RESUMO
Excitotoxicity and the concurrent loss of inhibition are well-defined mechanisms driving acute elevation in excitatory/inhibitory (E/I) balance and neuronal cell death following an ischemic insult to the brain. Despite the high prevalence of long-term disability in survivors of global cerebral ischemia (GCI) as a consequence of cardiac arrest, it remains unclear whether E/I imbalance persists beyond the acute phase and negatively affects functional recovery. We previously demonstrated sustained impairment of long-term potentiation (LTP) in hippocampal CA1 neurons correlating with deficits in learning and memory tasks in a murine model of cardiac arrest/cardiopulmonary resuscitation (CA/CPR). Here, we use CA/CPR and an in vitro ischemia model to elucidate mechanisms by which E/I imbalance contributes to ongoing hippocampal dysfunction in male mice. We reveal increased postsynaptic GABAA receptor (GABAAR) clustering and function in the CA1 region of the hippocampus that reduces the E/I ratio. Importantly, reduced GABAAR clustering observed in the first 24â h rebounds to an elevation of GABAergic clustering by 3â d postischemia. This increase in GABAergic inhibition required activation of the Ca2+-permeable ion channel transient receptor potential melastatin-2 (TRPM2), previously implicated in persistent LTP and memory deficits following CA/CPR. Furthermore, we find Ca2+-signaling, likely downstream of TRPM2 activation, upregulates Ca2+/calmodulin-dependent protein kinase II (CaMKII) activity, thereby driving the elevation of postsynaptic inhibitory function. Thus, we propose a novel mechanism by which inhibitory synaptic strength is upregulated in the context of ischemia and identify TRPM2 and CaMKII as potential pharmacological targets to restore perturbed synaptic plasticity and ameliorate cognitive function.
Assuntos
Proteína Quinase Tipo 2 Dependente de Cálcio-Calmodulina , Transdução de Sinais , Canais de Cátion TRPM , Animais , Masculino , Camundongos , Isquemia Encefálica/metabolismo , Região CA1 Hipocampal/metabolismo , Proteína Quinase Tipo 2 Dependente de Cálcio-Calmodulina/metabolismo , Neurônios GABAérgicos/metabolismo , Parada Cardíaca/complicações , Parada Cardíaca/metabolismo , Hipocampo/metabolismo , Camundongos Endogâmicos C57BL , Inibição Neural/fisiologia , Receptores de GABA-A/metabolismo , Canais de Cátion TRPM/metabolismoRESUMO
Astrocytes, a major glial cell type in the brain, are indispensable for the integration, maintenance and survival of neurons during development and adulthood. Both life phases make specific demands on the molecular and physiological properties of astrocytes, and most research projects traditionally focus on either developmental or adult astrocyte functions. In most brain regions, the generation of brain cells and the establishment of neural circuits ends with postnatal development. However, few neurogenic niches exist in the adult brain in which new neurons and glial cells are produced lifelong, and the integration of new cells into functional circuits represent a very special form of plasticity. Consequently, in the neurogenic niche, the astrocytes must be equipped to execute both mature and developmental tasks in order to integrate newborn neurons into the circuit and yet maintain overall homeostasis without affecting the preexisting neurons. In this review, we focus on astrocytes of the hippocampal dentate gyrus (DG), and discuss specific features of the astrocytic compartment that may allow the execution of both tasks. Firstly, astrocytes of the adult DG are molecularly, morphologically and functionally diverse, and the distinct astrocytes subtypes are characterized by their localization to DG layers. This spatial separation may lead to a functional specification of astrocytes subtypes according to the neuronal structures they are embedded in, hence a division of labor. Secondly, the astrocytic compartment is not static, but steadily increasing in numbers due to lifelong astrogenesis. Interestingly, astrogenesis can adapt to environmental and behavioral stimuli, revealing an unexpected astrocyte dynamic that allows the niche to adopt to changing demands. The diversity and dynamic of astrocytes in the adult DG implicate a vital contribution to hippocampal plasticity and represent an interesting model to uncover mechanisms how astrocytes simultaneously fulfill developmental and adult tasks.
