BACKGROUND Prolonged cardiac arrest(CA)produces extensive neuronal death and microglial proliferation and activation resulting in neuro-cognitive disabilities.Among other potential mechanisms,microglia have been impli...BACKGROUND Prolonged cardiac arrest(CA)produces extensive neuronal death and microglial proliferation and activation resulting in neuro-cognitive disabilities.Among other potential mechanisms,microglia have been implicated as triggers of neuronal death after hypoxic-ischemic insults.Minocycline is neuroprotective in some brain ischemia models,either by blunting the microglial response or by a direct effect on neurons.AIM To improve survival,attenuate neurologic deficits,neuroinflammation,and histological damage after ventricular fibrillation(VF)CA in rats.METHODS Adult male isoflurane-anesthetized rats were subjected to 6 min VF CA followed by 2 min resuscitation including chest compression,epinephrine,bicarbonate,and defibrillation.After return of spontaneous circulation(ROSC),rats were randomized to two groups:(1)Minocycline 90 mg/kg intraperitoneally(i.p.)at 15 min ROSC,followed by 22.5 mg/kg i.p.every 12 h for 72 h;and(2)Controls,receiving the same volume of vehicle(phosphate-buffered saline).The rats were kept normothermic during the postoperative course.Neurologic injury was assessed daily using Overall Performance Category(OPC;1=normal,5=dead)and Neurologic Deficit Score(NDS;0%=normal,100%=dead).Rats were sacrificed at 72 h.Neuronal degeneration(Fluoro-Jade C staining)and microglia proliferation(anti-Iba-1 staining)were quantified in four selectively vulnerable brain regions(hippocampus,striatum,cerebellum,cortex)by three independent reviewers masked to the group assignment.RESULTS In the minocycline group,8 out of 14 rats survived to 72 h compared to 8 out of 19 rats in the control group(P=0.46).The degree of neurologic deficit at 72 h[median,(interquartile range)]was not different between survivors in minocycline vs controls:OPC 1.5(1-2.75)vs 2(1.25-3),P=0.442;NDS 12(2-20)vs 17(7-51),P=0.328)or between all studied rats.The number of degenerating neurons(minocycline vs controls,mean±SEM:Hippocampus 58±8 vs 76±8;striatum 121±43 vs 153±32;cerebellum 20±7 vs 22±8;cortex 0±0 vs 0±0)or proliferating microglia(hippocampus 157±15 vs 193 cortex 0±0 vs 0±0;16;striatum 150±22 vs 161±23;cerebellum 20±7 vs 22±8;cortex 26±6 vs 31±7)was not different between groups in any region(all P>0.05).Numerically,there were approximately 20%less degenerating neurons and proliferating microglia in the hippocampus and striatum in the minocycline group,with a consistent pattern of histological damage across the individual regions of interest.CONCLUSION Minocycline did not improve survival and failed to confer substantial benefits on neurologic function,neuronal loss or microglial proliferation across multiple brain regions in our model of rat VF CA.展开更多
基金Supported by the Laerdal Foundation for Acute Medicine to Janata Athe Erwin Schroedinger Stipend by the Austrian Science Fund(#J 2931-818)to Janata A+3 种基金Medical Student Anesthesia Research Foundation Award from the International Anesthesia Research Society to Wilson CDSeed Grant from The Department of Anesthesiology,University of Pittsburgh to Drabek TStarter Grant from the Society of Cardiovascular Anesthesiologists to Drabek Tthe Laerdal Foundation for Acute Medicine to Drabek T
文摘BACKGROUND Prolonged cardiac arrest(CA)produces extensive neuronal death and microglial proliferation and activation resulting in neuro-cognitive disabilities.Among other potential mechanisms,microglia have been implicated as triggers of neuronal death after hypoxic-ischemic insults.Minocycline is neuroprotective in some brain ischemia models,either by blunting the microglial response or by a direct effect on neurons.AIM To improve survival,attenuate neurologic deficits,neuroinflammation,and histological damage after ventricular fibrillation(VF)CA in rats.METHODS Adult male isoflurane-anesthetized rats were subjected to 6 min VF CA followed by 2 min resuscitation including chest compression,epinephrine,bicarbonate,and defibrillation.After return of spontaneous circulation(ROSC),rats were randomized to two groups:(1)Minocycline 90 mg/kg intraperitoneally(i.p.)at 15 min ROSC,followed by 22.5 mg/kg i.p.every 12 h for 72 h;and(2)Controls,receiving the same volume of vehicle(phosphate-buffered saline).The rats were kept normothermic during the postoperative course.Neurologic injury was assessed daily using Overall Performance Category(OPC;1=normal,5=dead)and Neurologic Deficit Score(NDS;0%=normal,100%=dead).Rats were sacrificed at 72 h.Neuronal degeneration(Fluoro-Jade C staining)and microglia proliferation(anti-Iba-1 staining)were quantified in four selectively vulnerable brain regions(hippocampus,striatum,cerebellum,cortex)by three independent reviewers masked to the group assignment.RESULTS In the minocycline group,8 out of 14 rats survived to 72 h compared to 8 out of 19 rats in the control group(P=0.46).The degree of neurologic deficit at 72 h[median,(interquartile range)]was not different between survivors in minocycline vs controls:OPC 1.5(1-2.75)vs 2(1.25-3),P=0.442;NDS 12(2-20)vs 17(7-51),P=0.328)or between all studied rats.The number of degenerating neurons(minocycline vs controls,mean±SEM:Hippocampus 58±8 vs 76±8;striatum 121±43 vs 153±32;cerebellum 20±7 vs 22±8;cortex 0±0 vs 0±0)or proliferating microglia(hippocampus 157±15 vs 193 cortex 0±0 vs 0±0;16;striatum 150±22 vs 161±23;cerebellum 20±7 vs 22±8;cortex 26±6 vs 31±7)was not different between groups in any region(all P>0.05).Numerically,there were approximately 20%less degenerating neurons and proliferating microglia in the hippocampus and striatum in the minocycline group,with a consistent pattern of histological damage across the individual regions of interest.CONCLUSION Minocycline did not improve survival and failed to confer substantial benefits on neurologic function,neuronal loss or microglial proliferation across multiple brain regions in our model of rat VF CA.
