RESUMEN
As is well known, dexmedetomidine (DEX) serves a neuroprotective role in cerebral ischemiareperfusion (CIR) injury, and microRNA (miR)199a has been reported to be associated with IR injury. However, the association between DEX and miR199a in CIR injury remains unknown. Thus, the aim of the present study was to verify whether the neuroprotective effect of DEX on cerebral ischemiareperfusion rats is associated with miR199a. A rat model of CIR was established, and the modified neurological severity score (mNSS) was evaluated. The effect of DEX on the pathological structure of the cerebral cortex in CIR rats was observed by hematoxylin and eosin and Nissl staining. Reverse transcriptionquantitative PCR was used to analyze the expression levels of miR199a in brain tissue following intracerebroventricular injection of miR199a antagomir. The coexpression of NeuN and microtubuleassociated proteins 1A/1B light chain 3B in the cerebral cortex was analyzed by immunofluorescence staining. Western blotting and immunohistochemistry were performed to analyze the expression of autophagyassociated proteins in the brain tissue. DEX inhibited the expression of miR199a, decreased the mNSS and improved pathological damage to the cerebral cortex. DEX also inhibited autophagy and expression levels of associated proteins and decreased nerve cell injury. In conclusion, DEX inhibited expression of miR199a and improved neurocyte injury induced by CIR.
Asunto(s)
Isquemia Encefálica/tratamiento farmacológico , Isquemia Encefálica/genética , Dexmedetomidina/farmacología , MicroARNs/genética , Fármacos Neuroprotectores/farmacología , Daño por Reperfusión/tratamiento farmacológico , Daño por Reperfusión/genética , Animales , Antígenos Nucleares/metabolismo , Beclina-1/metabolismo , Isquemia Encefálica/etiología , Isquemia Encefálica/patología , Caspasa 3/metabolismo , Corteza Cerebral/efectos de los fármacos , Corteza Cerebral/metabolismo , Dexmedetomidina/administración & dosificación , Modelos Animales de Enfermedad , Infarto de la Arteria Cerebral Media/complicaciones , Inyecciones , Masculino , MicroARNs/antagonistas & inhibidores , MicroARNs/metabolismo , Proteínas Asociadas a Microtúbulos/metabolismo , Proteínas del Tejido Nervioso/metabolismo , Neuronas/efectos de los fármacos , Fármacos Neuroprotectores/administración & dosificación , Proteínas de Unión al ARN/metabolismo , Ratas Sprague-Dawley , Daño por Reperfusión/etiología , Daño por Reperfusión/patologíaRESUMEN
BACKGROUND The aim of this study was to investigate the protective effect of ß-casomorphin-7 (ß-CM-7) and its possible mechanisms on acute kidney injury (AKI). MATERIAL AND METHODS Rats were randomly divided into a sham group, a cecal ligation and puncture (CLP) group, and a CLP+ß-CM-7 group. Kidney index, kidney function, and histopathology changes were assessed. The expression of neutrophil gelatinase-associated lipocalin (NGAL), kidney injury molecule-1 (Kim-1), nuclear factor of kappa light polypeptide gene enhancer in B-cells inhibitor alpha (IκBα), and p-IκBα in kidney tissues were detected by Western blotting. Inflammatory and oxidative stress factors were detected by ELISA kits. RESULTS The results showed that treatment with ß-CM-7 reduced the levels of creatinine (Cre), blood urea nitrogen (BUN), NGAL, and Kim-1 induced by CLP, weakening the pathological damage. In the CLP + ß-CM-7 group, the tumor necrosis factor-α (TNF-α) level and the DNA-binding activity of NF-κB p65 were significantly reduced and the interleukin-10 (IL-10) level was significantly increased compared with the CLP group. ß-CM-7 decreased the expression of p-IκBα/IκBα. In addition, ß-CM-7 increased the activity of superoxide dismutase (SOD) and decreased the level of malondialdehyde (MDA) in kidney tissue. CONCLUSIONS ß-CM-7 attenuated sepsis-induced AKI through reducing inflammation and oxidative stress and by inhibition of nuclear factor (NF)κB activities. This study provides a new therapeutic agent for attenuating sepsis-induced kidney injury.
Asunto(s)
Lesión Renal Aguda/fisiopatología , Endorfinas/farmacología , FN-kappa B/metabolismo , Fragmentos de Péptidos/farmacología , Lesión Renal Aguda/tratamiento farmacológico , Animales , Nitrógeno de la Urea Sanguínea , Ciego/patología , Moléculas de Adhesión Celular , Creatinina/metabolismo , Endorfinas/metabolismo , Inflamación/patología , Riñón/lesiones , Riñón/patología , Ligadura , Lipocalina 2 , Masculino , Malondialdehído/metabolismo , Inhibidor NF-kappaB alfa , FN-kappa B/efectos de los fármacos , Estrés Oxidativo , Fragmentos de Péptidos/metabolismo , Ratas , Ratas Sprague-Dawley , Sepsis/complicaciones , Sepsis/tratamiento farmacológico , Transducción de Señal/efectos de los fármacosRESUMEN
Neuroinflammation plays a key role in many neurodegenerative disorders, including postoperative cognitive decline (POCD). Growing evidence has demonstrated that activation of the peroxisome proliferator-activated receptor-γ (PPARγ) attenuates the inflammatory response and improves cognitive dysfunction associated with many neuropsychiatric disorders. We hypothesize that down-regulation of PPARγ is linked to neuroinflammation and the subsequent cognitive deficits observed in an animal model of POCD. In the present study, the POCD animal model was established by performing an exploratory laparotomy under isoflurane anesthesia in 20-month-old male C57BL/6 mice. Behavioral tests, inflammatory biomarkers, including tumor necrosis factor-α (TNF-α), interleukin-6 (IL-6), interleukin-1ß, ionized calcium-binding adaptor molecule-1 (IBA1)-positive cells, as well as glial fibrillary acidic protein (GFAP)-positive cells and brain-derived neurotrophic factor (BDNF), were measured. Herein, we showed that surgery induced profound impairment in cognition that was associated with significant decreases in PPARγ and BDNF expression, and significant increases in IL-1ß, IBA1-positive cells, and GFAP-positive cells in the hippocampus. As expected, the PPARγ agonist pioglitazone attenuated the surgery-induced inflammatory changes and rescued the associated cognitive impairment. However, these beneficial effects were abolished by the PPARγ specific antagonist GW9662, suggesting a pivotal role of the PPARγ pathway in the pathogenesis of POCD. Taken together, our results provide evidence that down-regulation of PPARγ may be involved in neuroinflammation and subsequent POCD, and suggest that activation of PPARγ by pioglitazone may represent a new way to prevent or treat POCD.