Assuntos
Astrócitos , Giro Denteado , Neurogênese , Astrócitos/fisiologia , Astrócitos/metabolismo , Giro Denteado/fisiologia , Humanos , Animais , Neurogênese/fisiologia , Neurônios/fisiologia , Neurônios/metabolismo , Adulto , Plasticidade Neuronal/fisiologiaRESUMO
Hippocampal cell death and cognitive dysfunction are common following global cerebral ischemia across all ages, including children. Most research has focused on preventing neuronal death. Restoration of neuronal function after cell death is an alternative approach (neurorestoration). We previously identified transient receptor potential M2 (TRPM2) ion channels as a potential target for acute neuroprotection and delayed neurorestoration in an adult CA/CPR mouse model. Cardiac arrest/cardiopulmonary resuscitation (CA/CPR) in juvenile (p20-25) mice was used to investigate the role of ion TRPM2 channels in neuroprotection and ischemia-induced synaptic dysfunction in the developing brain. Our novel TRPM2 inhibitor, tatM2NX, did not confer protection against CA1 pyramidal cell death but attenuated synaptic plasticity (long-term plasticity (LTP)) deficits in both sexes. Further, in vivo administration of tatM2NX two weeks after CA/CPR reduced LTP impairments and restored memory function. These data provide evidence that pharmacological synaptic restoration of the surviving hippocampal network can occur independent of neuroprotection via inhibition of TRPM2 channels, providing a novel strategy to improve cognitive recovery in children following cerebral ischemia. Importantly, these data underscore the importance of age-appropriate models in disease research.
Assuntos
Isquemia Encefálica/tratamento farmacológico , Fragmentos de Peptídeos/farmacologia , Fragmentos de Peptídeos/uso terapêutico , Recuperação de Função Fisiológica/fisiologia , Canais de Cátion TRPM/antagonistas & inibidores , Canais de Cátion TRPM/fisiologia , Fatores Etários , Animais , Isquemia Encefálica/fisiopatologia , Reanimação Cardiopulmonar/métodos , Feminino , Parada Cardíaca/tratamento farmacológico , Parada Cardíaca/fisiopatologia , Hipocampo/efeitos dos fármacos , Hipocampo/fisiologia , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Rede Nervosa/efeitos dos fármacos , Rede Nervosa/fisiologia , Técnicas de Cultura de Órgãos , Recuperação de Função Fisiológica/efeitos dos fármacosRESUMO
Ischemic long-term potentiation (iLTP) is a form of synaptic plasticity that occurs in acute brain slices following oxygen-glucose deprivation. In vitro, iLTP can occlude physiological LTP (pLTP) through saturation of plasticity mechanisms. We used our murine cardiac arrest and cardiopulmonary resuscitation (CA/CPR) model to produce global brain ischemia and assess whether iLTP is induced in vivo, contributing to the functionally relevant impairment of pLTP. Adult male mice were subjected to CA/CPR, and slice electrophysiology was performed in the hippocampal CA1 region 7 or 30 days later. We observed increased miniature excitatory postsynaptic current amplitudes, suggesting a potentiation of postsynaptic AMPA receptor function after CA/CPR. We also observed increased phosphorylated GluR1 in the postsynaptic density of hippocampi after CA/CPR. These data support the in vivo induction of ischemia-induced plasticity. Application of a low-frequency stimulus (LFS) to CA1 inputs reduced excitatory postsynaptic potentials in slices from mice subjected to CA/CPR, while having no effects in sham controls. These results are consistent with a reversal, or depotentiation, of iLTP. Further, depotentiation with LFS partially restored induction of pLTP with theta burst stimulation. These data provide evidence for iLTP following in vivo ischemia, which occludes pLTP and likely contributes to network disruptions that underlie memory impairments.
Assuntos
Isquemia Encefálica/fisiopatologia , Região CA1 Hipocampal/fisiopatologia , Parada Cardíaca/fisiopatologia , Potenciação de Longa Duração , Neurônios/fisiologia , Animais , Isquemia Encefálica/complicações , Parada Cardíaca/complicações , Depressão Sináptica de Longo Prazo , Masculino , Camundongos Endogâmicos C57BL , Receptores de AMPA/fisiologiaRESUMO
BACKGROUND: Cardiac abnormalities are frequent in patients with atherosclerotic renovascular disease (ARVD). The Angioplasty and Stenting for Renal Artery Lesions (ASTRAL) trial studied the effect of percutaneous renal revascularization combined with medical therapy compared with medical therapy alone in 806 patients with ARVD. METHODS: This was a pre-specified sub-study of ASTRAL (clinical trials registration, current controlled trials number: ISRCTN59586944), designed to consider the effect of percutaneous renal artery angioplasty and stenting on change in cardiac structure and function, measured using cardiac magnetic resonance (CMR) imaging. Fifty-one patients were recruited from six selected ASTRAL centres. Forty-four completed the study (medical therapy n = 21; revascularization n = 23). Full analysis of CMR was possible in 40 patients (18 medical therapy and 22 revascularization). CMR measurements of left and right ventricular end systolic (LV and RVESV) and diastolic volume (LV and RVEDV), ejection fraction (LVEF) and mass (LVM) were made shortly after recruitment and before revascularization in the interventional group, and again after 12 months. Reporting was performed by CMR analysts blinded to randomization arm. RESULTS: Groups were well matched for mean age (70 versus 72 years), blood pressure (148/71 versus 143/74 mmHg), degree of renal artery stenosis (75 versus 75%) and comorbid conditions. In both randomized groups, improvements in cardiac structural parameters were seen at 12 months, but there were no significant differences between treatment groups. Median left ventricular changes between baseline and 12 months (medical versus revascularization) were LVEDV -1.9 versus -5.8 mL, P = 0.4; LVESV -2.1 versus 0.3 mL, P = 0.7; LVM -5.4 versus -6.3 g, P = 0.8; and LVEF -1.5 versus -0.8%, P = 0.7. Multivariate regression also found that randomized treatment assignment was not associated with degree of change in any of the CMR measurements. CONCLUSIONS: In this sub-study of the ASTRAL trial, renal revascularization did not offer additional benefit to cardiac structure or function in unselected patients with ARVD.
