RESUMO
BACKGROUND: Cannabis use suppresses the endocannabinoid system in healthy individuals. However, the association between cannabis use with the endocannabinoid system is understudied in individuals with psychosis despite the high rate of cannabis use in these individuals. METHODS: We enrolled 83 individuals who were admitted to an inpatient psychiatric unit with psychotic presentations, and measured their plasma levels of main endocannabinoids, Anandamide (AEA) and 2-Acylglycerol (2-AG), and endocannabinoid related compounds, Palmitoylethanolamine, and N-oleoylethanolamine. Cannabis use was assessed with urine toxicology and frequency of cannabis use was assessed using self-reported questionnaires. The Positive and Negative Syndrome Scale was used to assess the severity of psychotic symptoms. RESULTS: Overall, we had 38 individuals in cannabis positive group (CN+) and 45 individuals in cannabis negative group (CN-). Compared to CN-, CN+ group had lower plasma levels of AEA, which remained significant after controlling for age, gender, race/ethnicity, and use of other drugs. CONCLUSION: Cannabis use is associated with low plasma AEA levels in individuals with psychosis, which is in the same line with reported suppressive effects of cannabis on the endocannabinoid system in healthy individuals. Further studies are needed to investigate the clinical significance of this finding.
Assuntos
Cannabis , Alucinógenos , Transtornos Psicóticos , Humanos , Endocanabinoides , Agonistas de Receptores de Canabinoides , Alcamidas Poli-Insaturadas , Transtornos Psicóticos/tratamento farmacológicoAssuntos
Buprenorfina , Pessoas Mal Alojadas , Transtornos Relacionados ao Uso de Opioides , Humanos , Buprenorfina/uso terapêutico , Problemas Sociais , Transtornos Relacionados ao Uso de Opioides/tratamento farmacológico , Tratamento de Substituição de Opiáceos , Analgésicos Opioides/uso terapêuticoRESUMO
Cerebral ischemic stroke is a leading cause of death and disability, but current pharmacological therapies are limited in their utility and effectiveness. In vitro and in vivo models of ischemic stroke have been developed which allow us to further elucidate the pathophysiological mechanisms of injury and investigate potential drug targets. In vitro models permit mechanistic investigation of the biochemical and molecular mechanisms of injury but are reductionist and do not mimic the complexity of clinical stroke. In vivo models of ischemic stroke directly replicate the reduction in blood flow and the resulting impact on nervous tissue. The most frequently used in vivo model of ischemic stroke is the intraluminal suture middle cerebral artery occlusion (iMCAO) model, which has been fundamental in revealing various aspects of stroke pathology. However, the iMCAO model produces lesion volumes with large standard deviations even though rigid surgical and data collection protocols are followed. There is a need to refine the MCAO model to reduce variability in the standard outcome measure of lesion volume. The typical approach to produce vessel occlusion is to induce an obstruction at the origin of the middle cerebral artery and reperfusion is reliant on the Circle of Willis (CoW). However, in rodents the CoW is anatomically highly variable which could account for variations in lesion volume. Thus, we developed a refined approach whereby reliance on the CoW for reperfusion was removed. This approach improved reperfusion to the ischemic hemisphere, reduced variability in lesion volume by 30%, and reduced group sizes required to determine an effective treatment response by almost 40%. This refinement involves a methodological adaptation of the original surgical approach which we have shared with the scientific community via publication of a visualised methods article and providing hands-on training to other experimental stroke researchers.
