and facilitate the development of therapeutic interventions.


Asunto(s)
Isquemia Encefálica , Diabetes Mellitus , Accidente Cerebrovascular Isquémico , Accidente Cerebrovascular , Encéfalo/metabolismo , Isquemia Encefálica/metabolismo , Diabetes Mellitus/metabolismo , Metabolismo Energético , Glucosa/metabolismo , Humanos , Fumar/efectos adversos , Accidente Cerebrovascular/complicaciones
3.
J Pharmacol Exp Ther ; 375(3): 498-509, 2020 12.
Artículo en Inglés | MEDLINE | ID: mdl-33033170

RESUMEN

Coronavirus disease 2019 (COVID-19), caused by the severe acute respiratory syndrome coronavirus 2 virus, is turning out to be one of the most devastating global pandemics in the history of humankind. There is a shortage of effective therapeutic strategies or preventative vaccines for this disease to date. A rigorous investigation is needed for identifying and developing more effective therapeutic strategies for COVID-19. Angiotensin-converting enzyme 2 (ACE2), a crucial factor in COVID-19 pathogenesis, has been identified as a potential target for COVID-19 treatment. Smoking and vaping are potential risk factors for COVID-19 that are also shown to upregulate ACE2 expression. In this review, we have discussed the pathobiology of COVID-19 in the lungs and brain and the role of ACE2 in the transmission and pathobiology of this disease. Furthermore, we have shown possible interactions between nicotine/smoking and ACE2 in the lungs and brain, which could aggravate the transmission and pathobiology of COVID-19, resulting in a poor disease outcome. SIGNIFICANCE STATEMENT: This review addresses the present global pandemic of coronavirus disease 2019 (COVID-19) with respect to its pathobiology in the lungs and brain. It focuses on the potential negative impact of tobacco and nicotine exposure on the outcomes of this disease by interaction with the angiotensin-converting enzyme 2 receptor. It adds to the time-sensitive and critically important growing knowledge about the risk factors, transmission, pathobiology, and prognosis of COVID-19.


Asunto(s)
COVID-19/epidemiología , Fumar/epidemiología , Enzima Convertidora de Angiotensina 2/metabolismo , Animales , Encéfalo/efectos de los fármacos , Encéfalo/metabolismo , Encéfalo/virología , COVID-19/etiología , COVID-19/transmisión , Humanos , Pulmón/efectos de los fármacos , Pulmón/metabolismo , Pulmón/virología , Nicotina/metabolismo , Nicotina/toxicidad , SARS-CoV-2/patogenicidad , Fumar/efectos adversos
4.
Mol Biol Rep ; 47(9): 7073-7082, 2020 Sep.
Artículo en Inglés | MEDLINE | ID: mdl-32880833

RESUMEN

Inter-individual genetic makeup can trigger variability in platinum-based chemotherapeutic responses and corresponding adverse drug reactions and toxicities. Exploring the genetic causes behind these inter-individual variabilities in platinum-based chemotherapeutic responses by investigating the effects of GSTP1 (rs1695), XRCC1 (rs25487), XPC (rs2228001) and ERCC1 (rs11615) genetic polymorphisms on toxicity and therapeutic response of this treatment among Bangladeshi advanced non-small cell lung cancer (NSCLC) patients was the aim of this study. 285 Clinically proven either stage IIIB or IV (advanced) NSCLC patients aging not less than 18 years old and receiving platinum-based chemotherapy were recruited to assess the influence of these four single nucleotide polymorphisms (SNPs) on peripheral leukocytes. Toxicity and response were evaluated by multivariate regression analyses using SPSS statistical software (version 17.0). XRCC1 (rs25487) polymorphism was found to act as a predictive factor for not only grade 3 and 4 anemia (p = 0.008), neutropenia (p = 0.010), thrombocytopenia (p = 0.025) and gastrointestinal toxicity (p = 0.002) but also for therapeutic response (p = 0.012) in platinum-based chemotherapy. Although GSTP1 (rs1695) polymorphism might serve as prognostic factor regarding grade 3 or 4 neutropenia, a significant (p = 0.044) improvement in response to platinum-based chemotherapy was observed. However, XPC (rs2228001) and ERCC1 (rs11615) polymorphisms could not establish any significant relation with toxicity or therapeutic response. XRCC1 (rs2228001) and GSTP1 (rs1695) polymorphisms might explain platinum-induced clinical outcomes in terms of both toxicity and therapeutic response variations among Bangladeshi advanced NSCLC patients.