Assuntos
Aterosclerose/cirurgia , Ventrículos do Coração/patologia , Obstrução da Artéria Renal/cirurgia , Idoso , Idoso de 80 Anos ou mais , Angioplastia , Aterosclerose/fisiopatologia , Pressão Sanguínea , Feminino , Taxa de Filtração Glomerular , Ventrículos do Coração/diagnóstico por imagem , Ventrículos do Coração/fisiopatologia , Humanos , Imageamento por Ressonância Magnética , Masculino , Pessoa de Meia-Idade , Miocárdio/patologia , Artéria Renal/cirurgia , Obstrução da Artéria Renal/fisiopatologia , Resultado do TratamentoRESUMO
BACKGROUND: Current trial data may not be directly applicable to patients with the highest risk presentations of atherosclerotic renovascular disease, including flash pulmonary edema, rapidly declining kidney function, and refractory hypertension. We consider the prognostic implications of these presentations and response to percutaneous revascularization. STUDY DESIGN: Single-center prospective cohort study; retrospectively analyzed. SETTING & PARTICIPANTS: 467 patients with renal artery stenosis ≥50%, managed according to clinical presentation and physician/patient preference. PREDICTORS: Presentation with flash pulmonary edema (n = 37 [7.8%]), refractory hypertension (n = 116 [24.3%]), or rapidly declining kidney function (n = 46 [9.7%]) compared to low-risk presentation with none of these phenotypes (n = 230 [49%]). Percutaneous revascularization (performed in 32% of flash pulmonary edema, 28% of rapidly declining kidney function, and 28% of refractory hypertension patients) compared to medical management. OUTCOMES: Death, cardiovascular (CV) event, end-stage kidney disease. RESULTS: During a median follow-up of 3.8 (IQR, 1.8-5.8) years, 55% died, 33% had a CV event, and 18% reached end-stage kidney disease. In medically treated patients, flash pulmonary edema was associated with increased risk of death (HR, 2.2; 95% CI, 1.4-3.5; P < 0.001) and CV event (HR, 3.1; 95% CI, 1.7-5.5; P < 0.001), but not end-stage kidney disease, compared to the low-risk phenotype. No increased risk for any end point was observed in patients presenting with rapidly declining kidney function or refractory hypertension. Compared to medical treatment, revascularization was associated with reduced risk for death (HR, 0.4; 95% CI, 0.2-0.9; P = 0.01), but not CV event or end-stage kidney disease, in patients presenting with flash pulmonary edema. Revascularization was not associated significantly with reduced risk for any end point in rapidly declining kidney function or refractory hypertension. When these presentations were present in combination (n = 31), revascularization was associated with reduced risk for death (HR, 0.15; 95% CI, 0.02-0.9; P = 0.04) and CV event (HR, 0.23; 95% CI, 0.1-0.6; P = 0.02). LIMITATIONS: Observational study; retrospective analysis; potential treatment bias. CONCLUSIONS: This analysis supports guidelines citing flash pulmonary edema as an indication for renal artery revascularization in atherosclerotic renovascular disease. Patients presenting with a combination of rapidly declining kidney function and refractory hypertension also may benefit from revascularization and may represent a subgroup worthy of further investigation in more robust trials.