Assuntos
Isquemia Encefálica , Acidente Vascular Cerebral , Animais , Modelos Animais de Doenças , Infarto da Artéria Cerebral Média , ReperfusãoRESUMO
The successful treatment of depressive disorders critically depends on adherence to prescribed treatment regimens. Despite increasing rates of antidepressant medication prescription, adherence to the full treatment course remains poor. Rates of antidepressant non-adherence are higher for uninsured patients and members of some marginalized racial and ethnic communities due to factors such as inequities in healthcare and access to insurance. Among patients treated in a free, student-run and faculty-supervised clinic serving uninsured patients in a majority Hispanic community in East Harlem, adherence rates are lower than those observed in patients with private or public New York State health insurance coverage. A prior study of adherence in these patients revealed that difficulty in obtaining medications from an off-site hospital pharmacy was a leading factor that patients cited for non-adherence. To alleviate this barrier to obtaining prescriptions, we tested the effectiveness of on-site, in-clinic medication dispensing for improving antidepressant medication adherence rates among uninsured patients. We found that dispensing medications directly to patients in clinic was associated with increased visits at which patients self-reported proper adherence and increased overall adherence rates. Furthermore, we found evidence that higher rates of antidepressant medication adherence were associated with more favorable treatment outcomes. All patients interviewed reported increased satisfaction with on-site dispensing. Overall, this study provides promising evidence that on-site antidepressant dispensing in a resource-limited setting improves medication adherence rates and leads to more favorable treatment outcomes with enhanced patient satisfaction.
Assuntos
Antidepressivos , Pessoas sem Cobertura de Seguro de Saúde , Antidepressivos/uso terapêutico , Prescrições de Medicamentos , Humanos , Adesão à Medicação , Satisfação do PacienteRESUMO
Overdose of stimulant drugs has been associated with increased risk of adverse cardiovascular events (ACVE), some of which may be ascribed to endothelial dysfunction. The aims of this study were to evaluate biomarkers of endothelial dysfunction in emergency department (ED) patients with acute cocaine overdose and to assess the association between in-hospital ACVE in ED patients with any acute drug overdose. This was a prospective consecutive cohort study over 9 months (2015-2016) at two urban, tertiary-care hospital EDs. Consecutive adults (≥18 years) presenting with suspected acute drug overdose were eligible and separated into three groups: cocaine (n = 47), other drugs (n = 128), and controls (n = 11). Data were obtained from medical records and linked to waste serum specimens, sent as part of routine clinical care, for biomarker analysis. Serum specimens were collected and analyzed using enzyme-linked immunosorbent assay kit for three biomarkers of endothelial dysfunction: (a) endothelin-1 (ET-1), (b) regulated upon activation normal T cell expressed and secreted (RANTES), and (c) soluble intercellular adhesion molecule-1 (siCAM-1). Mean siCAM was elevated for cocaine compared with controls and other drugs (p < .01); however, mean RANTES and ET-1 levels were not significantly different for any drug exposure groups. Receiver operating characteristics curve analysis for prediction of in-hospital ACVE revealed excellent performance of siCAM-1 (area under curve, 0.86; p < .001) but lack of predictive utility for either RANTES or ET-1. These results suggest that serum siCAM-1 is a viable biomarker for acute cocaine overdose and that endothelial dysfunction may be an important surrogate for adverse cardiovascular events following any drug overdose.
Assuntos
Doenças Cardiovasculares/induzido quimicamente , Cocaína/intoxicação , Overdose de Drogas/sangue , Endotélio Vascular/efeitos dos fármacos , Adulto , Biomarcadores , Quimiocina CCL5/sangue , Serviço Hospitalar de Emergência , Endotelina-1/sangue , Ensaio de Imunoadsorção Enzimática , Feminino , Humanos , Molécula 1 de Adesão Intercelular/sangue , Masculino , Pessoa de Meia-Idade , Estudos Prospectivos , Curva ROC , Fatores de Risco , Centros de Atenção TerciáriaRESUMO
Inflammatory abnormalities are well-documented in individuals with chronic psychotic disorders. Particular attention has focused on interleukin-6 (IL-6) and its correlation with psychotic symptom severity. Cannabis use is associated with an increased risk of psychosis and also has immunomodulating properties. It has been hypothesized that inflammatory disturbances are a common underlying pathology between cannabis use and psychosis. We measured inflammatory markers in individuals admitted to a psychiatric unit with acute psychosis who had toxicology positive for natural and/or synthetic cannabinoids (n = 59) compared to patients with negative cannabinoid toxicology (n = 60). Psychosis severity was assessed using the Positive and Negative Syndrome Scale (PANSS). While PANSS scores were similar between groups, cannabinoid-positive participants were more likely to receive pro re nata (PRN or as-needed) medications for agitation in the psychiatric emergency room, particularly synthetic cannabinoid-positive participants. In unadjusted models, cannabinoid-positive participants had lower interferon-γ (IFN-γ) levels (p = 0.046), but this finding was not significant after adjusting for covariates and multiple comparisons. Among cannabinoid-positive participants, IL-6 levels negatively correlated with PANSS total score (p = 0.040), as well as positive (p = 0.035) and negative (p = 0.024) subscales. Results suggest inflammatory alterations among psychotic individuals with comorbid cannabinoid use.
