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1.
Eur J Neurosci ; 55(5): 1344-1355, 2022 03.
Artigo em Inglês | MEDLINE | ID: mdl-35060208

RESUMO

Recent evidence suggests that treatment with antidepressants may promote functional recovery. However, the timeframe in which these pharmacological agents can influence stroke recovery is not well understood. This research investigated whether delayed administration of citalopram, used clinically in the management of post-stroke depression, could improve long-term functional recovery following experimental stroke. MacGreen mice carrying an enhanced green fluorescent protein reporter gene in monocyte and macrophage populations were subjected to 45 min occlusion of the middle cerebral artery. Animals were administered citalopram (10 mg/kg/day, n = 20) or saline (n = 20) starting 3 days after stroke for 28 days. Neurological deficits and skilled motor performance in the staircase task were recorded for 9 weeks post stroke. Grey and white matter structural lesions were quantified at Week 9, and enhanced green fluorescent protein immunohistochemistry was used to evaluate the effect of citalopram on inflammation. Twenty-five animals were included in the final analysis. Citalopram-treated animals (n = 13) showed a significant increase in impaired forepaw use in the staircase task compared with saline-treated animals (n = 12) 2, 3 and 7 weeks post stroke but no difference in neurological score at any time point examined. Citalopram treatment was associated with decreased monocyte/macrophage cell density and increased white matter tract integrity within the ipsilateral cortex. In conclusion, delayed administration of citalopram decreased brain inflammation and produced functional gains in our mouse model of stroke. Beneficial effects on skilled motor functions were long-lasting.


Assuntos
Isquemia Encefálica , Encefalite , AVC Isquêmico , Doenças do Sistema Nervoso , Acidente Vascular Cerebral , Animais , Citalopram/farmacologia , Citalopram/uso terapêutico , Modelos Animais de Doenças , Encefalite/complicações , Camundongos
2.
Drugs Real World Outcomes ; 9(1): 165-173, 2022 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-34580835

RESUMO

BACKGROUND: Patients who develop seizures after stroke have disproportionately poorer outcomes and increased mortality. OBJECTIVE: Our objective was to investigate whether exposure to anti-epileptic medications influenced long-term functional status after stroke. METHODS: We used linked health administrative data from a cohort of adult stroke patients in New Zealand. Demographics and prescription information were obtained from the National Minimum Dataset and Pharmaceutical Collection, respectively. Activities of daily living (ADL) scores for the same patients were obtained using the International Resident Assessment Instrument. Beta regression was used to investigate the relationship between anti-epileptic drug (AED) exposure and functional status. RESULTS: The study included 3606 patients with a single ischaemic stroke between 2012 and 2017. In total, 15% were dispensed an AED in the 3 months before or after stroke. The adjusted odds ratio (OR) for AED exposure was 1.29 (95% confidence interval [CI] 1.15-1.45). Overall AED exposure, categorical body mass index (BMI), ethnicity, length of hospital stay, and exposure to paracetamol, opioids, anti-psychotics, and anti-nausea medications were significantly associated with changes in the mean ADL score percentages. Considering the exposure timeframe, the ORs for AED exposure only after stroke and for exposure both before and after stroke were 1.52 (95% CI 1.31-1.78) and 1.09 (95% CI 0.93-1.27), respectively. CONCLUSION: Stroke patients with AED exposure had greater odds of a higher ADL score, indicating a poorer long-term functional status than those unexposed to AEDs. The timeframe of exposure impacted on functional status, with patients exposed only after stroke having increased odds of higher ADL scores than those exposed both before and after stroke.

3.
J Stroke Cerebrovasc Dis ; 30(5): 105711, 2021 May.
Artigo em Inglês | MEDLINE | ID: mdl-33714074

RESUMO

OBJECTIVE: Obesity is a risk factor for ischaemic stroke but provides a survival advantage. The relationship between body mass index (BMI) and long-term function is less clear. The presence of an obesity paradox can inform clinical care and identify vulnerable patients who need additional support post-stroke. MATERIALS AND METHODS: This study used linked health administrative data of a population based cohort of adult patients who experienced an ischaemic stroke between 2012 and 2017 in New Zealand. Patient demographics were obtained from the National Minimum Dataset (NMDS). BMI and Activities of Daily Living scores (ADLs) for the same patients were obtained from the International Resident Assessment Instrument (InterRAI™). RESULTS: Linked data was obtained for 3731 patients. Ninety-five percent of the cohort were aged 65 or older and the average age of stroke was 84.5 years. The majority of patients (55%) identified as New Zealand European. Beta regression indicated BMI and European ethnicity were negatively associated with ADL score. Univariate analysis confirmed patients with underweight stroke had significantly higher ADL scores than other BMI categories (p<0.001), however functional status for patients with overweight and obesity were comparable. Further, Asian and Pacific Peoples had higher ADL scores than Europeans (p<0.05). A higher BMI was advantageous to all ADL subscores. CONCLUSION: An abridged obesity paradox was evident in our cohort of stroke patients where a BMI in the overweight, but not obese range conferred a long-term functional status advantage. Collectively these results suggest underweight and non-European patients may require additional supportive clinical care post-stroke.