Assuntos
Aterectomia , Aterosclerose/diagnóstico , Obstrução da Artéria Renal/diagnóstico , Obstrução da Artéria Renal/cirurgia , Idoso , Idoso de 80 Anos ou mais , Aterectomia/métodos , Aterosclerose/cirurgia , Estudos de Coortes , Feminino , Seguimentos , Humanos , Falência Renal Crônica/diagnóstico , Falência Renal Crônica/cirurgia , Masculino , Pessoa de Meia-Idade , Prognóstico , Estudos Prospectivos , Estudos RetrospectivosRESUMO
BACKGROUND: Controversy exists as to the relative merits of surgical and endovascular treatment of femoropoliteal arterial disease. METHODS: A systematic review of the literature was undertaken to identify studies comparing open surgical and percutaneous transluminal methods for the treatment of femoropopliteal arterial disease. Outcome data were pooled and combined overall effect sizes were calculated using fixed or random effects models. RESULTS: Four randomized controlled trials and six observational studies reporting on a total of 2817 patients (1387 open, 1430 endovascular) were included. Endovascular treatment was accompanied by lower 30-day morbidity (odds ratio [OR], 2.93; 95% confidence interval [CI], 1.34-6.41) and higher technical failure (OR, 0.10; 95% CI, 0.05-0.22) than bypass surgery, whereas no differences in 30-day mortality between the two groups were identified (OR, 0.92; 95% CI, 0.55-1.51). Higher primary patency in the surgical treatment arm was found at 1 (OR, 2.42; 95% CI, 1.37-4.28), 2 (OR, 2.03; 95% CI, 1.20-3.45), and 3 (OR, 1.48; 95% CI, 1.12-1.97) years of intervention. Progression to amputation was found to occur more commonly in the endovascular group at the end of the second (OR, 0.60; 95% CI, 0.42-0.86) and third (OR, 0.55; 95% CI, 0.39-0.77) year of intervention. Higher amputation-free and overall survival rates were found in the bypass group at 4 years (OR, 1.31; 95% CI, 1.07-1.61 and OR, 1.29; 95% CI, 1.04-1.61, respectively). CONCLUSIONS: High-level evidence demonstrating the superiority of one method over the other is lacking. An endovascular-first approach may be advisable in patients with significant comorbidity, whereas for fit patients with a longer-term perspective a bypass procedure may be offered as a first-line interventional treatment.
Assuntos
Procedimentos Endovasculares , Artéria Femoral/cirurgia , Doença Arterial Periférica/terapia , Artéria Poplítea/cirurgia , Procedimentos Cirúrgicos Vasculares , Idoso , Idoso de 80 Anos ou mais , Amputação Cirúrgica , Comorbidade , Procedimentos Endovasculares/efeitos adversos , Procedimentos Endovasculares/mortalidade , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Razão de Chances , Doença Arterial Periférica/mortalidade , Doença Arterial Periférica/cirurgia , Reoperação , Medição de Risco , Fatores de Risco , Fatores de Tempo , Resultado do Tratamento , Procedimentos Cirúrgicos Vasculares/efeitos adversos , Procedimentos Cirúrgicos Vasculares/mortalidadeRESUMO
PURPOSE: To review emerging evidence regarding the use of bare metal (BMS) vs. drug-eluting stents (DES) in the treatment of infrapopliteal occlusive disease. METHODS: A systematic review of the literature was undertaken to identify all studies comparing stent treatments of infragenicular vessels in patients with chronic lower limb ischemia. Validated methods to assess the methodological quality of the included studies were applied. Outcome data were pooled, and combined overall effect sizes were calculated using fixed or random effects models. The search identified 4 randomized clinical trials and 2 observational studies reporting on 544 patients (287 treated with DES and 257 treated with BMS). Data are presented as the odds ratio (OR) with 95% confidence interval (CI) and the number-needed-to-treat (NNT). RESULTS: Primary patency, freedom from target lesion revascularization, and clinical improvement at 1 year were significantly higher in the DES recipients compared to patients treated with BMS (OR 4.511, 95% CI 2.897 to 7.024, p<0.001, NNT 3.5; OR 3.238, 95% CI 2.019 to 5.192, p<0.001, NNT 6.0; and OR 1.792, 95% CI 1.039 to 3.090, p=0.036, NNT 7.3, respectively). No significant differences in limb salvage and overall survival at 1 year were identified between the groups (OR 2.008, 95% CI 0.722 to 5.585, p=0.181; OR 1.262, 95% CI 0.605 to 2.634, p=0.535, respectively). Sensitivity analyses investigating the potential effects of study design and type of DES on the combined outcome estimates validated the results. CONCLUSION: Our analysis has demonstrated superior short-term results with DES compared with BMS, expressed by increased patency and freedom from target lesion revascularization. The influence of this finding on clinical surrogate endpoints, such as limb salvage, remains unknown.