Assuntos
Mediadores da Inflamação/sangue , Uso da Maconha/sangue , Uso da Maconha/psicologia , Transtornos Psicóticos/sangue , Transtornos Psicóticos/psicologia , Índice de Gravidade de Doença , Adulto , Biomarcadores/sangue , Canabinoides/efeitos adversos , Feminino , Humanos , Masculino , Uso da Maconha/epidemiologia , Pessoa de Meia-Idade , Transtornos Psicóticos/epidemiologia , Adulto JovemRESUMO
Hypertension is an important risk factor for age-related cognitive decline and neuronal pathologies. Studies have shown a correlation between hypertension, disruption in neurovascular coupling and cerebral autoregulation, and cognitive decline. However, the mechanisms behind this are unclear. To further understand this, it is advantageous to study neurovascular coupling as hypertension progresses in a rodent model. Here, we use a longitudinal functional MRI (fMRI) protocol to assess the impact of hypertension on neurovascular coupling in spontaneously hypertensive rats (SHRs). Eight female SHRs were studied at 2, 4, and 6 months of age, as hypertension progressed. Under an IV infusion of propofol, animals underwent fMRI, functional MR spectroscopy, and cerebral blood flow (CBF) quantification to study changes in neurovascular coupling over time. Blood pressure significantly increased at 4 and 6 months (P < .0001). CBF significantly increased at 4 months old (P < .05), in the acute stage of hypertension. The size of the active region decreased significantly at 6 months old (P < .05). Change in glutamate signal during activation, and N-acetyl-aspartate (NAA) signal, remained constant. This study shows that, while cerebral autoregulation is impaired in acute hypertension, the blood oxygenation-level-dependent (BOLD) response remains unaltered until later stages. At this stage, the consistent NAA and glutamate signals show that neuronal death has not occurred, and that neuronal activity is not affected at this stage. This suggests that neuronal activity and viability is not lost until much later, and changes observed here in BOLD activity are due to vascular effects.
Assuntos
Encéfalo/diagnóstico por imagem , Circulação Cerebrovascular/fisiologia , Hipertensão/diagnóstico por imagem , Imageamento por Ressonância Magnética/métodos , Acoplamento Neurovascular/fisiologia , Animais , Pressão Sanguínea/fisiologia , Encéfalo/irrigação sanguínea , Feminino , Hipertensão/fisiopatologia , Ratos , Ratos Endogâmicos SHRRESUMO
Background: Following ischemic stroke, recanalisation and restoration of blood flow to the affected area of the brain is critical and directly correlates with patient recovery. In vivo models of ischemic stroke show high variability in outcomes, which may be due to variability in reperfusion. We previously reported that a surgical refinement in the middle cerebral artery occlusion (MCAO) model of stroke, via repair of the common carotid artery (CCA), removes the reliance on the Circle of Willis for reperfusion and reduced infarct variability. Here we further assess this refined surgical approach on reperfusion characteristics following transient MCAO in mice. Methods: Mice underwent 60 min of MCAO, followed by either CCA repair or ligation at reperfusion. All mice underwent laser speckle contrast imaging at baseline, 24 h and 48 h post-MCAO. Results: CCA ligation reduced cerebral perfusion in the ipsilateral hemisphere compared to baseline (102.3 ± 4.57%) at 24 h (85.13 ± 16.09%; P < 0.01) and 48 h (75.04 ± 12.954%; P < 0.001) post-MCAO. Repair of the CCA returned perfusion to baseline (94.152 ± 2.44%) levels and perfusion was significantly improved compared to CCA ligation at both 24 h (102.83 ± 8.41%; P < 0.05) and 48 h (102.13 ± 9.34%; P < 0.001) post-MCAO. Conclusions: Our findings show CCA repair, an alternative surgical approach for MCAO, results in improved ischemic hemisphere perfusion during the acute phase.