Assuntos
Índice de Massa Corporal , Estado Funcional , AVC Isquêmico/terapia , Sobrepeso/diagnóstico , Magreza/diagnóstico , Fatores Etários , Idoso , Idoso de 80 Anos ou mais , Feminino , Avaliação Geriátrica , Humanos , AVC Isquêmico/diagnóstico , AVC Isquêmico/mortalidade , AVC Isquêmico/fisiopatologia , Masculino , Pessoa de Meia-Idade , Nova Zelândia , Sobrepeso/mortalidade , Sobrepeso/fisiopatologia , Prognóstico , Fatores de Proteção , Estudos Retrospectivos , Medição de Risco , Fatores de Risco , Magreza/mortalidade , Magreza/fisiopatologia
4.
Neurobiol Dis ; 146: 105092, 2020 12.
Artigo em Inglês | MEDLINE | ID: mdl-32979507

RESUMO

Huntington's disease (HD) is a neurodegenerative disorder caused by a CAG trinucleotide repeat expansion in exon 1 of the huntingtin gene. Emerging evidence shows that additional epigenetic factors can modify disease phenotypes. Harnessing the ability of the epigenome to modify the disease for therapeutic purposes is therefore of interest. Epigenome modifiers, such as histone deacetylase inhibitors (HDACi), have improved pathology in a range of HD models. Yet in clinical trials, HDACi have failed to alleviate HD symptoms in patients. This study investigated potential reasons for the lack of translation of the therapeutic benefits of HDACi from lab to clinic. We analysed histone acetylation patterns of immuno-positive nuclei from brain sections and tissue microarrays from post-mortem human control and HD cases alongside several well-established HD models (OVT73 transgenic HD sheep, YAC128 mice, and an in vitro cell model expressing 97Q mutant huntingtin). Significant increases in histone H4 acetylation were observed in post-mortem HD cases, OVT73 transgenic HD sheep and in vitro models; these changes were absent in YAC128 mice. In addition, nuclear labelling for acetyl-histone H4 levels were inversely proportional to mutant huntingtin aggregate load in HD human cortex. Our data raise concerns regarding the utility of HDACi for the treatment of HD when regions of pathology exhibit already elevated histone acetylation patterns and emphasize the importance of searching for alternative epigenetic targets in future therapeutic strategies aiming to rescue HD phenotypes.


Assuntos
Encéfalo/metabolismo , Inibidores de Histona Desacetilases/farmacologia , Doença de Huntington/genética , Doença de Huntington/metabolismo , Animais , Animais Geneticamente Modificados/genética , Animais Geneticamente Modificados/metabolismo , Encéfalo/efeitos dos fármacos , Encéfalo/fisiopatologia , Modelos Animais de Doenças , Histona Desacetilases/efeitos dos fármacos , Histona Desacetilases/metabolismo , Humanos , Proteínas do Tecido Nervoso/efeitos dos fármacos , Proteínas do Tecido Nervoso/metabolismo , Processamento de Proteína Pós-Traducional/efeitos dos fármacos , Ovinos/genética , Ovinos/fisiologia
6.
Hypertension ; 75(3): 740-747, 2020 03.
Artigo em Inglês | MEDLINE | ID: mdl-31957520

RESUMO

Over 80% of patients exhibit an acute increase in blood pressure (BP) following stroke. Current clinical guidelines make no distinction in BP management between patients with or without prior hypertension. Spontaneously hypertensive (SH) rats were preinstrumented with telemeters to record BP, intracranial pressure, and brain tissue oxygen in the predicted ischemic penumbra for 3 days before and 10 days after transient middle cerebral artery occlusion (n=8 per group) or sham (n=5). Before stroke, BP was either left untreated or chronically treated to a normotensive level (enalapril 10 mg/kg per day). Poststroke elevations in BP were either left uncontrolled, controlled (to the prestroke baseline level), or overcontrolled (to a normotensive level) via subcutaneous infusion of labetalol. Baseline values of intracranial pressure and brain tissue oxygen were similar between all groups, whereas BP was lower in treated SH rats (144±3 versus 115±5 mm Hg; P<0.001). Following middle cerebral artery occlusion, a similar rise in BP was observed in untreated (+16±2 mm Hg; P=0.005) and treated SH rats (+13±5 mm Hg; P=0.021). Intervening to prevent BP from increasing after stroke did not worsen outcome. However, reducing BP below prestroke baseline levels was associated with higher intracranial pressure (days 1-3; P<0.001), reduced cerebral perfusion pressure (days 2-4; P<0.001), higher mortality, slower functional recovery and larger infarct volumes. Although treating to maintain BP at the prestroke baseline level was not detrimental, our results suggest that when setting BP targets after stroke, consideration must be given to the potential negative impact of inadvertent excessive BP lowering in subjects with undiagnosed or poorly controlled hypertension.


Assuntos
Inibidores da Enzima Conversora de Angiotensina/efeitos adversos , Anti-Hipertensivos/efeitos adversos , Pressão Sanguínea/fisiologia , Isquemia Encefálica/fisiopatologia , Enalapril/efeitos adversos , Hipertensão/complicações , Infarto da Artéria Cerebral Média/fisiopatologia , Inibidores da Enzima Conversora de Angiotensina/uso terapêutico , Animais , Anti-Hipertensivos/uso terapêutico , Encéfalo/patologia , Química Encefálica , Enalapril/uso terapêutico , Hipertensão/tratamento farmacológico , Infarto da Artéria Cerebral Média/complicações , Infarto da Artéria Cerebral Média/metabolismo , Infarto da Artéria Cerebral Média/patologia , Hipertensão Intracraniana/etiologia , Masculino , Transtornos dos Movimentos/etiologia , Oxigênio/análise , Distribuição Aleatória , Ratos , Ratos Endogâmicos SHR , Recuperação de Função Fisiológica , Fatores de Tempo
7.
Stroke ; 50(9): 2522-2530, 2019 09.
Artigo em Inglês | MEDLINE | ID: mdl-31449479