Assuntos
Angioplastia com Balão/instrumentação , Arteriopatias Oclusivas/terapia , Stents Farmacológicos , Isquemia/terapia , Extremidade Inferior/irrigação sanguínea , Artéria Poplítea , Angioplastia com Balão/efeitos adversos , Angioplastia com Balão/mortalidade , Arteriopatias Oclusivas/mortalidade , Arteriopatias Oclusivas/fisiopatologia , Distribuição de Qui-Quadrado , Constrição Patológica , Humanos , Isquemia/mortalidade , Isquemia/fisiopatologia , Salvamento de Membro , Razão de Chances , Artéria Poplítea/fisiopatologia , Desenho de Prótese , Fatores de Tempo , Resultado do Tratamento , Grau de Desobstrução VascularRESUMO
BACKGROUND: Percutaneous revascularization of the renal arteries improves patency in atherosclerotic renovascular disease, yet evidence of a clinical benefit is limited. METHODS: In a randomized, unblinded trial, we assigned 806 patients with atherosclerotic renovascular disease either to undergo revascularization in addition to receiving medical therapy or to receive medical therapy alone. The primary outcome was renal function, as measured by the reciprocal of the serum creatinine level (a measure that has a linear relationship with creatinine clearance). Secondary outcomes were blood pressure, the time to renal and major cardiovascular events, and mortality. The median follow-up was 34 months. RESULTS: During a 5-year period, the rate of progression of renal impairment (as shown by the slope of the reciprocal of the serum creatinine level) was -0.07x10(-3) liters per micromole per year in the revascularization group, as compared with -0.13x10(-3) liters per micromole per year in the medical-therapy group, a difference favoring revascularization of 0.06x10(-3) liters per micromole per year (95% confidence interval [CI], -0.002 to 0.13; P=0.06). Over the same time, the mean serum creatinine level was 1.6 micromol per liter (95% CI, -8.4 to 5.2 [0.02 mg per deciliter; 95% CI, -0.10 to 0.06]) lower in the revascularization group than in the medical-therapy group. There was no significant between-group difference in systolic blood pressure; the decrease in diastolic blood pressure was smaller in the revascularization group than in the medical-therapy group. The two study groups had similar rates of renal events (hazard ratio in the revascularization group, 0.97; 95% CI, 0.67 to 1.40; P=0.88), major cardiovascular events (hazard ratio, 0.94; 95% CI, 0.75 to 1.19; P=0.61), and death (hazard ratio, 0.90; 95% CI, 0.69 to 1.18; P=0.46). Serious complications associated with revascularization occurred in 23 patients, including 2 deaths and 3 amputations of toes or limbs. CONCLUSIONS: We found substantial risks but no evidence of a worthwhile clinical benefit from revascularization in patients with atherosclerotic renovascular disease. (Current Controlled Trials number, ISRCTN59586944.)
Assuntos
Angioplastia com Balão , Anti-Hipertensivos/uso terapêutico , Obstrução da Artéria Renal/terapia , Adulto , Idoso , Idoso de 80 Anos ou mais , Angioplastia com Balão/efeitos adversos , Pressão Sanguínea , Terapia Combinada , Quimioterapia Combinada , Feminino , Humanos , Inibidores de Hidroximetilglutaril-CoA Redutases/uso terapêutico , Estimativa de Kaplan-Meier , Masculino , Pessoa de Meia-Idade , Inibidores da Agregação Plaquetária/uso terapêutico , Obstrução da Artéria Renal/tratamento farmacológico , Obstrução da Artéria Renal/mortalidade , Obstrução da Artéria Renal/fisiopatologia , Stents , Resultado do TratamentoRESUMO
Neuronal heterogeneity has been established as a pillar of higher central nervous system function, but glial heterogeneity and its implications for neural circuit function are poorly understood. Here we show that the adult mouse dentate gyrus (DG) of the hippocampus is populated by molecularly distinct astrocyte subtypes that are associated with distinct DG layers. Astrocytes localized to different DG compartments also exhibit subtype-specific morphologies. Physiologically, astrocytes in upper DG layers form large syncytia, while those in lower DG compartments form smaller networks. Astrocyte subtypes differentially express glutamate transporters, which is associated with different amplitudes of glutamate transporter-mediated currents. Key molecular and morphological features of astrocyte diversity in the mice DG are conserved in humans. This adds another layer of complexity to our understanding of brain network composition and function, which will be crucial for further studies on astrocytes in health and disease.
Assuntos
Astrócitos , Neuroglia , Adulto , Humanos , Animais , Camundongos , Hipocampo , Encéfalo , Giro DenteadoRESUMO
BACKGROUND: Transplant renal artery stenosis (TRAS) is a recognized complication resulting in post-transplant hypertension associated with allograft dysfunction. It is a commonly missed but potentially treatable complication that may present from months to years after transplant surgery. In this retrospective study, we compared management strategies and outcomes of TRAS from 1990 to 2005. METHODS: Case notes of transplant recipients with TRAS demonstrated by angiography were reviewed. Angiography and was carried out when there was a clinical or Doppler ultrasound suspicion of TRAS. The clinical diagnosis of TRAS was based on uncontrolled refractory/new-onset hypertension and/or unexplained graft dysfunction in the absence of another diagnosis, such as rejection, obstruction or infection. The two-tailed Student t-test was used to analyse the differences between mean arterial pressure, serum creatinine, and estimated glomerular filtration rate before and after the intervention. RESULTS: Sixty-seven patients with angiogram-confirmed TRAS were included. Forty-four, 9 and 14 patients were managed with primary percutaneous transluminal renal angioplasty (PTRA), surgical intervention and conservative treatment, respectively. Uncontrolled hypertension was the most common presentation noted in 74.62%. Post-anastamotic single stenosis was the commonest occurrence (n = 53). Angioplasty had the highest 1- and 5-year graft survival rate of 91% and 86%, respectively. The worst prognosis was noted in patients treated with secondary PTRA after failed surgery or secondary surgery after failed primary PTRA. CONCLUSIONS: TRAS is a recognized complication resulting in loss of renal allografts. Early Doppler ultrasound is a good primary diagnostic tool. Early intervention is associated with a good long-term graft function.