Assuntos
Infarto da Artéria Cerebral Média/cirurgia , Reperfusão , Acidente Vascular Cerebral , Animais , Modelos Animais de Doenças , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Acidente Vascular Cerebral/cirurgiaRESUMO
As the population ages, the incidence of age-related neurological diseases and cognitive decline increases. To further understand disease-related changes in brain function it is advantageous to examine brain activity changes in healthy aging rodent models to permit mechanistic investigation. Here, we examine the suitability, in rodents, of using a novel, minimally invasive anaesthesia protocol in combination with a functional MRI protocol to assess alterations in neuronal activity due to physiological aging. 11 Wistar Han female rats were studied at 7, 9, 12, 15 and 18 months of age. Under an intravenous infusion of propofol, animals underwent functional magnetic resonance imaging (fMRI) and functional magnetic resonance spectroscopy (fMRS) with forepaw stimulation to quantify neurotransmitter activity, and resting cerebral blood flow (CBF) quantification using arterial spin labelling (ASL) to study changes in neurovascular coupling over time. Animals showed a significant decrease in size of the active region with age (P â< â0.05). fMRS results showed a significant decrease in glutamate change with stimulation (ΔGlu) with age (P â< â0.05), and ΔGlu became negative from 12 months onwards. Global CBF remained constant for the duration of the study. This study shows age related changes in the blood oxygen level dependent (BOLD) response in rodents that correlate with those seen in humans. The results also suggest that a reduction in synaptic glutamate turnover with age may underlie the reduction in the BOLD response, while CBF is preserved.
Assuntos
Envelhecimento/fisiologia , Encéfalo/fisiologia , Modelos Animais , Neuroimagem/métodos , Anestésicos Intravenosos/farmacologia , Animais , Encéfalo/efeitos dos fármacos , Feminino , Estudos Longitudinais , Imageamento por Ressonância Magnética/métodos , Espectroscopia de Ressonância Magnética/métodos , Propofol/farmacologia , Ratos , Ratos WistarRESUMO
BACKGROUND: Cerebral ischemic stroke is a significant cause of morbidity and mortality. Sex differences exist following stroke in terms of incidence, symptoms, outcomes and response to some treatments. Importantly, molecular mechanisms of injury, activated following ischemia may differ between the sexes and if so may account, at least in part, for sex differences seen in treatment response. Here we aimed to determine, using single-sex organotypic hippocampal slice cultures, whether the effectiveness of a potential treatment option, i.e. sex steroids, exhibited any sexual dimorphism and whether sex affected the mechanisms of apoptosis activated following ischemia. RESULTS: Following exposure to ischemia, male-derived tissue exhibited higher levels of cell death than female-derived tissue. Various sex steroid hormones, i.e. progesterone, allopregnanolone, and estradiol, were protective in terms of reducing the amount of cell death in male- and female-derived tissue whereas medoxyprogesterone acetate (MPA) was only protective in female-derived tissue. The protective effect of progesterone was abolished in the presence of finasteride, a 5α-reductase inhibitor, suggesting it was largely mediated via its conversion to allopregnanolone. To test the hypothesis that sex differences exist in the activation of specific elements of the apoptotic pathway activated following ischemia we administered Q-VD-OPH, a caspase inhibitor, or PJ34, an inhibitor of poly (ADP ribose) polymerase (PARP). Caspase inhibition was only effective, in terms of reducing cell death, in female-derived tissue, whereas PARP inhibition was only protective in male-derived tissue. However, in both sexes, the protective effects of progesterone and estradiol were not observed in the presence of either caspase or PARP inhibition. CONCLUSIONS: Sex differences exist in both the amount of cell death produced and those elements of the cell death pathway activated following an ischemic insult. There are also some sex differences in the effectiveness of steroid hormones to provide neuroprotection following an ischemic insult-namely MPA was only protective in female-derived tissue. This adds further support to the notion sex is an important factor to consider when investigating future drug targets for CNS disorders, such as ischemic stroke.