RESUMO

Background and Purpose- Over 80% of ischemic stroke patients show an abrupt increase in arterial blood pressure in the hours and days following ischemic stroke. Whether this poststroke hypertension is beneficial or harmful remains controversial and the underlying physiological basis is unclear. Methods- To investigate the dynamic cardiovascular response to stroke, adult Wistar rats (n=5-8 per group, 393±34 g) were instrumented with telemeters to blood pressure, intracranial pressure, renal sympathetic nerve activity, and brain tissue oxygen in the predicted penumbra (Po2). After 2 weeks of recovery, cardiovascular signals were recorded for a 3-day baseline period, then ischemic stroke was induced via transient middle cerebral artery occlusion, or sham surgery. Cardiovascular signals were then recorded for a further 10 days, and the functional sensorimotor recovery assessed using the cylinder and sticky dot tests. Results- Baseline values of all variables were similar between groups. Compared to sham, in the 2 days following stroke middle cerebral artery occlusion produced an immediate, transient rise above baseline in mean blood pressure (21±3 versus 2±4 mm Hg; P<0.001), renal sympathetic nerve activity (54±11% versus 7±4%; P=0.006), and cerebral perfusion pressure (12±5 versus 1±4; P≤0.001). Intracranial pressure increased more slowly, peaking 3 days after middle cerebral artery occlusion (14±6 versus -1±1 mm Hg; P<0.001). Treating with the antihypertensive agent nifedipine after stroke (1.5-0.75 mg/kg per hour SC) ameliorated poststroke hypertension (12±3 mm Hg on day 1; P=0.041), abolished the intracranial pressure increase (3±1; P<0.001) and reduced cerebral perfusion pressure (10±3 mm Hg; P=0.017). Preventing poststroke hypertension affected neither the recovery of sensorimotor function nor infarct size. Conclusions- These findings suggest that poststroke hypertension is immediate, temporally matched to an increase in sympathetic outflow, and elevates cerebral perfusion pressure for several days after stroke, which may enhance cerebral perfusion. Preventing poststroke hypertension does not appear to worsen prognosis after stroke in young, normotensive, and otherwise healthy rats. Visual Overview- An online visual overview is available for this article.


Assuntos
Anti-Hipertensivos/farmacologia , Isquemia Encefálica/fisiopatologia , Hipertensão/etiologia , Acidente Vascular Cerebral/tratamento farmacológico , Acidente Vascular Cerebral/fisiopatologia , Animais , Pressão Sanguínea/efeitos dos fármacos , Encéfalo/efeitos dos fármacos , Encéfalo/fisiopatologia , Isquemia Encefálica/induzido quimicamente , Circulação Cerebrovascular/efeitos dos fármacos , Hipertensão/induzido quimicamente , Infarto da Artéria Cerebral Média/fisiopatologia , Pressão Intracraniana/efeitos dos fármacos , Masculino , Ratos Wistar , Recuperação de Função Fisiológica/efeitos dos fármacos
8.
Endocrinology ; 160(5): 1081-1096, 2019 05 01.
Artigo em Inglês | MEDLINE | ID: mdl-30997487

RESUMO

Mice with a targeted mutation in the pro-opiomelanocortin (Pomc) gene (Pomctm1/tm1 mice) are unable to synthesize desacetyl-α-MSH and α-MSH and they develop obesity when fed chow diet. In this study, we hypothesized that a chronic high-fat (HF) diet exacerbates Pomctm1/tm1 mouse obesity. Male and female Pomcwt/wt and Pomctm1/tm1 mice were fed low-fat (LF) (10 kcal percent fat) or HF (45 kcal percent fat) diets from weaning for 23 weeks. We show that Pomctm1/tm1 mouse obesity is sexually dimorphic and exacerbated by an HF diet. Male Pomctm1/tm1 mice develop obesity because they are hyperphagic compared with Pomcwt/wt mice when fed an LF or HF diet. Female Pomctm1/tm1 mice develop obesity when feeding on an LF or HF diet because they exhibit signs of reduced energy expenditure (no change in feed efficiency; body weight gained exceeding energy intake) compared with Pomcwt/wt mice. A chronic HF diet exacerbates male Pomctm1/tm1 and Pomcwt/wt mouse obesity, and the increased energy intake fully accounts for increased weight gain. In contrast, female Pomcwt/wt mice are protected from chronic HF diet-induced obesity because they reduce the amount of HF diet eaten, and they appear to increase their energy expenditure (no change in feed efficiency but energy intake exceeding body weight gained). A chronic HF diet exacerbates female Pomctm1/tm1 mouse obesity due to impaired ability to reduce the amount of HF diet eaten and apparent impaired HF diet-induced adaptive thermogenesis. Our data show that desacetyl-α-MSH and α-MSH are required for sexually dimorphic HF diet-induced C57BL/6J obesity. In conclusion, desacetyl-α-MSH and α-MSH play salutary roles in sexually dimorphic melanocortin obesity and sexually dimorphic HF diet-induced C57BL/6J obesity.