Asunto(s)
Carcinoma de Pulmón de Células no Pequeñas , Proteínas de Unión al ADN/genética , Endonucleasas/genética , Gutatión-S-Transferasa pi/genética , Neoplasias Pulmonares , Proteínas de Neoplasias/genética , Platino (Metal)/efectos adversos , Polimorfismo de Nucleótido Simple , Proteína 1 de Reparación por Escisión del Grupo de Complementación Cruzada de las Lesiones por Rayos X/genética , Bangladesh , Carcinoma de Pulmón de Células no Pequeñas/tratamiento farmacológico , Carcinoma de Pulmón de Células no Pequeñas/genética , Carcinoma de Pulmón de Células no Pequeñas/patología , Femenino , Humanos , Neoplasias Pulmonares/tratamiento farmacológico , Neoplasias Pulmonares/genética , Neoplasias Pulmonares/patología , Masculino , Persona de Mediana Edad , Platino (Metal)/administración & dosificación , Valor Predictivo de las Pruebas
5.
BMC Neurosci ; 18(1): 71, 2017 10 11.
Artículo en Inglés | MEDLINE | ID: mdl-29020944

RESUMEN

BACKGROUND: A sensitive, rapid and selective UHPLC-MS/MS method has been developed and validated for the quantification of Nicotine (NT) and Cotinine (CN) using Continine-d 3 as internal standard (IS) as per FDA guidelines. Sample preparation involved simple protein precipitation of 20 µL mouse plasma or brain homogenate using acetonitrile at 1:8 ratio. Mass Spectrometer was operated in positive polarity under the multiple reaction-monitoring mode using electro spray ionization technique and the transitions of m/z 163.2 â†’ 132.1, 177.2 â†’ 98.0 and 180.2 â†’ 101.2 were used to measure the NT, CN and IS, respectively. The elution of NT, CN and IS are at 1.89, 1.77 and 1.76 min, respectively. This was achieved with a gradient mobile phase consisting of 5 mM ammonium bicarbonate, acetonitrile and methanol (3:1, v/v) at a flow rate of 0.3 mL/min on a Kinetex EVO C18 column. The method was validated with a lower limit of quantitation 3.0 ng/mL in mouse plasma and brain for both the analytes. RESULTS: A linear response function was established for the range of concentrations 3-200 (r > 0.995) for NT and 3-600 ng/mL (r > 0.995) for CN. The intra- and inter-day precision values met the acceptance criteria. NT and CN are stable in the battery of stability studies viz., stock solution, bench-top and auto-sampler. CONCLUSION: This method was successfully utilized to validate a newly developed preclinical smoking model in mice.


Asunto(s)
Cotinina , Nicotina , Fumar , Espectrometría de Masas en Tándem , Animales , Encéfalo/enzimología , Encéfalo/metabolismo , Cromatografía Líquida de Alta Presión/métodos , Cotinina/sangre , Cotinina/líquido cefalorraquídeo , Ratones , Nicotina/sangre , Nicotina/líquido cefalorraquídeo , Reproducibilidad de los Resultados , Sensibilidad y Especificidad , Fumar/fisiopatología , Espectrometría de Masas en Tándem/métodos
6.
Redox Biol ; 75: 103266, 2024 09.
Artículo en Inglés | MEDLINE | ID: mdl-39094400

