RESUMO
INTRODUCTION: Beta-blockers (BB) after traumatic brain injury (TBI) accelerate cognitive recovery weeks after injury. BBs also inhibit leukocyte (LEU) mobilization to the penumbral blood brain barrier (BBB) 48-h after TBI. It is unclear whether the latter effects persist longer and accompany the persistent cognitive improvement. We hypothesized that 2 wk of BB after TBI reduce penumbral BBB leukocyte-endothelial interactions. METHODS: Thirty CD1 mice underwent TBI (controlled cortical impact, CCI: 6 m/s velocity, 1 mm depth, 3 mm diameter) or sham craniotomy followed by i.p. saline (NS) or propranolol (1, 2, 4 mg/kg) every 12 h for 14 d. On day 14, in vivo pial intravital microscopy visualized endothelial-LEU interactions and BBB microvascular leakage. Day 14 Garcia neurological test scores and animal weights were compared to preinjury levels reflecting concurrent clinical recovery. RESULTS: LEU rolling was greatest in CCI + NS when compared to sham (P = 0.03). 4 mg/kg propranolol significantly reduced postCCI LEU rolling down to uninjured sham levels (P = 0.03). LEU adhesion and microvascular permeability were not impacted at this time interval. Untreated injured animals (CCI + NS) scored lower Garcia neurological test and greater weight loss recovery at day 14 when compared to preinjury (P < 0.05). Treatment with higher doses of propranolol (2, 4 mg/kg), improved weight loss recovery (P < 0.001). CONCLUSIONS: LEU rolling alone, was influenced by BB therapy 14 d after TBI suggesting that certain penumbral neuroinflammatory cellular effects of BB therapy after TBI persist up to 2 wk after injury potentially explaining the pervasive beneficial effects of BBs on learning and memory.
Assuntos
Edema Encefálico , Lesões Encefálicas Traumáticas , Animais , Camundongos , Barreira Hematoencefálica , Lesões Encefálicas Traumáticas/complicações , Lesões Encefálicas Traumáticas/tratamento farmacológico , Modelos Animais de Doenças , Leucócitos , Propranolol/farmacologia , Propranolol/uso terapêutico , Redução de PesoRESUMO
BACKGROUND: Tranexamic acid (TXA) given early, but not late, after traumatic brain injury (TBI) appears to improve survival. This may be partly related to TXA-driven profibrinolysis and increased leukocyte (LEU)-mediated inflammation when administered late post-injury. We hypothesized that early TXA (1 hour post-TBI), blunts penumbral, blood-brain barrier (BBB) leukocyte-endothelial cell (LEU-EC) interactions and microvascular permeability, in vivo when compared with late administration (24 hours post-TBI). METHODS: CD1 male mice (n = 35) were randomized to severe TBI (injury by controlled cortical impact; injury: velocity, 6 m/s; depth, 1 mm; diameter, 3 mm) or sham craniotomy followed by intravenous saline (placebo) at 1 hour, or TXA (30 mg/kg) at 1 hour or 24 hours. At 48 hours, in vivo pial intravital microscopy visualized live penumbral LEU-EC interactions and BBB microvascular fluorescent albumin leakage. Neuroclinical recovery was assessed by the Garcia Neurological Test (motor, sensory, reflex, and balance assessments) and body weight loss recovery at 1 and 2 days after injury. Analysis of variance with Bonferroni correction assessed intergroup differences ( p < 0.05). RESULTS: One-hour, but not 24-hour, TXA improved Garcia Neurological Test performance on day 1 post-TBI compared with placebo. Both 1 hour and 24 hours TXA similarly improved day 1 weight loss recovery, but only 1 hour TXA significantly improved weight loss recovery on day 2 compared with placebo ( p = 0.04). No intergroup differences were found in LEU rolling or adhesion between injured animal groups. Compared with untreated injured animals, only TXA at 1 hour reduced BBB permeability. CONCLUSION: Only early post-TBI TXA consistently improves murine neurological recovery. Tranexamic acid preserves BBB integrity but only when administered early. This effect appears independent of LEU-EC interactions and demonstrates a time-sensitive effect that supports only early TXA administration.