Assuntos
Dieta Hiperlipídica/efeitos adversos , Mutação , Obesidade/genética , Pró-Opiomelanocortina/genética , Animais , Gorduras na Dieta/administração & dosagem , Ingestão de Energia/genética , Metabolismo Energético/genética , Feminino , Masculino , Camundongos Endogâmicos C57BL , Obesidade/etiologia , Obesidade/metabolismo , Pró-Opiomelanocortina/metabolismo , Fatores Sexuais , Termogênese/genética , Aumento de Peso/genética , alfa-MSH/metabolismo
9.
Mol Metab ; 9: 207-216, 2018 03.
Artigo em Inglês | MEDLINE | ID: mdl-29226825

RESUMO

OBJECTIVE: Regulation of energy balance depends on pro-opiomelanocortin (POMC)-derived peptides and melanocortin-4 receptor (MC4R). Alpha-melanocyte stimulating hormone (α-MSH) is the predicted natural POMC-derived peptide that regulates energy balance. Desacetyl-α-MSH, the precursor for α-MSH, is present in brain and blood. Desacetyl-α-MSH is considered to be unimportant for regulating energy balance despite being more potent (compared with α-MSH) at activating the appetite-regulating MC4R in vitro. Thus, the physiological role for desacetyl-α-MSH is still unclear. METHODS: We created a novel mouse model to determine whether desacetyl-α-MSH plays a role in regulating energy balance. We engineered a knock in targeted QKQR mutation in the POMC protein cleavage site that blocks the production of both desacetyl-α-MSH and α-MSH from adrenocorticotropin (ACTH1-39). RESULTS: The mutant ACTH1-39 (ACTHQKQR) functions similar to native ACTH1-39 (ACTHKKRR) at the melanocortin 2 receptor (MC2R) in vivo and MC4R in vitro. Male and female homozygous mutant ACTH1-39 (Pomctm1/tm1) mice develop the characteristic melanocortin obesity phenotype. Replacement of either desacetyl-α-MSH or α-MSH over 14 days into Pomctm1/tm1 mouse brain significantly reverses excess body weight and fat mass gained compared to wild type (WT) (Pomcwt/wt) mice. Here, we identify both desacetyl-α-MSH and α-MSH peptides as regulators of energy balance and highlight a previously unappreciated physiological role for desacetyl-α-MSH. CONCLUSIONS: Based on these data we propose that there is potential to exploit the naturally occurring POMC-derived peptides to treat obesity but this relies on first understanding the specific function(s) for desacetyl-α-MSH and α-MSH.


Assuntos
Metabolismo Energético , alfa-MSH/metabolismo , Animais , Feminino , Masculino , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Endogâmicos C57BL , Mutação , Ligação Proteica , Proteólise , Receptor Tipo 2 de Melanocortina/metabolismo , Receptor Tipo 4 de Melanocortina/metabolismo , Aumento de Peso
10.
J Stroke Cerebrovasc Dis ; 26(12): 2778-2787, 2017 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-28797614

RESUMO

BACKGROUND: Pharmacological activation of the cholinergic anti-inflammatory pathway (CAP), specifically by activating α7 nicotinic acetylcholine receptors, has been shown to confer short-term improvements in outcome. Most studies have investigated administration within 24 hours of stroke, and few have investigated drugs approved for use in human patients. We investigated whether delayed administration of varenicline, a high-affinity agonist at α7 nicotinic receptors and an established therapy for nicotine addiction, decreased brain inflammation and improved functional performance in a mouse model of experimental stroke. METHODS: CSF-1R-EGFP (MacGreen) mice were subjected to transient middle cerebral artery occlusion and administered varenicline (2.5 mg/kg/d for 7 days) or saline (n = 10 per group) 3 days after stroke. Forelimb asymmetry was assessed in the Cylinder test every 2 days after surgery, and structural lesions were quantified at day 10. Enhanced green fluorescent protein (EGFP) and growth associated protein 43 (GAP43) immunohistochemistry were used to evaluate the effect of varenicline on inflammation and axonal regeneration, respectively. RESULTS: Varenicline-treated animals showed a significant increase in impaired forelimb use compared with saline-treated animals 10 days after stroke. Varenicline treatment was associated with reduced EGFP expression and increased GAP43 expression in the striatum of MacGreen mice. CONCLUSION: Our results show that delayed administration of varenicline promotes recovery of function following experimental stroke. Motor function improvements were accompanied by decreased brain inflammation and increased axonal regeneration in nonpenumbral areas. These results suggest that the administration of an exogenous nicotinic agonist in the subacute phase following stroke may be a viable therapeutic strategy for stroke patients.


Assuntos
Encefalite/tratamento farmacológico , Membro Anterior/inervação , Infarto da Artéria Cerebral Média/tratamento farmacológico , Atividade Motora/efeitos dos fármacos , Agonistas Nicotínicos/administração & dosagem , Vareniclina/administração & dosagem , Animais , Axônios/efeitos dos fármacos , Axônios/metabolismo , Axônios/patologia , Gânglios da Base/efeitos dos fármacos , Gânglios da Base/metabolismo , Gânglios da Base/patologia , Modelos Animais de Doenças , Esquema de Medicação , Encefalite/metabolismo , Encefalite/fisiopatologia , Proteína GAP-43/metabolismo , Proteínas de Fluorescência Verde/biossíntese , Proteínas de Fluorescência Verde/genética , Infarto da Artéria Cerebral Média/metabolismo , Infarto da Artéria Cerebral Média/fisiopatologia , Masculino , Camundongos Transgênicos , Regeneração Nervosa , Receptores de Fator Estimulador das Colônias de Granulócitos e Macrófagos/genética , Recuperação de Função Fisiológica , Fatores de Tempo , Receptor Nicotínico de Acetilcolina alfa7/agonistas , Receptor Nicotínico de Acetilcolina alfa7/metabolismo
11.
Oncotarget ; 8(22): 36614-36627, 2017 May 30.
Artigo em Inglês | MEDLINE | ID: mdl-28402271