RESUMEN

Despite the protective nature of the blood-brain barrier (BBB) and brain-protecting tissues, some types of CNS injury or stress can cause cerebral cytokine production and profound alterations in brain function. Neuroinflammation, which can also be accompanied by increased cerebral cytokine production, has a remarkable impact on the pathogenesis of many neurological illnesses, including loss of BBB integrity and ischemic stroke, yet effective treatment choices for these diseases are currently lacking. Although little is known about the brain effects of Metformin (MF), a commonly prescribed first-line antidiabetic drug, prior research suggested that it may be useful in preventing BBB deterioration and the increased risk of stroke caused by tobacco smoking (TS). Therefore, reducing neuroinflammation by escalating anti-inflammatory cytokine production and declining pro-inflammatory cytokine production could prove an effective therapeutic strategy for ischemic stroke. Hence, the current investigation was planned to explore the potential role of MF against stroke and TS-induced neuroinflammation and reactive oxygen species (ROS) production. Our studies revealed that MF suppressed releasing pro-inflammatory mediators like tumor necrosis factor-α (TNF-α) and interleukin-1ß (IL-1ß) by aiming at the nuclear factor kappa B (NF-κB) signaling pathway in primary neurons and astrocytes. MF also upregulated anti-inflammatory mediators, like interleukin-10 (IL-10), and interleukin-4 (IL-4), by upregulating the Nrf2-ARE signaling pathway. Adolescent mice receiving MF along with TS exposure also showed a notable decrease in NF-κB expression compared to the mice not treated with MF and significantly decreased the level of TNF-α, IL-1ß, MCP-1, and MIP-2 and increased the levels of IL-10 and IL-4 through the activation of Nrf2-ARE signaling pathway. These results suggest that MF has anti-neuroinflammatory effects via inhibiting NF-κB signaling by activating Nrf2-ARE. These studies support that MF could be a strong candidate drug for treating and or preventing TS-induced neuroinflammation and ischemic stroke.


Asunto(s)
Astrocitos , Metformina , Factor 2 Relacionado con NF-E2 , Neuronas , Accidente Cerebrovascular , Animales , Factor 2 Relacionado con NF-E2/metabolismo , Ratones , Metformina/farmacología , Astrocitos/metabolismo , Astrocitos/efectos de los fármacos , Accidente Cerebrovascular/metabolismo , Accidente Cerebrovascular/tratamiento farmacológico , Neuronas/metabolismo , Neuronas/efectos de los fármacos , Enfermedades Neuroinflamatorias/tratamiento farmacológico , Enfermedades Neuroinflamatorias/metabolismo , Enfermedades Neuroinflamatorias/etiología , Especies Reactivas de Oxígeno/metabolismo , Transducción de Señal/efectos de los fármacos , Citocinas/metabolismo , Humanos , Modelos Animales de Enfermedad , FN-kappa B/metabolismo
7.
Front Pharmacol ; 14: 1227145, 2023.
Artículo en Inglés | MEDLINE | ID: mdl-37693917

RESUMEN

Introduction: Despite the prevalence of the perception that electronic cigarettes (e-cig) are a safer alternative to tobacco smoke, growing concern about their potential toxic impact warrants adequate investigation focusing on special populations like maternal and pediatric groups. This study evaluated the consequences of maternal e-cig use on neonatal neuroinflammation, oxidative stress, and mitochondrial function in primary cultured neurons and postnatal day (PD) 7 and 90 brain. Methodology: Pregnant CD1 mice were exposed to e-cig vapor (2.4% nicotine) from gestational day 5 (E5) till PD7, and the primary neurons were isolated from pups at E16/17. Cellular total reactive oxygen species (ROS) and mitochondrial superoxide were measured in primary neurons using CM-H2DCFDA and Mitosox red, respectively. Mitochondrial function was assessed by Seahorse XF Cell Mitostress analysis. The level of pro-inflammatory cytokines was measured in primary neurons and PD7 and PD90 brains by RT-PCR and immunobead assay. Western blot analysis evaluated the expression of antioxidative markers (SOD-2, HO-1, NRF2, NQO1) and that of the proinflammatory modulator NF-κB. Results: Significantly higher level of total cellular ROS (p < 0.05) and mitochondrial superoxide (p < 0.01) was observed in prenatally e-cig-exposed primary neurons. We also observed significantly reduced antioxidative marker expression and increased proinflammatory modulator and cytokines expression in primary neurons and PD7 (p < 0.05) but not in PD90 postnatal brain. Conclusion: Our findings suggest that prenatal e-cig exposure induces postnatal neuroinflammation by promoting oxidative stress (OS), increasing cytokines' levels, and disrupting mitochondrial function. These damaging events can alter the fetal brain's immune functions, making such offspring more vulnerable to brain insults.