Assuntos
Sobrevivência de Enxerto , Hipertensão/mortalidade , Transplante de Rim/mortalidade , Complicações Pós-Operatórias , Obstrução da Artéria Renal/mortalidade , Obstrução da Artéria Renal/cirurgia , Injúria Renal Aguda/terapia , Angioplastia com Balão , Seguimentos , Taxa de Filtração Glomerular , Humanos , Hipertensão/complicações , Obstrução da Artéria Renal/complicações , Estudos Retrospectivos , Taxa de Sobrevida , Transplante Homólogo , Resultado do TratamentoRESUMO
CaMKIIα plays a dual role in synaptic plasticity, as it can mediate synaptic changes in opposing directions. We hypothesized that CaMKIIα plays a similar dual role also in neuronal cell death and survival. Indeed, the CaMKII inhibitor tatCN21 is neuroprotective when added during or after excitotoxic/ischemic insults, but was described to cause sensitization when applied long-term prior to such insult. However, when comparing long-term CaMKII inhibition by several different inhibitors in neuronal cultures, we did not detect any sensitization. Likewise, in a mouse in vivo model of global cerebral ischemia (cardiac arrest followed by cardiopulmonary resuscitation), complete knockout of the neuronal CaMKIIα isoform did not cause sensitization but instead significant neuroprotection.
Assuntos
Isquemia Encefálica/metabolismo , Proteína Quinase Tipo 2 Dependente de Cálcio-Calmodulina/metabolismo , Morte Celular/fisiologia , Parada Cardíaca/metabolismo , Animais , Isquemia Encefálica/genética , Proteína Quinase Tipo 2 Dependente de Cálcio-Calmodulina/genética , Córtex Cerebral/metabolismo , Modelos Animais de Doenças , Parada Cardíaca/genética , Camundongos , Camundongos Knockout , Neurônios/metabolismo , FosforilaçãoRESUMO
Ischemic brain damage is triggered by glutamate excitotoxicity resulting in neuronal cell death. Previous research has demonstrated that N-methly-D-aspartate (NMDA) receptor activation triggers downstream calcium-dependent signaling pathways, specifically Ca2+/calmodulin-dependent protein kinase II (CaMKII). Inhibiting CaMKII is protective against hippocampal ischemic injury, but there is little known about its role in the cerebellum. To examine the neuroprotective potential of CaMKII inhibition in Purkinje cells, we subjected C57BL/6 or CaMKIIα KO male mice (8-12 weeks old) to cardiac arrest followed by cardiopulmonary resuscitation (CA/CPR). We performed a dose-response study for tat-CN19o and cerebellar injury was analyzed at 7 days after CA/CPR. Acute signaling was assessed at 6 h after CA/CPR using Western blot analysis. We observed increased phosphorylation of the T286 residue of CaMKII, suggesting increased autonomous activation. Analysis of Purkinje cell density revealed a decrease in cell density at 7 days after CA/CPR that was prevented with tat-CN19o at doses of 0.1 and 1 mg/kg. However, neuroprotection in the cerebellum required doses that were 10-fold higher than what was needed in the hippocampus. CaMKIIα KO mice subjected to sham surgery or CA/CPR had similar Purkinje cell densities, suggesting CaMKIIα is required for CA/CPR-induced injury in the cerebellum. We also observed a CA/CPR-induced activation of death-associated protein kinase (DAPK1) that tat-CN19o did not block. In summary, our findings indicate that inhibition of autonomous CaMKII activity is a promising therapeutic approach that is effective across multiple brain regions.
Assuntos
Cálcio/metabolismo , Calmodulina/efeitos dos fármacos , Substâncias Protetoras/farmacologia , Células de Purkinje/efeitos dos fármacos , Animais , Sinalização do Cálcio/efeitos dos fármacos , Proteína Quinase Tipo 2 Dependente de Cálcio-Calmodulina/efeitos dos fármacos , Proteína Quinase Tipo 2 Dependente de Cálcio-Calmodulina/metabolismo , Masculino , Camundongos Endogâmicos C57BL , Neurônios/efeitos dos fármacos , Neurônios/metabolismo , Células de Purkinje/metabolismoRESUMO
DAPK1 binding to GluN2B was prominently reported to mediate ischemic cell death in vivo. DAPK1 and CaMKII bind to the same GluN2B region, and their binding is mutually exclusive. Here, we show that mutating the binding region on GluN2B (L1298A/R1300Q) protected against neuronal cell death induced by cardiac arrest followed by resuscitation. Importantly, the GluN2B mutation selectively abolished only CaMKII, but not DAPK1, binding. During ischemic or excitotoxic insults, CaMKII further accumulated at excitatory synapses, and this accumulation was mediated by GluN2B binding. Interestingly, extra-synaptic GluN2B decreased after ischemia, but its relative association with DAPK1 increased. Thus, ischemic neuronal death requires CaMKII binding to synaptic GluN2B, whereas any potential role for DAPK1 binding is restricted to a different, likely extra-synaptic population of GluN2B.