RESUMO

The efficacy of boron neutron capture therapy depends on the selective delivery of 10B to the target. Integrins αvß3 are transmembrane receptors over-expressed in both glioblastoma cells and its neovasculature. In this study, a novel approach to dual-target glioblastoma vasculature and tumor cells was investigated. Liposomes (124 nm) were conjugated with a αvß3 ligand, cyclic arginine-glycine-aspartic acid-tyrosine-cysteine peptide (c(RGDyC)-LP) (1% molar ratio) through thiol-maleimide coupling. Expression of αvß3 in glioblastoma cells (U87) and human umbilical vein endothelial cells (HUVEC), representing tumor angiogenesis, was determined using Western Blotting with other cells as references. The results showed that both U87 and HUVEC had stronger expression of αvß3 than other cell types, and the degree of cellular uptake of c(RGDyC)-LP correlated with the αvß3-expression levels of the cells. In contrast, control liposomes without c(RGDyC) showed little cellular uptake, regardless of cell type. In an in vitro boron neutron capture therapy study, the c(RGDyC)-LP containing sodium borocaptate generated more rapid and significant lethal effects to both U87 and HUVEC than the control liposomes and drug solution. Interestingly, neutron irradiated U87 and HUVEC showed different types of subsequent cell death. In conclusion, this study has demonstrated the potential of a new dual-targeting strategy using c(RGDyC)-LP to improve boron neutron capture therapy for glioblastoma.


Assuntos
Terapia por Captura de Nêutron de Boro , Lipossomos , Neovascularização Patológica , Peptídeos Cíclicos/administração & dosagem , Linhagem Celular Tumoral , Sobrevivência Celular/efeitos dos fármacos , Sobrevivência Celular/efeitos da radiação , Composição de Medicamentos , Liberação Controlada de Fármacos , Estabilidade de Medicamentos , Células Endoteliais/efeitos dos fármacos , Células Endoteliais/metabolismo , Células Endoteliais/efeitos da radiação , Glioblastoma/patologia , Glioblastoma/terapia , Humanos , Integrina alfaVbeta3/genética , Integrina alfaVbeta3/metabolismo , Lipossomos/química , Lipossomos/ultraestrutura , Neovascularização Patológica/terapia , Peptídeos Cíclicos/química
12.
Neuropharmacology ; 116: 233-246, 2017 04.
Artigo em Inglês | MEDLINE | ID: mdl-28025093

RESUMO

OBJECTIVE: Studies in the post mortem human brain and in genetic mouse model suggest that dysfunctional cholinergic neurotransmission, through a loss of agonist rather than receptors may be a significant contributing factor to HD pathology. If correct, pharmacological replacement may therefore be a potential treatment strategy. We have investigated whether chronic administration of the selective nicotinic partial agonist varenicline improved motor, cognitive and affective symptoms in a transgenic mouse model of Huntington's disease. METHOD: The performance of 15 month old YAC128 mice and age-matched wild-type littermates was assessed in the rotarod, T-maze, novel object recognition, novelty suppressed feeding and forced swim tests prior to and after treatment with varenicline (5 mg/kg/day for 28 days via miniosmotic pump). Thymidine analogues, whilst DARPP32 and EM48 immunohistochemistry were used to assess the effect of varenicline on progenitor cell proliferation and survival, medium spiny neurons and aggregate formation respectively. RESULTS: Chronic treatment with varenicline significantly improved motor coordination, delay-dependent memory and reduced depressive-like behaviour in late stage YAC128 mice. Varenicline also produced genotype-independent improvements in recognition memory and reduced anxiety. In addition, varenicline displayed anxiolytic effects and improved spatial memory in the absence of compromised function. Functional improvements were accompanied by neuropathological changes including increased aggregate formation, neuroprotection and increased progenitor cell proliferation and survival. INTERPRETATION: Our findings provide evidence that administration of an exogenous nicotinic agonist may be of clinical benefit in the treatment of late-stage Huntington's disease.


Assuntos
Transtornos Cognitivos/tratamento farmacológico , Depressão/tratamento farmacológico , Doença de Huntington/tratamento farmacológico , Transtornos dos Movimentos/tratamento farmacológico , Agonistas Nicotínicos/farmacologia , Vareniclina/farmacologia , Animais , Ansiedade/tratamento farmacológico , Ansiedade/patologia , Ansiedade/fisiopatologia , Proliferação de Células/efeitos dos fármacos , Transtornos Cognitivos/patologia , Transtornos Cognitivos/fisiopatologia , Corpo Estriado/efeitos dos fármacos , Corpo Estriado/patologia , Corpo Estriado/fisiopatologia , Depressão/patologia , Depressão/fisiopatologia , Modelos Animais de Doenças , Feminino , Hipocampo/efeitos dos fármacos , Hipocampo/patologia , Hipocampo/fisiopatologia , Doença de Huntington/patologia , Doença de Huntington/fisiopatologia , Doença de Huntington/psicologia , Masculino , Aprendizagem em Labirinto/efeitos dos fármacos , Memória/efeitos dos fármacos , Camundongos Transgênicos , Atividade Motora/efeitos dos fármacos , Transtornos dos Movimentos/patologia , Transtornos dos Movimentos/fisiopatologia , Células-Tronco Neurais/efeitos dos fármacos , Células-Tronco Neurais/patologia , Células-Tronco Neurais/fisiologia , Fármacos Neuroprotetores/farmacologia
13.
Neuropsychiatr Dis Treat ; 12: 2381-2386, 2016.
Artigo em Inglês | MEDLINE | ID: mdl-27695336