Assuntos
Antifibrinolíticos , Edema Encefálico , Lesões Encefálicas Traumáticas , Ácido Tranexâmico , Animais , Masculino , Camundongos , Antifibrinolíticos/farmacologia , Antifibrinolíticos/uso terapêutico , Barreira Hematoencefálica , Edema Encefálico/prevenção & controle , Lesões Encefálicas Traumáticas/tratamento farmacológico , Ácido Tranexâmico/farmacologia , Ácido Tranexâmico/uso terapêutico , Redução de PesoRESUMO
BACKGROUND: Traumatic brain injury (TBI) is accompanied by a hyperadrenergic catecholamine state that can cause penumbral neuroinflammation. Prospective human studies demonstrate improved TBI survival with beta blockade (bb), although mechanisms remain unclear. We hypothesized that deranged post-TBI penumbral blood brain barrier (BBB) leukocyte mobilization and permeability are improved by bb. METHODS: CD1 male mice (n = 64) were randomly assigned to severe TBI-controlled cortical impact: 6 m/s velocity, 1 mm depth, 3 mm diameter-or sham craniotomy, and IP injection of either saline or propranolol (1, 2, or 4 mg/kg) every 12 hours for 2 days. At 48 hours, in vivo pial intravital microscopy visualized live endothelial-leukocyte (LEU) interactions and BBB microvascular leakage. Twice daily clinical recovery was assessed by regaining of lost body weight and the Garcia Neurological Test (motor, sensory, reflex, balance assessments). Brain edema was determined by hemispheric wet-to-dry ratios. RESULTS: Propranolol after TBI reduced both in vivo LEU rolling and BBB permeability in a dose-dependent fashion compared with no treatment (p < 0.001). Propranolol reduced cerebral edema (p < 0.001) and hastened recovery of lost body weight at 48 hours (p < 0.01). Compared with no treatment (14.9 ± 0.2), 24-hour Garcia Neurologic Test scores were improved with 2 (15.8 ± 0.2, p = 0.02) and 4 (16.1 ± 0.1, p = 0.001) but not with 1 mg/kg propranolol. CONCLUSION: Propranolol administration reduces post-TBI LEU mobilization and microvascular permeability in the murine penumbral neurovasculature and leads to reduced cerebral edema. This is associated with hastened recovery of post-TBI weight loss and neurologic function with bb treatment. Dose-dependent effects frame a mechanistic relationship between bb and improved human outcomes after TBI.
Assuntos
Edema Encefálico , Lesões Encefálicas Traumáticas , Encefalopatia Traumática Crônica , Animais , Feminino , Masculino , Camundongos , Barreira Hematoencefálica , Peso Corporal , Edema Encefálico/etiologia , Edema Encefálico/prevenção & controle , Lesões Encefálicas Traumáticas/complicações , Lesões Encefálicas Traumáticas/tratamento farmacológico , Modelos Animais de Doenças , Leucócitos , Permeabilidade , Propranolol/farmacologia , Propranolol/uso terapêutico , Estudos ProspectivosRESUMO
AIMS: Type 1 and type 2 diabetes, complicated with renal disease, have a significantly higher incidence in the Canary Islands than in mainland Spain and other European countries. Present-day Canarian inhabitants consist of a mixed population with North African indigenous and European colonizer ancestors who have rapidly evolved from a rural to an urban life style. The aim of this work was to assess the possible role of genetic and environmental factors on diabetes-related end-stage renal disease incidence in the Canary Islands. RESULTS: For both types of diabetes there is an ethnic susceptibility increased by diabetes family history. Whereas the Y-chromosome does not play a significant role, mitochondrial DNA (mtDNA) haplogroup differences point to a maternal origin for this ethnic predisposition, confirming susceptible and protective effects for haplogroups J and T, respectively. In addition, urban life style seems to be an additional risk factor for type 1 diabetes. CONCLUSIONS: The maternal ethnic predisposition to diabetes complicated with kidney disease detected in the Canary Islands signals mtDNA and X-chromosome markers as the best candidates to uncover the genetic predisposition to this disease.