RESUMEN
Despite the great search for an effective approach to minimize secondary injury in spinal cord injury (SCI) setting, there have been limited advances. Roflumilast is a selective inhibitor of phosphodiesterase 4 with potent anti-inflammatory properties. Here, we sought to explore Roflumilast efficacy in the improvement of locomotor and sensory deficits of SCI. In an animal setting, 50 male rats were randomly assigned to five groups: an SCI group receiving Placebo, three SCI groups receiving Roflumilast at the doses of 0.25, 0.5, and 1 mg/kg prior to T9 vertebra laminectomy, and a sham-operated group. Locomotor, mechanical, and thermal activities were evaluated for 28 days. At the end of the study, spinal cord samples were taken to assess the relative ratio of microglial subtypes, including M1 and M2, histopathological changes, levels of pro-inflammatory (TNF-α and IL-1ß) and anti-inflammatory (IL-10) biomarkers, and cAMP level. Repeated measure analysis revealed significant effect for time-treatment interaction on locomotion [F (24, 270) = 280.7, p < 0.001], thermal sensitivity [F (16, 180) = 4.35, p < 0.001], and mechanical sensitivity [F (16, 180) = 7.96, p < 0.001]. As expected, Roflumilast significantly increased the expression of spinal cAMP. H&E staining exhibited lesser histopathological disruptions in Roflumilast-treated rodents. We also observed a significant reduction in the M1/M2 ratio (p values < 0.001) as well as in pro-inflammatory biomarkers following the administration of Roflumilast to the injured rats. Furthermore, IL-10 level was increased in rodents receiving 1 mg/kg of the reagent. In conclusion, the increased spinal cAMP following Roflumilast therapy might attenuate neuroinflammation via altering microglial activity; therefore, it could be considered as an alternative therapeutic agent for SCI complications.
Asunto(s)
Agnosia/metabolismo , Aminopiridinas/uso terapéutico , Benzamidas/uso terapéutico , Microglía/metabolismo , Inhibidores de Fosfodiesterasa 4/uso terapéutico , Traumatismos de la Médula Espinal/metabolismo , Médula Espinal/metabolismo , Tabes Dorsal/metabolismo , Agnosia/etiología , Agnosia/prevención & control , Animales , AMP Cíclico/metabolismo , Fosfodiesterasas de Nucleótidos Cíclicos Tipo 4/metabolismo , Ciclopropanos/uso terapéutico , Modelos Animales de Enfermedad , Humanos , Masculino , Microglía/patología , Inflamación Neurogénica , Ratas , Médula Espinal/patología , Traumatismos de la Médula Espinal/complicaciones , Traumatismos de la Médula Espinal/tratamiento farmacológico , Tabes Dorsal/etiología , Tabes Dorsal/prevención & controlRESUMEN
AIMS: We previously reported that minocycline attenuates acute brain injury and inflammation after focal cerebral ischemia, and this is partly mediated by inhibition of 5-lipoxygenase (5-LOX) expression. Here, we determined the protective effect of minocycline on chronic ischemic brain injury and its relation with the inhibition of 5-LOX expression after focal cerebral ischemia. MAIN METHODS: Focal cerebral ischemia was induced by 90 min of middle cerebral artery occlusion followed by reperfusion for 36 days. Minocycline (45 mg/kg) was administered intraperitoneally 2h and 12h after ischemia and then every 12h for 5 days. Sensorimotor function was evaluated 1-28 days after ischemia and cognitive function was determined 30-35 days after ischemia. Thereafter, infarct volume, neuron density, astrogliosis, and 5-LOX expression in the brain were determined. KEY FINDINGS: Minocycline accelerated the recovery of sensorimotor and cognitive functions, attenuated the loss of neuron density, and inhibited astrogliosis in the boundary zone around the ischemic core, but did not affect infarct volume. Minocycline significantly inhibited the increased 5-LOX expression in the proliferated astrocytes in the boundary zone, and in the macrophages/microglia in the ischemic core. SIGNIFICANCE: Minocycline accelerates functional recovery in the chronic phase of focal cerebral ischemia, which may be partly associated with the reduction of 5-LOX expression.
Asunto(s)
Isquemia Encefálica/tratamiento farmacológico , Encéfalo/efectos de los fármacos , Inhibidores de la Lipooxigenasa , Minociclina/uso terapéutico , Fármacos Neuroprotectores/uso terapéutico , Agnosia/etiología , Agnosia/prevención & control , Animales , Astrocitos/efectos de los fármacos , Astrocitos/enzimología , Astrocitos/patología , Encéfalo/enzimología , Encéfalo/patología , Isquemia Encefálica/enzimología , Isquemia Encefálica/fisiopatología , Recuento de Células , Proliferación Celular/efectos de los fármacos , Enfermedad Crónica , Inmunohistoquímica , Inyecciones Intraperitoneales , Macrófagos/efectos de los fármacos , Macrófagos/enzimología , Macrófagos/patología , Masculino , Aprendizaje por Laberinto/efectos de los fármacos , Microglía/efectos de los fármacos , Microglía/enzimología , Microglía/patología , Minociclina/administración & dosificación , Minociclina/farmacología , Neuronas/efectos de los fármacos , Neuronas/enzimología , Neuronas/patología , Fármacos Neuroprotectores/administración & dosificación , Fármacos Neuroprotectores/farmacología , Ratas , Ratas Sprague-Dawley , Recuperación de la FunciónRESUMEN
OBJECTIVE: To examine the association between caffeine intake, cognitive decline, and incident dementia in a community-based sample of subjects aged 65 years and over. METHODS: Participants were 4,197 women and 2,820 men from a population-based cohort recruited from three French cities. Cognitive performance, clinical diagnosis of dementia, and caffeine consumption were evaluated at baseline and at 2 and 4 year follow-up. RESULTS: Caffeine consumption is associated with a wide range of sociodemographic, lifestyle, and clinical variables which may also affect cognitive decline. Multivariate mixed models and multivariate adjusted logistic regression indicated that women with high rates of caffeine consumption (over three cups per day) showed less decline in verbal retrieval (OR = 0.67, CI = 0.53, 0.85), and to a lesser extent in visuospatial memory (OR = 0.82, CI = 0.65, 1.03) over 4 years than women consuming one cup or less. The protective effect of caffeine was observed to increase with age (OR = 0.73, CI = 0.53, 1.02 in the age range 65 to 74; OR = 0.3, CI = 0.14, 0.63 in the range 80+). No relation was found between caffeine intake and cognitive decline in men. Caffeine consumption did not reduce dementia risk over 4 years. CONCLUSIONS: The psychostimulant properties of caffeine appear to reduce cognitive decline in women without dementia, especially at higher ages. Although no impact is observed on dementia incidence, further studies are required to ascertain whether caffeine may nonetheless be of potential use in prolonging the period of mild cognitive impairment in women prior to a diagnosis of dementia.