RESUMO

The aim of this study was to describe the effects of varenicline, a smoking cessation aid that acts as a nicotinic agonist, on cognitive function in patients with early clinical Huntington's disease (HD) who were current smokers. Three gene-positive patients transitioning to symptomatic HD were evaluated using the Unified Huntington's Disease Rating Scale part I and III (motor and behavioral subscales) at baseline and after 4 weeks of treatment. Cognitive function was assessed using a touch screen computer-based neurocognitive test battery (IntegNeuro®). Varenicline (1 mg twice daily) significantly improved performance in executive function and emotional recognition tasks. Our case reports describe no clinically significant adverse effects and suggest that varenicline improves aspects of cognitive function in patients with early HD. A randomized controlled study is now underway.

14.
Cell Signal ; 27(9): 1860-72, 2015 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-25982509

RESUMO

Human megakaryocytes release glutamate and express glutamate-gated Ca(2+)-permeable N-methyl-D-aspartate receptors (NMDARs) that support megakaryocytic maturation. While deregulated glutamate pathways impact oncogenicity in some cancers, the role of glutamate and NMDARs in megakaryocytic malignancies remains unknown. The aim of this study was to determine if NMDARs participate in Ca(2+) responses in leukemic megakaryoblasts and if so, whether modulating NMDAR activity could influence cell growth. Three human cell lines, Meg-01, Set-2 and K-562 were used as models of leukemic megakaryoblasts. NMDAR components were examined in leukemic cells and human bone marrow, including in megakaryocytic disease. Well-established NMDAR modulators (agonists and antagonists) were employed to determine NMDAR effects on Ca(2+) flux, cell viability, proliferation and differentiation. Leukemic megakaryoblasts contained combinations of NMDAR subunits that differed from normal bone marrow and the brain. NMDAR agonists facilitated Ca(2+) entry into Meg-01 cells, amplified Ca(2+) responses to adenosine diphosphate (ADP) and promoted growth of Meg-01, Set-2 and K-562 cells. Low concentrations of NMDAR inhibitors (riluzole, memantine, MK-801 and AP5; 5-100µM) were weakly cytotoxic but mainly reduced cell numbers by suppressing proliferation. The use-dependent NMDAR inhibitor, memantine (100µM), reduced numbers and proliferation of Meg-01 cells to less than 20% of controls (IC50 20µM and 36µM, respectively). In the presence of NMDAR inhibitors cells acquired morphologic and immunophenotypic features of megakaryocytic differentiation. In conclusion, NMDARs provide a novel pathway for Ca(2+) entry into leukemic megakaryoblasts that supports cell proliferation but not differentiation. NMDAR inhibitors counteract these effects, suggesting a novel opportunity to modulate growth of leukemic megakaryoblasts.


Assuntos
Sinalização do Cálcio , Cálcio/metabolismo , Diferenciação Celular , Proliferação de Células , Ácido Glutâmico/metabolismo , Leucemia Megacarioblástica Aguda/metabolismo , Feminino , Humanos , Células K562 , Leucemia Megacarioblástica Aguda/genética , Leucemia Megacarioblástica Aguda/patologia , Masculino , Receptores de N-Metil-D-Aspartato/genética , Receptores de N-Metil-D-Aspartato/metabolismo
15.
Cancer Chemother Pharmacol ; 73(3): 639-49, 2014 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-24477604

RESUMO

PURPOSE: Glioblastomas are amongst the most highly vascularised tumours, and the pursuit of anti-angiogenic approaches such as bevacizumab has provided short-term benefits. The purpose of this study was to determine whether the vascular-disrupting agent, dimethylxanthenone-4-acetic acid (DMXAA), could provide longer-lasting therapeutic benefits in a murine model of glioblastoma. METHODS: Luciferase-expressing murine GL261 glioma cells were inoculated subcutaneously or intracranially into C57Bl/6 mice. Mice with tumours were administered DMXAA, and tumours measured using callipers or by optical imager. Concentrations of DMXAA in plasma and brain were measured by LC-MS/MS. RESULTS: DMXAA (25 mg/kg) caused widespread necrosis at 24 h, a 9-day growth delay and complete regressions in 50 % of the mice with subcutaneous GL261 tumours. Co-administered lenalidomide (100 mg/kg) increased the growth delay to 20 days and the percentage of cures to 83 %. The same dose of DMXAA with or without lenalidomide had minimal effects on intracranial GL261 tumours. Concentrations of DMXAA extracted from brain tissue were approximately 25-fold lower than those measured in plasma 15 min to 4 h after DMXAA administration. The presence of intracranial GL261 tumours did not alter the concentrations of DMXAA entering the brain. CONCLUSIONS: DMXAA does not appear to cross the blood-brain barrier efficiently. Thus, whilst excellent activity was obtained against subcutaneous GL261 gliomas, minimal effects were observed against intracranial GL261 tumours. These results emphasise the need to use appropriate orthotopic models for the evaluation of new approaches for the treatment of brain cancers.