8.
Fluids Barriers CNS ; 20(1): 17, 2023 Mar 10.
Artículo en Inglés | MEDLINE | ID: mdl-36899432

RESUMEN

Electronic nicotine delivery systems (ENDS), also commonly known as electronic cigarettes (e-cigs) are considered in most cases as a safer alternative to tobacco smoking and therefore have become extremely popular among all age groups and sex. It is estimated that up to 15% of pregnant women are now using e-cigs in the US which keeps increasing at an alarming rate. Harmful effects of tobacco smoking during pregnancy are well documented for both pregnancy and postnatal health, however limited preclinical and clinical studies exist to evaluate the long-term effects of prenatal e-cig exposure on postnatal health. Therefore, the aim of our study is to evaluate the effect of maternal e-cig use on postnatal blood-brain barrier (BBB) integrity and behavioral outcomes of mice of varying age and sex. In this study, pregnant CD1 mice (E5) were exposed to e-Cig vapor (2.4% nicotine) until postnatal day (PD) 7. Weight of the offspring was measured at PD0, PD7, PD15, PD30, PD45, PD60 and PD90. The expression of structural elements of the BBB, tight junction proteins (ZO-1, claudin-5, occludin), astrocytes (GFAP), pericytes (PDGFRß) and the basement membrane (laminin α1, laminin α4), neuron specific marker (NeuN), water channel protein (AQP4) and glucose transporter (GLUT1) were analyzed in both male and female offspring using western blot and immunofluorescence. Estrous cycle was recorded by vaginal cytology method. Long-term motor and cognitive functions were evaluated using open field test (OFT), novel object recognition test (NORT) and morris water maze test (MWMT) at adolescence (PD 40-45) and adult (PD 90-95) age. In our study, significantly reduced expression of tight junction proteins and astrocyte marker were observed in male and female offspring until PD 90 (P < 0.05). Additionally, prenatally e-cig exposed adolescent and adult offspring showed impaired locomotor, learning, and memory function compared to control offspring (P < 0.05). Our findings suggest that prenatal e-cig exposure induces long-term neurovascular changes of neonates by disrupting postnatal BBB integrity and worsening behavioral outcomes.


Asunto(s)
Sistemas Electrónicos de Liberación de Nicotina , Vapeo , Embarazo , Femenino , Animales , Masculino , Ratones , Humanos , Barrera Hematoencefálica , Nicotina , Proteínas de Uniones Estrechas
9.
Eur J Med Chem ; 254: 115309, 2023 Jun 05.
Artículo en Inglés | MEDLINE | ID: mdl-37054561

RESUMEN

Using the structure of gliotoxin as a starting point, we have prepared two different chemotypes with selective affinity to the kappa opioid receptor (KOR). Using medicinal chemistry approaches and structure-activity relationship (SAR) studies, structural features required for the observed affinity were identified, and advanced molecules with favorable Multiparameter Optimization (MPO) and Ligand Lipophilicity (LLE) profiles were prepared. Using the Thermal Place Preference Test (TPPT), we have shown that compound2 blocks the antinociceptive effect of U50488, a known KOR agonist. Multiple reports suggest that modulation of KOR signaling is a promising therapeutic strategy in treating neuropathic pain (NP). As a proof-of-concept study, we tested compound 2 in a rat model of NP and recorded its ability to modulate sensory and emotional pain-related behaviors. Observed in vitro and in vivo results suggest that these ligands can be used to develop compounds with potential application as pain therapeutics.


Asunto(s)
Neuralgia , Receptores Opioides , Animales , Ratas , Analgésicos Opioides/química , Dicetopiperazinas , Ligandos , Receptores Opioides kappa , 3,4-Dicloro-N-metil-N-(2-(1-pirrolidinil)-ciclohexil)-bencenacetamida, (trans)-Isómero/química
10.
Fluids Barriers CNS ; 19(1): 74, 2022 Sep 09.
Artículo en Inglés | MEDLINE | ID: mdl-36085043

RESUMEN

BACKGROUND: The short and long-term health effects of JUUL electronic cigarette (e-Cig) are largely unknown and warrant extensive research. We hypothesized that JUUL exposure could cause cerebrovascular toxicities impacting the progression and outcome of ischemic stroke comparable to tobacco smoke (TS) exposure. METHODS: We exposed male C57 mice to TS/JUUL vapor for 14 days. LCMS/MS was used to measure brain and plasma nicotine and cotinine level. Transient middle cerebral artery occlusion (tMCAO) followed by reperfusion was used to mimic ischemic stroke. Plasma levels of IL-6 and thrombomodulin were assessed by enzyme-linked immunosorbent assay. At the same time, western blotting was used to study blood-brain barrier (BBB) tight junction (TJ) proteins expression and key inflammatory and oxidative stress markers. RESULTS: tMCAO upregulated IL-6 and decreased plasma thrombomodulin levels. Post-ischemic brain injury following tMCAO was significantly worsened by JUUL/TS pre-exposure. TJ proteins expression was also downregulated by JUUL/TS pre-exposure after tMCAO. Like TS, exposure to JUUL downregulated the expression of the antioxidant Nrf2. ICAM-1 was upregulated in mice subjected to tMCAO following pre-exposure to TS or JUUL, with a greater effect of TS than JUUL. CONCLUSIONS: These results suggest that JUUL exposure could negatively impact the cerebrovascular system, although to a lesser extent than TS exposure.


