RESUMEN
Studies have found that Platonin has neuroprotective effect, but its molecular mechanism needs further study. We found that at the early stage of cerebral ischemia/reperfusion injury, Platonin treatment significantly reduced cerebral infarct lesions, improved neurological scores, and exerted neuroprotective effects. Our group has shown that NLRP3 inflammasomes activation is required to mediate neuronal injury during cerebral ischemia /reperfusion injury. The brain protective effect of Platonin is related to its ability to effectively regulate autophagy and NLRP3 inflammasomes-derived inflammation. Platonin treatment effectively induced autophagy (LC3II/I, p62) and reduced NLRP3 inflammasomes activation(NLRP3, cleaved-IL-1ßï¼cleaved-IL-18, cleaved-caspase1). However, 3-MA (15 mg/kg) treatment downregulated the inhibitory effect of Platonin on NLRP3 inflammasomes. We also studied the location of BNIP3 in Platonin-mediated neuroprotection and found that Platonin induced the expression of autophagic protein BNIP3 and enhanced the co-immunoprecipitation of BNIP3 with LC3, and double-labeled immunofluorescence also showed enhanced co-localization of BNIP3 with LC3. Finally, si-BNIP3 transfection attenuated the co localization of BNIP3 with LC3, decreased the autophagy activity to a certain extent and blocked the inhibition of NLRP3 inflammasomes-derived inflammation by Platonin. This study demonstrated that Platonin may play a neuroprotection role in cerebral I / R injury by inhibiting NLRP3 inflammasomes activation through upregulating autophagy via BNIP3 / LC3 pathway.
Asunto(s)
Autofagia/efectos de los fármacos , Inflamasomas/efectos de los fármacos , Proteínas de la Membrana/efectos de los fármacos , Proteínas Asociadas a Microtúbulos/efectos de los fármacos , Proteínas Mitocondriales/efectos de los fármacos , Proteína con Dominio Pirina 3 de la Familia NLR/efectos de los fármacos , Fármacos Neuroprotectores/farmacología , Daño por Reperfusión/tratamiento farmacológico , Tiazoles/farmacología , Animales , Modelos Animales de Enfermedad , RatasRESUMEN
Traumatic brain injury (TBI) is one of the leading causes of mortality worldwide and leads to persistent cognitive, sensory, motor dysfunction, and emotional disorders. TBI-caused primary injury results in structural damage to brain tissues. Following the primary injury, secondary injuries which are accompanied by neuroinflammation, microglial activation, and additional cell death subsequently occur. Platonin, a cyanine photosensitizing dye, has been used to treat trauma, ulcers, and some types of acute inflammation. In the present study, the neuroprotective effects of platonin against TBI were explored in a controlled cortical impact (CCI) injury model in mice. Treatment with platonin (200 µg/kg) significantly reduced the neurological severity score, general locomotor activity, and anxiety-related behavior, and improved the rotarod performance of CCI-injured mice. In addition, platonin reduced lesion volumes, the expression of cleaved caspase-3, and microglial activation in TBI-insulted brains. Platonin also suppressed messenger (m)RNA levels of caspase-3, caspase-1, cyclooxygenase-2, tumor necrosis factor-α, interleukin-6, and interleukin-1ß. On the other hand, free radical production after TBI was obviously attenuated in platonin-treated mice. Treatment with platonin exhibited prominent neuroprotective properties against TBI in a CCI mouse model through its anti-inflammatory, anti-apoptotic, and anti-free radical capabilities. This evidence collectively indicates that platonin may be a potential therapeutic medicine for use with TBIs.
Asunto(s)
Antiinflamatorios/uso terapéutico , Lesiones Traumáticas del Encéfalo/tratamiento farmacológico , Fármacos Neuroprotectores/uso terapéutico , Tiazoles/uso terapéutico , Animales , Caspasas/genética , Caspasas/metabolismo , Corteza Cerebral/metabolismo , Ciclooxigenasa 2/genética , Ciclooxigenasa 2/metabolismo , Fuerza de la Mano , Interleucinas/genética , Interleucinas/metabolismo , Locomoción , Masculino , Ratones , Ratones Endogámicos C57BL , Microglía/metabolismo , Microglía/patología , Factor de Necrosis Tumoral alfa/genética , Factor de Necrosis Tumoral alfa/metabolismoRESUMEN
BACKGROUND: Vascular hyporeactivity contributes to hemodynamic alterations and circulatory failure in severe sepsis. Among the identified mechanisms, inflammation and oxidative stress are the most crucial ones in mediating the development of vascular hyporeactivity induced by sepsis. Platonin, a photosensitive dye and an antioxidant, possesses potent antiinflammation effects. We elucidated whether platonin could mitigate vascular hyporeactivity of thoracic aorta in septic rats. MATERIAL AND METHODS: Adult male Sprague-Dawley rats were randomized to receive sham operation (Sham), Sham plus platonin (100 µg/kg), cecal ligation and puncture (CLP), or CLP plus platonin (10, 50, or 100 µg/kg) and designated as the Sham, P, CLP, CLP + P(10), CLP + P(50), and CLP + P(100) group, respectively (n = 6 in each group). After maintaining for 12 hours, surviving rats were euthanized and thoracic aorta was isolated and vascular reactivity of aortic rings was determined. RESULTS: Vascular reactivity induced by vasoconstrictors phenylephrine and angiotensin II of the Sham and the P groups (n = 6 in both groups) were similar, whereas vascular reactivity of the CLP group (n = 5) were significantly lower than those of the Sham group (both P < 0.001). Of note, vascular reactivity induced by phenylephrine and angiotensin II of the CLP + P(10) group (n = 5) and the CLP group were not significantly different. In contrast, vascular reactivity induced by phenylephrine and angiotensin II of the CLP + P(50) and the CLP + P(100) groups (n = 6 in both groups) were significantly higher than those of the CLP group (phenylephrine: P = 0.024 and 0.017; angiotensin II: P = 0.031 and 0.036). CONCLUSION: Platonin could mitigate vascular hyporeactivity of thoracic aorta in septic rats.