Assuntos
Antineoplásicos/farmacologia , Neoplasias Encefálicas/tratamento farmacológico , Glioma/tratamento farmacológico , Xantonas/farmacologia , Animais , Antineoplásicos/sangue , Antineoplásicos/farmacocinética , Barreira Hematoencefálica/metabolismo , Neoplasias Encefálicas/sangue , Neoplasias Encefálicas/irrigação sanguínea , Neoplasias Encefálicas/metabolismo , Linhagem Celular Tumoral , Modelos Animais de Doenças , Feminino , Glioma/sangue , Glioma/irrigação sanguínea , Glioma/metabolismo , Infusões Subcutâneas , Lenalidomida , Camundongos , Camundongos Endogâmicos C57BL , Neovascularização Patológica/tratamento farmacológico , Distribuição Aleatória , Talidomida/análogos & derivados , Talidomida/farmacologia , Xantonas/sangue , Xantonas/farmacocinética
16.
Neuropharmacology ; 63(8): 1315-26, 2012 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-22939998

RESUMO

Chronic stress has been implicated as a causal factor in depression and anxiety, and is associated with neuroendocrine dysfunction and impaired hippocampal neurogenesis. The neurosteroid allopregnanolone (3α,5α-THP; ALLO) has been shown to be reduced in depressed patients. ALLO is "stress responsive" and plays a major role in regulating hypothalamic-pituitary-adrenal (HPA) axis function. We propose that reduced ALLO levels following chronic stress leads to HPA hyperactivity due to diminished ALLO regulation. This will result in increased glucocorticoid levels and reduced BDNF expression, leading to impaired hippocampal neurogenesis and the precipitation of depression/anxiety. To investigate this, chronic stress was induced using the social isolation model and depressive/anxiety-like behaviour assessed using the novelty-suppressed feeding test and forced-swim test. The social isolation model was associated with a significant reduction in endogenous ALLO levels and a depressive/anxiety-like behavioural profile. When exogenous ALLO was administered from the onset of isolation it prevented the development of depressive/anxiety-like behaviours and impairment of hippocampal neurogenesis. When treatment was initiated following six weeks of social isolation, behavioural profile was restored and deficits in BDNF and neurogenesis were not observed. Supporting our hypothesis we observed that socially isolated animals exhibited reduced HPA responsiveness, which was either prevented or normalised with ALLO treatment. Combined, these results indicate that administration of exogenous ALLO either during or following a period of chronic stress can prevent or normalise HPA dysfunction and impairment of hippocampal neurogenesis respectively, precluding the establishment of depressive/anxiety-like behaviours. ALLO may therefore provide a novel therapeutic target for the treatment of depression/anxiety.


Assuntos
Ansiedade/psicologia , Depressão/psicologia , Neurogênese/fisiologia , Pregnanolona/fisiologia , Isolamento Social , Estresse Psicológico/psicologia , Animais , Ansiedade/etiologia , Comportamento Animal/efeitos dos fármacos , Fator Neurotrófico Derivado do Encéfalo/metabolismo , Sobrevivência Celular/efeitos dos fármacos , Doença Crônica , Depressão/etiologia , Dexametasona , Comportamento Alimentar/efeitos dos fármacos , Hipocampo/citologia , Hipocampo/efeitos dos fármacos , Hipocampo/metabolismo , Imuno-Histoquímica , Masculino , Atividade Motora/efeitos dos fármacos , Células-Tronco Neurais/efeitos dos fármacos , Pregnanolona/metabolismo , Pregnanolona/farmacologia , Ratos , Ratos Wistar , Natação/psicologia
17.
Mol Cell Neurosci ; 41(2): 219-32, 2009 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-19332124

RESUMO

In this study we demonstrate the chemokines MCP-1, MIP-1alpha and GRO-alpha play a role in directing adult subventricular zone (SVZ)-derived progenitor cell migration following striatal cell death. MCP-1, MIP-1alpha and GRO-alpha were significantly upregulated in the striatum 2-3 days following QA-induced lesioning, correlating with maximum SVZ-derived progenitor cell recruitment into the lesioned striatum. We established that SVZ-derived progenitor cells express receptors for each chemokine, and demonstrated MCP-1, MIP-1alpha and GRO-alpha to be potent chemoattractants for SVZ-derived progenitor cells in vitro. Immunofluorescence revealed MCP-1, MIP-1alpha and GRO-alpha are predominantly expressed in the striatum by NG2-positive cells that appear to infiltrate from the bloodstream 6 h following QA lesioning. These results indicate that upregulation of MCP-1, MIP-1alpha and GRO-alpha following striatal cell death leads to chemoattraction of SVZ-derived progenitor cells into the damaged striatum and raises a potential role for blood-derived cells in directing the recruitment of SVZ-derived progenitors following brain injury.


Assuntos
Movimento Celular/fisiologia , Quimiocinas/metabolismo , Corpo Estriado/citologia , Corpo Estriado/patologia , Neurônios/fisiologia , Células-Tronco/fisiologia , Animais , Células Cultivadas , Quimiocina CCL2/genética , Quimiocina CCL2/metabolismo , Quimiocina CCL3/genética , Quimiocina CCL3/metabolismo , Quimiocina CXCL1/genética , Quimiocina CXCL1/metabolismo , Quimiocinas/genética , Fatores Quimiotáticos/metabolismo , Corpo Estriado/efeitos dos fármacos , Corpo Estriado/metabolismo , Humanos , Masculino , Neurônios/citologia , Ácido Quinolínico/toxicidade , Ratos , Ratos Wistar , Receptores de Quimiocinas/metabolismo , Células-Tronco/citologia
18.
J Cereb Blood Flow Metab ; 27(3): 477-87, 2007 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-16804548