Asunto(s)
Sistemas Electrónicos de Liberación de Nicotina , Accidente Cerebrovascular Isquémico , Animales , Barrera Hematoencefálica , Interleucina-6 , Masculino , Ratones , Trombomodulina , Proteínas de Uniones Estrechas
12.
Biomolecules ; 9(1)2019 01 21.
Artículo en Inglés | MEDLINE | ID: mdl-30669679

RESUMEN

Nicotinamide mononucleotide (NMN) is a nucleotide that is most recognized for its role as an intermediate of nicotinamide adenine dinucleotide (NAD+) biosynthesis. Although the biosynthetic pathway of NMN varies between eukaryote and prokaryote, two pathways are mainly followed in case of eukaryotic human-one is through the salvage pathway using nicotinamide while the other follows phosphorylation of nicotinamide riboside. Due to the unavailability of a suitable transporter, NMN enters inside the mammalian cell in the form of nicotinamide riboside followed by its subsequent conversion to NMN and NAD+. This particular molecule has demonstrated several beneficial pharmacological activities in preclinical studies, which suggest its potential therapeutic use. Mostly mediated by its involvement in NAD+ biosynthesis, the pharmacological activities of NMN include its role in cellular biochemical functions, cardioprotection, diabetes, Alzheimer's disease, and complications associated with obesity. The recent groundbreaking discovery of anti-ageing activities of this chemical moiety has added a valuable essence in the research involving this molecule. This review focuses on the biosynthesis of NMN in mammalian and prokaryotic cells and mechanism of absorption along with the reported pharmacological activities in murine model.


Asunto(s)
Enfermedad de Alzheimer/tratamiento farmacológico , Enfermedades Cardiovasculares/tratamiento farmacológico , Diabetes Mellitus/tratamiento farmacológico , Mononucleótido de Nicotinamida/uso terapéutico , Animales , Humanos , NAD/biosíntesis , Mononucleótido de Nicotinamida/metabolismo , Obesidad/complicaciones
13.
Drug Discov Today ; 23(7): 1385-1395, 2018 07.
Artículo en Inglés | MEDLINE | ID: mdl-29501910

RESUMEN

Novel neuroprotective therapies are desperately needed to improve neuronal recovery after ischemic stroke and extend the therapeutic window or offset some of the adverse effects of tissue-type plasminogen activator (tPA). These advances could provide a more effective and safe therapeutic regimen for patients with ischemic stroke. The opioid system has gained intense interest over the past few years and is currently being investigated as a viable target for the pharmacological treatment of stroke. In this review, we focus on different opioid receptors (ORs) and their distribution in the central nervous system (CNS), and the effect of ischemic stroke on their redistribution. We also discuss studies involving the use of the selective and nonselective and/or simultaneous targeting of ORs for neuroprotection during ischemic stroke.


Asunto(s)
Analgésicos Opioides/uso terapéutico , Isquemia Encefálica/tratamiento farmacológico , Encéfalo/efectos de los fármacos , Descubrimiento de Drogas/métodos , Fármacos Neuroprotectores/uso terapéutico , Receptores Opioides/agonistas , Accidente Cerebrovascular/tratamiento farmacológico , Analgésicos Opioides/efectos adversos , Analgésicos Opioides/química , Animales , Encéfalo/metabolismo , Encéfalo/patología , Isquemia Encefálica/metabolismo , Isquemia Encefálica/patología , Relación Dosis-Respuesta a Droga , Humanos , Fármacos Neuroprotectores/efectos adversos , Fármacos Neuroprotectores/química , Receptores Opioides/metabolismo , Transducción de Señal/efectos de los fármacos , Accidente Cerebrovascular/metabolismo , Accidente Cerebrovascular/patología
14.
AAPS J ; 19(4): 957-972, 2017 07.
Artículo en Inglés | MEDLINE | ID: mdl-28484963