Assuntos
Proteína Quinase Tipo 2 Dependente de Cálcio-Calmodulina/metabolismo , Proteínas Quinases Associadas com Morte Celular/metabolismo , Parada Cardíaca/metabolismo , Parada Cardíaca/patologia , Isquemia/metabolismo , Isquemia/patologia , Receptores de N-Metil-D-Aspartato/metabolismo , Animais , Morte Celular/efeitos dos fármacos , Espinhas Dendríticas/efeitos dos fármacos , Espinhas Dendríticas/metabolismo , Feminino , Ácido Glutâmico/toxicidade , Células HEK293 , Humanos , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Mutação/genética , Neuroproteção/efeitos dos fármacos , Fármacos Neuroprotetores/farmacologia , Neurotoxinas/toxicidade , Ligação Proteica/efeitos dos fármacos , Ratos Sprague-Dawley , Receptores de N-Metil-D-Aspartato/genética , RessuscitaçãoRESUMO
Hippocampal injury and cognitive impairments are common after cardiac arrest and stroke and do not have an effective intervention despite much effort. Therefore, we developed a new approach aimed at reversing synaptic dysfunction by targeting TRPM2 channels. Cardiac arrest/cardiopulmonary resuscitation (CA/CPR) in mice was used to investigate cognitive deficits and the role of the calcium-permeable ion channel transient receptor potential-M2 (TRPM2) in ischemia-induced synaptic dysfunction. Our data indicates that absence (TRPM2-/-) or acute inhibition of TRPM2 channels with tatM2NX reduced hippocampal cell death in males only, but prevented synaptic plasticity deficits in both sexes. Remarkably, administration of tatM2NX weeks after injury reversed hippocampal plasticity and memory deficits. Finally, TRPM2-dependent activation of calcineurin-GSK3ß pathway contributes to synaptic plasticity impairments. These data suggest persistent TRPM2 activity following ischemia contributes to impairments of the surviving hippocampal network and that inhibition of TRPM2 channels at chronic time points may represent a novel strategy to improve functional recovery following cerebral ischemia that is independent of neuroprotection.
Assuntos
Disfunção Cognitiva/fisiopatologia , Parada Cardíaca/complicações , Hipocampo/fisiopatologia , Isquemia/complicações , Neurônios/fisiologia , Canais de Cátion TRPM/fisiologia , Animais , Calcineurina/fisiologia , Reanimação Cardiopulmonar , Disfunção Cognitiva/etiologia , Feminino , Glicogênio Sintase Quinase 3 beta/fisiologia , Isquemia/fisiopatologia , Masculino , Camundongos Knockout , Plasticidade Neuronal , Canais de Cátion TRPM/antagonistas & inibidores , Canais de Cátion TRPM/genéticaRESUMO
On page 1553, the caption on Table 1 should read: Retrieval of filter by filter make/model and % retrievals within the manufacturer timescale.
RESUMO
Global ischemia in childhood often leads to poor neurologic outcomes, including learning and memory deficits. Using our novel model of childhood cardiac arrest/cardiopulmonary resuscitation (CA/CPR), we investigate the mechanism of ischemia-induced cognitive deficits and recovery. Memory is impaired seven days after juvenile CA/CPR and completely recovers by 30 days. Consistent with this remarkable recovery not observed in adults, hippocampal long-term potentiation (LTP) is impaired 7-14 days after CA/CPR, recovering by 30 days. This recovery is not due to the replacement of dead neurons (neurogenesis), but rather correlates with brain-derived neurotrophic factor (BDNF) expression, implicating BDNF as the molecular mechanism underlying impairment and recovery. Importantly, delayed activation of TrkB receptor signaling reverses CA/CPR-induced LTP deficits and memory impairments. These data provide two new insights (1) endogenous recovery of memory and LTP through development may contribute to improved neurological outcome in children compared to adults and (2) BDNF-enhancing drugs speed recovery from pediatric cardiac arrest during the critical school ages.