RESUMO

Apolipoprotein E (apoE, protein; APOE, gene) is the major lipid-transport protein in the brain and plays an important role in modulating the outcome and regenerative processes after acute brain injury. The aim of the present study was to determine if gene transfer of the epsilon3 form of APOE improves outcome in a murine model of transient focal cerebral ischaemia. Mice received an intrastriatal injection of vehicle, a second-generation adenoviral vector containing the green fluorescent protein gene (Ad-GFP) or a vector containing the APOE epsilon3 gene (Ad-APOE) 3 days before 60 mins focal ischaemia. Green fluorescent protein expression was observed in cells throughout the striatum and subcortical white matter indicating successful gene transfer and expression. ApoE levels in the brain were significantly increased after Ad-APOE compared with Ad-GFP or vehicle treatment. Ad-APOE treatment reduced the volume of ischaemic damage by 50% compared with Ad-GFP or vehicle treatment (13+/-3 versus 29+/-4 versus 27+/-5 mm(3)). The extent of postischaemic apoE immunoreactivity was enhanced in Ad-APOE compared with Ad-GFP or vehicle treated mice. These results show the ability of APOE gene transfer to markedly improve outcome after cerebral ischaemia and suggest that modulating apoE levels may be a potential strategy in human stroke therapy.


Assuntos
Apolipoproteína E3/genética , Encéfalo/patologia , Terapia Genética , Acidente Vascular Cerebral/terapia , Adenoviridae , Animais , Apolipoproteína E3/metabolismo , Apolipoproteína E3/uso terapêutico , Ensaio de Imunoadsorção Enzimática , Técnicas de Transferência de Genes , Vetores Genéticos , Proteínas de Fluorescência Verde/genética , Proteínas de Fluorescência Verde/metabolismo , Humanos , Imuno-Histoquímica , Camundongos , Acidente Vascular Cerebral/patologia
19.
Neurosci Lett ; 383(1-2): 58-62, 2005.
Artigo em Inglês | MEDLINE | ID: mdl-15936512

RESUMO

Ischaemia induces activation of resident microglia and infiltration of peripheral monocyte/macrophage cells into the central nervous system. The role of scavenger receptors, receptors critical to the recognition and clearance of cell debris, has not been investigated during cerebral ischaemia. MARCO is an inducible member of the scavenger receptor family unique to cells of monocytic lineage and is a cell surface marker that plays a critical role in the differentiation of monocytes to dendritic cells. To understand the role of MARCO in cerebral ischaemia, we investigated its expression in mice following middle cerebral artery (MCA) occlusion. No MARCO mRNA expression was observed in naive mouse brain. There was no significant increase in expression of MARCO mRNA following transient occlusion (60min) of the MCA at any time point up to 24 h. However, a significant, marked increase in MARCO mRNA expression was observed at 24 h in the cortex of mouse brains after a permanent occlusion of the MCA. The increased expression of MARCO mRNA at 24 h after prolonged ischaemia is consistent with its putative role in the clearance of debris and/or degenerating cells after severe ischaemia and supports previous publications showing the presence of dendritic cells around permanently occluded lesions.


Assuntos
Córtex Cerebral/patologia , Regulação da Expressão Gênica/fisiologia , Infarto da Artéria Cerebral Média/metabolismo , Macrófagos/metabolismo , Receptores Imunológicos/metabolismo , Análise de Variância , Animais , Northern Blotting/métodos , Linhagem Celular , Córtex Cerebral/metabolismo , Relação Dose-Resposta a Droga , Regulação da Expressão Gênica/efeitos dos fármacos , Lipopolissacarídeos/farmacologia , Masculino , Camundongos , Camundongos Endogâmicos C57BL , RNA Mensageiro/biossíntese , Receptores Imunológicos/genética , Receptores Depuradores , Reação em Cadeia da Polimerase Via Transcriptase Reversa/métodos , Baço/metabolismo , Fatores de Tempo
20.
Neuroreport ; 14(2): 215-7, 2003 Feb 10.
Artigo em Inglês | MEDLINE | ID: mdl-12598732

RESUMO

Apoptosis is an important route to neuronal death in experimental models of stroke, the leading neurological cause of death and disability. Here we explore a role for ataxia telangiectasia mutated protein (ATM), an activator of p53, in a primary cortical culture model of stroke. NMDA-induced apoptosis was reduced in cultures derived from mice with targeted deletions in the ATM gene. In addition, NMDA-induced caspase-3 activity was abolished in cultures lacking two functioning copies of the ATM gene. These data provide evidence to suggest that, in primary cortical culture, NMDA-induced apoptosis is partially mediated through ATM. They provide further evidence to support the hypothesis that DNA damage is one route to apoptosis following neuronal injury.


Assuntos
Apoptose/efeitos dos fármacos , N-Metilaspartato/farmacologia , Neurônios/efeitos dos fármacos , Proteínas Serina-Treonina Quinases/deficiência , Animais , Apoptose/genética , Proteínas Mutadas de Ataxia Telangiectasia , Proteínas de Ciclo Celular , Sobrevivência Celular/efeitos dos fármacos , Sobrevivência Celular/genética , Células Cultivadas , Proteínas de Ligação a DNA , Feminino , Masculino , Camundongos , Camundongos Knockout , Camundongos Transgênicos , Neurônios/citologia , Neurônios/metabolismo , Proteínas Serina-Treonina Quinases/genética , Proteínas Supressoras de Tumor
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