RESUMEN

The blood-brain barrier (BBB) is a vital component of the neurovascular unit (NVU) containing tight junctional (TJ) proteins and different ion and nutrient transporters which maintain normal brain physiology. BBB disruption is a major pathological hallmark in the course of ischemic stroke which is regulated by the actions of different factors working at different stages of cerebral ischemia including matrix metalloproteinases (MMPs), inflammatory modulators, vesicular trafficking, oxidative pathways, and junctional-cytoskeletal interactions. These components interact further to disrupt maintenance of both the paracellular and transport barriers of the central nervous system (CNS) to worsen ischemic brain injury and the propensity for hemorrhagic transformation (HT) associated with injury and/or thrombolytic therapy with tissue-type plasminogen activator (tPA). We propose that these complex molecular pathways should be evaluated further so that they could be targeted alone or in combination to protect the BBB during cerebral ischemia. These types of novel interventions should be guided by advanced imaging techniques for better diagnosis of BBB damage which may exert significant therapeutic benefit including the extension of therapeutic window of tPA. This review will focus on the different stages and mechanisms of BBB damage in acute ischemic stroke and novel therapeutic strategies to target those pathways for better therapeutic outcome in stroke.


Asunto(s)
Barrera Hematoencefálica , Isquemia Encefálica/terapia , Accidente Cerebrovascular/terapia , Enfermedad Aguda , Isquemia Encefálica/diagnóstico por imagen , Isquemia Encefálica/metabolismo , Humanos , Accidente Cerebrovascular/diagnóstico por imagen , Accidente Cerebrovascular/metabolismo , Rehabilitación de Accidente Cerebrovascular , Terapia Trombolítica
15.
Redox Biol ; 13: 353-362, 2017 10.
Artículo en Inglés | MEDLINE | ID: mdl-28646795

RESUMEN

Recently published in vitro and in vivo findings strongly suggest that BBB impairment and increased risk for stroke by tobacco smoke (TS) closely resemble that of type-2 diabetes (2DM) and develop largely in response to common key modulators such oxidative stress (OS), inflammation and alterations of the endogenous antioxidative response system (ARE) regulated by the nuclear factor erythroid 2-related factor (Nrf2). Preclinical studies have also shown that nicotine (the principal e-liquid's ingredient used in e-cigarettes) can also cause OS, exacerbation of cerebral ischemia and secondary brain injury. Herein we provide evidence that likewise to TS, chronic e-Cigarette (e-Cig) vaping can be prodromal to the loss of blood-brain barrier (BBB) integrity and vascular inflammation as well as act as a promoting factor for the onset of stroke and worsening of post-ischemic brain injury. In addition, recent reports have shown that Metformin (MF) treatment before and after ischemic injury reduces stress and inhibits inflammatory responses. Recent published data by our group revealead that MF promotes the activation of counteractive mechanisms mediated by the activation of Nrf2 which drastically reduce TS toxicity at the brain and cerebrovascular levels and protect BBB integrity. In this study we provide additional in vivo evidence showing that MF can effectively reduce the oxidative and inflammatory risk for stroke and attenuate post-ischemic brain injury promoted by TS and e-Cig vaping. Our data also suggest that MF administration could be extended as prophylactic care during the time window required for the renormalization of the risk levels of stroke following smoking cessation thus further studies in that direction are warrated.


Asunto(s)
Antioxidantes/uso terapéutico , Barrera Hematoencefálica/efectos de los fármacos , Hipoglucemiantes/uso terapéutico , Infarto de la Arteria Cerebral Media/tratamiento farmacológico , Metformina/uso terapéutico , Fumar Tabaco/efectos adversos , Vapeo/efectos adversos , Animales , Antioxidantes/farmacología , Barrera Hematoencefálica/metabolismo , Células Cultivadas , Hipoglucemiantes/farmacología , Masculino , Metformina/farmacología , Ratones , Ratones Endogámicos C57BL , Factor 2 Relacionado con NF-E2/genética , Factor 2 Relacionado con NF-E2/metabolismo , Estrés Oxidativo , Fumar Tabaco/tratamiento farmacológico
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