Assuntos
Apoptose/efeitos dos fármacos , Isquemia Encefálica/metabolismo , Fármacos Neuroprotetores/administração & dosagem , Neuroesteroides/administração & dosagem , Caracteres Sexuais , Acidente Vascular Cerebral/metabolismo , Animais , Proteínas Reguladoras de Apoptose/efeitos dos fármacos , Proteínas Reguladoras de Apoptose/metabolismo , Feminino , Hipocampo/efeitos dos fármacos , Hipocampo/metabolismo , Masculino , Camundongos Endogâmicos C57BL , Técnicas de Cultura de ÓrgãosRESUMO
Disability and effectiveness of physical therapy are highly variable following ischemic stroke due to different brain regions being affected. Functional magnetic resonance imaging (fMRI) studies of patients in the months and years following stroke have given some insight into how the brain recovers lost functions. Initially, new pathways are recruited to compensate for the lost region, showing as a brighter blood oxygen-level-dependent (BOLD) signal over a larger area during a task than in healthy controls. Subsequently, activity is reduced to baseline levels as pathways become more efficient, mimicking the process of learning typically seen during development. Preclinical models of ischemic stroke aim to enhance understanding of the biology underlying recovery following stroke. However, the pattern of recruitment and focusing seen in humans has not been observed in preclinical fMRI studies that are highly variable methodologically. Resting-state fMRI studies show more consistency; however, there are still confounding factors to address. Anesthesia and method of stroke induction are the two main sources of variability in preclinical studies; improvements here can reduce variability and increase the intensity and reproducibility of the BOLD response detected by fMRI. Differences in task or stimulus and differences in analysis method also present a source of variability. This review compares clinical and preclinical fMRI studies of recovery following stroke and focuses on how refinement of preclinical models and MRI methods may obtain more representative fMRI data in relation to human studies.
Assuntos
Isquemia Encefálica/diagnóstico por imagem , Encéfalo/diagnóstico por imagem , Recuperação de Função Fisiológica/fisiologia , Acidente Vascular Cerebral/diagnóstico por imagem , Humanos , Imageamento por Ressonância Magnética/métodos , Reprodutibilidade dos TestesRESUMO
The ischemic stroke is a major cause of adult long-term disability and death worldwide. The current treatments available are limited, with only tissue plasminogen activator (tPA) as an approved drug treatment to target ischemic strokes. Current research in the field of ischemic stroke focuses on better understanding the pathophysiology of stroke, to develop and investigate novel pharmaceutical targets. Reliable experimental stroke models are crucial for the progression of potential treatments. The middle cerebral artery occlusion (MCAO) model is clinically relevant and the most frequently used surgical model of ischemic stroke in rodents. However, the outcomes of this model, such as lesion volume, are associated with high levels of variability, particularly in mice. The alternative MCAO model described here allows the reperfusion of the common carotid artery (CCA) and the increased perfusion of the middle cerebral artery (MCA) territory, using a tissue pad with fibrinogen-based sealant to repair the vessel, and the improved welfare of the mice by avoiding external carotid artery (ECA) ligation. This reduces the reliance on the Circle of Willis, which is known to be highly anatomically variable in mice. Representative data show that using this alternative surgical approach decreases the variability in lesion volumes between the traditional MCAO approach and the alternative approach described here.
Assuntos
Artéria Carótida Primitiva/cirurgia , Artéria Cerebral Média/cirurgia , Reperfusão Miocárdica , Acidente Vascular Cerebral , Animais , Artéria Carótida Primitiva/patologia , Modelos Animais de Doenças , Masculino , Camundongos , Acidente Vascular Cerebral/patologiaRESUMO
Experimental stroke in rodents, via middle cerebral artery occlusion (MCAO), can be associated with a negative impact on wellbeing and mortality. In hypertensive rodents, pre-stroke craniotomy increased survival and decreased body weight loss post-MCAO. Here we determined the effect, in normotensive Sprague-Dawley rats following 60 minutes MCAO, with or without pre-surgical craniotomy, on post-stroke outcomes in terms of weight loss, neurological deficit, lesion volume and functional outcomes. There was no effect of pre-stroke craniotomy on indicators of wellbeing including survival rate (P = 0.32), body weight loss (P = 0.42) and neurological deficit (P = 0.75). We also assessed common outcome measures following experimental stroke and found no effect of pre-stroke craniotomy on lesion volume as measured by T2-weighted MRI (P = 0.846), or functional performance up to 28 days post-MCAO (staircase test, P = 0.32; adhesive sticker test, P = 0.49; cylinder test, P = 0.38). Thus, pre-stroke craniotomy did not improve animal welfare in terms of body weight loss and neurological deficit. However, it is important, given that a number of drug delivery studies utilise the craniotomy procedure, to note that there was no effect on lesion volume or functional outcome following experimental stroke.
