Background:Subarachnoid hemorrhage(SAH),an acute cerebrovascular accident,features with its high death and disability rate.Sirtuin3(SIRT3)is a NAD+dependent deacetylase which mainly located in mitochondria.Reduced SIR...Background:Subarachnoid hemorrhage(SAH),an acute cerebrovascular accident,features with its high death and disability rate.Sirtuin3(SIRT3)is a NAD+dependent deacetylase which mainly located in mitochondria.Reduced SIRT3 function was indicated to involve in many disorders of central nervous system.Herein,we aimed to explore the neuroprotective effects of SIRT3 on SAH and to furtherly explore the underlying mechanisms.Methods:Adult C57BL/6 J male mice(8-10 weeks)were used to establish SAH models.The pharmacological agonist of SIRT3,Honokiol(HKL),was injected in an intraperitoneal manner(10 mg/kg)immediately after the operation.Brain edema and neurobehavioral score were assessed.Nissl staining and FJC staining were used to evaluate the extent of neuronal damage.The changes of mitochondria morphology were observed with transmission electron microscopy.Western blot was used for analyzing the protein level of SIRT3 and the downstream signaling molecules.Result:SIRT3 was downregulated after SAH,and additional treatment of SIRT3 agonist HKL alleviated brain edema and neurobehavioral deficits after SAH.Additionally,electron microscopy showed that HKL significantly alleviated the morphological damage of mitochondria induced by SAH.Further studies showed that HKL could increase the level of mitochondrial fusion protein Mfn1 and Mfn2,thus maintaining(mitochondrial morphology),protecting mitochondrial function and promoting neural survival.While,additional Compound C(CC)treatment,a selective AMPK inhibitor,abolished these protective effects.Conclusions:Activation of SIRT3 protects against SAH injury through improving mitochondrial fusion in an AMPK dependent manner.展开更多
基金This work was supported by grants from the State Key Program of National Natural Science Foundation of China 81630027(to Dr.Qu)the National Natural Science Foundation of China 81571215(to Dr.Qu)the Chang Jiang Scholar Program of China(to Dr.Qu).
文摘Background:Subarachnoid hemorrhage(SAH),an acute cerebrovascular accident,features with its high death and disability rate.Sirtuin3(SIRT3)is a NAD+dependent deacetylase which mainly located in mitochondria.Reduced SIRT3 function was indicated to involve in many disorders of central nervous system.Herein,we aimed to explore the neuroprotective effects of SIRT3 on SAH and to furtherly explore the underlying mechanisms.Methods:Adult C57BL/6 J male mice(8-10 weeks)were used to establish SAH models.The pharmacological agonist of SIRT3,Honokiol(HKL),was injected in an intraperitoneal manner(10 mg/kg)immediately after the operation.Brain edema and neurobehavioral score were assessed.Nissl staining and FJC staining were used to evaluate the extent of neuronal damage.The changes of mitochondria morphology were observed with transmission electron microscopy.Western blot was used for analyzing the protein level of SIRT3 and the downstream signaling molecules.Result:SIRT3 was downregulated after SAH,and additional treatment of SIRT3 agonist HKL alleviated brain edema and neurobehavioral deficits after SAH.Additionally,electron microscopy showed that HKL significantly alleviated the morphological damage of mitochondria induced by SAH.Further studies showed that HKL could increase the level of mitochondrial fusion protein Mfn1 and Mfn2,thus maintaining(mitochondrial morphology),protecting mitochondrial function and promoting neural survival.While,additional Compound C(CC)treatment,a selective AMPK inhibitor,abolished these protective effects.Conclusions:Activation of SIRT3 protects against SAH injury through improving mitochondrial fusion in an AMPK dependent manner.