Assuntos
Isquemia Encefálica/metabolismo , Fator Neurotrófico Derivado do Encéfalo/metabolismo , Glicoproteínas de Membrana/metabolismo , Proteínas Tirosina Quinases/metabolismo , Recuperação de Função Fisiológica/fisiologia , Animais , Isquemia Encefálica/fisiopatologia , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Plasticidade Neuronal/fisiologia , Transdução de Sinais/fisiologiaRESUMO
Pseudoaneurysms of the popliteal artery are a rare clinical entity, accounting for <4% of all popliteal aneurysms. Accurate diagnosis and effective intervention is required to prevent potentially limb-threatening complications. We present the case of a 37-year-old man with acute limb ischaemia due to distal calf vessel thrombosis secondary to a popliteal pseudoaneurysm that was managed with covered stent placement and thrombolysis.
RESUMO
AIMS: This study reports long-term outcomes after endovascular salvage (EVS) for acute dialysis fistula/graft dysfunction. METHODS: All patients presenting with acute fistula or graft dysfunction, excluding primary failures, referred for endovascular salvage were included in this single-centre prospective study. RESULTS: Altogether, 410 procedures were carried out in 232 patients. Overall, the incidence of thrombosis/occlusion (per patient-year) was 0.12 for fistulae and 0.9 for grafts. The anatomical success rate for EVS was 94% for fistulae and 92% for grafts. Primary patency rates for fistulae at 1, 6, 12, 24 and 36 months were 82, 64, 44, 34 and 26%, respectively, whereas secondary patency rates were 88, 84, 74, 69 and 61%, respectively. Primary patency rates for grafts at 1, 6 and 12 months were 50, 14 and 8%. The overall rate of complications was 6% with no incidence of symptomatic pulmonary embolism. In a Cox regression model, upper-arm location of fistula (HR 1.9, p = 0.04, n = 144) was associated with lower primary patency, whereas the presence of thrombosis was associated lower primary (HR 1.9, p = 0.004, n = 144) and secondary patency (HR 3.7, p < 0.001, n = 144). Aspirin therapy was associated with longer primary patency (HR 0.6, p = 0.02, n = 144) and secondary patency (HR 0.58, p = 0.08, n = 144). CONCLUSION: EVS is effective but longer-term outcomes are poor. Presence of thrombosis portends poor fistula survival and strategies for prevention need attention. Balloon maceration, our preferred declotting technique, is safe and the most cost-effective method. Aspirin therapy for patients presenting with failure of fistulae deserves further investigation.
Assuntos
Procedimentos Endovasculares/métodos , Terapia de Salvação/métodos , Dispositivos de Acesso Vascular/efeitos adversos , Idoso , Anastomose Arteriovenosa/patologia , Feminino , Seguimentos , Antebraço/irrigação sanguínea , Humanos , Masculino , Pessoa de Meia-Idade , Estudos Prospectivos , Diálise Renal/métodos , Trombectomia , Trombose/etiologia , Trombose/terapia , Falha de Tratamento , Resultado do TratamentoRESUMO
PURPOSE: The British Society of Interventional Radiology (BSIR) Inferior Vena Cava (IVC) Filter Registry was produced to provide an audit of current United Kingdom (UK) practice regarding placement and retrieval of IVC filters to address concerns regarding their safety. METHODS: The IVC filter registry is a web-based registry, launched by the BSIR on behalf of its membership in October 2007. This report is based on prospectively collected data from October 2007 to March 2011. This report contains analysis of data on 1,434 IVC filter placements and 400 attempted retrievals performed at 68 UK centers. Data collected included patient demographics, insertion and retrieval data, and patient follow-up. RESULTS: IVC filter use in the majority of patients in the UK follows accepted CIRSE guidelines. Filter placement is usually a low-risk procedure, with a low major complication rate (<0.5 %). Cook Gunther Tulip (560 filters: 39 %) and Celect (359 filters: 25 %) filters constituted the majority of IVC filters inserted, with Bard G2, Recovery filters, Cordis Trapease, and OptEase constituting most of the remainder (445 filters: 31 %). More than 96 % of IVC filters deployed as intended. Operator inexperience (<25 procedure) was significantly associated with complications (p < 0.001). Of the IVC filters initially intended for temporary placement, retrieval was attempted in 78 %. Of these retrieval was technically successful in 83 %. Successful retrieval was significantly reduced for implants left in situ for >9 weeks versus those with a shorter dwell time. New lower limb deep vein thrombosis (DVT) and/or IVC thrombosis was reported in 88 patients following filter placement, there was no significant difference of incidence between filter types. CONCLUSIONS: This registry report provides interventional radiologists and clinicians with an improved understanding of the technical aspects of IVC filter placement to help improve practice, and the potential consequences of IVC filter placement so that we are better able to advise patients. There is a significant learning curve associated with IVC filter insertion, and when a filter is placed with the intention of removal, procedures should be in place to avoid the patient being lost to follow-up.