Assuntos
Craniotomia , Infarto da Artéria Cerebral Média/prevenção & controle , Ataque Isquêmico Transitório/prevenção & controle , Animais , Pressão Sanguínea , Cérebro/irrigação sanguínea , Cérebro/diagnóstico por imagem , Modelos Animais de Doenças , Humanos , Infarto da Artéria Cerebral Média/diagnóstico por imagem , Infarto da Artéria Cerebral Média/etiologia , Infarto da Artéria Cerebral Média/mortalidade , Ataque Isquêmico Transitório/diagnóstico por imagem , Ataque Isquêmico Transitório/etiologia , Ataque Isquêmico Transitório/mortalidade , Imageamento por Ressonância Magnética , Masculino , Ratos , Ratos Sprague-Dawley , Taxa de Sobrevida , Resultado do Tratamento , Redução de PesoRESUMO
Most in vivo models of ischaemic stroke target the middle cerebral artery and a spectrum of stroke severities, from mild to substantial, can be achieved. This review describes opportunities to improve the in vivo modelling of ischaemic stroke and animal welfare. It provides a number of recommendations to minimise the level of severity in the most common rodent models of middle cerebral artery occlusion, while sustaining or improving the scientific outcomes. The recommendations cover basic requirements pre-surgery, selecting the most appropriate anaesthetic and analgesic regimen, as well as intraoperative and post-operative care. The aim is to provide support for researchers and animal care staff to refine their procedures and practices, and implement small incremental changes to improve the welfare of the animals used and to answer the scientific question under investigation. All recommendations are recapitulated in a summary poster (see supplementary information).
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Bem-Estar do Animal/normas , Isquemia Encefálica/patologia , Acidente Vascular Cerebral/patologia , Animais , Modelos Animais de Doenças , Guias como Assunto , Humanos , Infarto da Artéria Cerebral Média/patologiaRESUMO
Animal models are essential for understanding the pathology of stroke and investigating potential treatments. However, in vivo stroke models are associated, particularly in mice, with high variability in lesion volume. We investigated whether a surgical refinement where reperfusion is not reliant on the Circle of Willis reduced outcome variability. Mice underwent 60â min of transient middle cerebral artery occlusion avoiding ligation of the external carotid artery. During reperfusion, the common carotid artery was either ligated (standard approach), or it was repaired to allow re-establishment of blood flow through the common carotid artery. All mice underwent MRI scanning for assessment of infarct volume, apparent diffusion coefficient and fractional anisotropy, along with terminal assessment of infarct volume by 2,3,5-triphenyltetrazolium chloride (TTC) staining. Repairing the common carotid artery following middle cerebral artery occlusion enhanced reperfusion (P<0.01) and reduced the variability seen in both total (histological analysis, P=0.008; T2-weighted MRI, P=0.015) and core (diffusion tensor MRI, P=0.043) lesion volume. Avoiding external carotid artery ligation may improve animal wellbeing, through reduced weight loss, while using an alternative surgical approach that enabled reperfusion through the common carotid artery decreased the variability in lesion volume seen within groups.
Assuntos
Acidente Vascular Cerebral/patologia , Acidente Vascular Cerebral/cirurgia , Analgesia , Animais , Anisotropia , Isquemia Encefálica/complicações , Isquemia Encefálica/patologia , Isquemia Encefálica/fisiopatologia , Artérias Carótidas/cirurgia , Circulação Cerebrovascular , Imagem de Difusão por Ressonância Magnética , Imageamento Tridimensional , Infarto da Artéria Cerebral Média/complicações , Infarto da Artéria Cerebral Média/patologia , Infarto da Artéria Cerebral Média/fisiopatologia , Imageamento por Ressonância Magnética , Masculino , Camundongos Endogâmicos C57BL , Tamanho do Órgão , Traumatismo por Reperfusão/patologia , Traumatismo por Reperfusão/fisiopatologia , Acidente Vascular Cerebral/fisiopatologia , Sais de Tetrazólio/metabolismoRESUMO
BACKGROUND: Stroke continues to be a leading cause of mortality and morbidity worldwide, and novel therapeutic options for ischaemic stroke are urgently needed. In this context, drug combination therapies seem to be a viable approach, which has not been fully explored in preclinical studies. OBJECTIVES: In this work, we assessed the dose-response relationship and therapeutic time window, in global brain ischaemia, of a combined therapeutic approach of recombinant human epidermal growth factor (EGF) and growth hormone-releasing peptide-6 (GHRP-6). METHODS: Mongolian gerbils underwent 15âminutes occlusion of both common carotid arteries. Four different doses of rhEGF, GHRP-6 and these combined agents were intraperitoneally administered immediately after the onset of reperfusion. Having identified a better response with both agents, rhEGF+GHRP-6 were administered at 2, 4, 6, 8 or 24âhours after the onset of reperfusion to assess the time window of effectiveness. Animals were evaluated daily for neurological deficits. Three days post-occlusion, the animals were sacrificed and 2,3,5-triphenyltetrazolium chloride was used to quantify infarcted tissues. RESULTS: The coadministration of rhEGF and GHRP-6 at doses of 100 and 600 µg/kg, respectively, administered up to 4âhours following the ischaemic insult, significantly improved survival and neurological outcome, and reduced infarct volume compared with vehicle treatment. These results are considered as an additional proof of concept as supporting a combined therapeutic approach and justify the further development of this preclinical research.
Assuntos
Avaliação Pré-Clínica de Medicamentos , Fator de Crescimento Epidérmico/uso terapêutico , Oligopeptídeos/uso terapêutico , Acidente Vascular Cerebral/tratamento farmacológico , Animais , Modelos Animais de Doenças , Relação Dose-Resposta a Droga , Gerbillinae , Humanos , Masculino , Exame Neurológico , Acidente Vascular Cerebral/patologia , Fatores de TempoRESUMO
Two multi-centre phase III clinical trials examining the protective potential of progesterone following traumatic brain injury have recently failed to demonstrate any improvement in outcome. Thus, it is timely to consider how this impacts on the translational potential of progesterone treatment for ischaemic stroke. A wealth of experimental evidence supports the neuroprotective properties of progesterone, and associated metabolites, following various types of central nervous system injury. In particular, for ischaemic stroke, studies have also begun to reveal possible mechanisms of such neuroprotection. However, the results in traumatic brain injury now question whether further clinical development of progesterone for ischaemic stroke is relevant.
Assuntos
Lesões Encefálicas/tratamento farmacológico , Isquemia Encefálica/tratamento farmacológico , Encéfalo/efeitos dos fármacos , Fármacos Neuroprotetores/uso terapêutico , Progesterona/uso terapêutico , Acidente Vascular Cerebral/tratamento farmacológico , Encéfalo/fisiopatologia , Lesões Encefálicas/fisiopatologia , Isquemia Encefálica/fisiopatologia , Ensaios Clínicos Fase III como Assunto , Humanos , Acidente Vascular Cerebral/fisiopatologiaRESUMO
Cerebral ischemic stroke is a leading cause of mortality and functional disability. However, unfortunately few effective treatments exist to counteract the deleterious pathological mechanisms triggered following an ischemic event. Epidemiological and experimental studies have revealed a significant difference in the vulnerability of males versus females to both the incidence of stroke and amount of resulting pathology following an ischemic stroke which is also dependent on the stage of lifespan. Here we review the evidence for gender differences in both the overall pathology and cellular mechanisms of injury following ischemic stroke. In addition, we discuss the evidence for any gender differences that may occur in the effectiveness of treatments and how this supports the need for the investigation and development of gender-specific therapies.