Perinatal hypoxic-ischemic encephalopathy is a leading cause of neonatal death and disability.Therapeutic hypothermia significantly reduces death and major disability associated with hypoxic-ischemic encephalopathy;ho...Perinatal hypoxic-ischemic encephalopathy is a leading cause of neonatal death and disability.Therapeutic hypothermia significantly reduces death and major disability associated with hypoxic-ischemic encephalopathy;however,many infants still experience lifelong disabilities to movement,sensation and cognition.Clinical guidelines,based on strong clinical and preclinical evidence,recommend therapeutic hypothermia should be started within 6 hours of birth and continued for a period of 72 hours,with a target brain temperature of 33.5 ±0.5℃ for infants with moderate to severe hypoxic-ischemic encephalopathy.The clinical guidelines also recommend that infants be re warmed at a rate of 0.5℃ per hour,but this is not based on strong evidence.There are no randomized controlled trials investigating the optimal rate of rewarming after therapeutic hypothermia for infants with hypoxic-ischemic encephalopathy.Preclinical studies of rewarming are conflicting and results were confounded by treatment with sub-optimal durations of hypothermia.In this review,we evaluate the evidence for the optimal start time,duration and depth of hypothermia,and whether the rate of rewarming after treatment affects brain injury and neurological outcomes.展开更多
目的观察半胱氨酸天冬氨酸蛋白酶(caspase)-3在新生儿缺氧缺血性脑病(NHIE)小鼠模型脑组织中表达的变化。方法选取7 d CD1新生小鼠30只,按随机数字表法分为假手术组(9只)和NHIE模型组(21只),后者制备NHIE动物模型。用TTC染色法检查2组...目的观察半胱氨酸天冬氨酸蛋白酶(caspase)-3在新生儿缺氧缺血性脑病(NHIE)小鼠模型脑组织中表达的变化。方法选取7 d CD1新生小鼠30只,按随机数字表法分为假手术组(9只)和NHIE模型组(21只),后者制备NHIE动物模型。用TTC染色法检查2组的脑组织梗死面积;DAPI染色观察脑组织病理变化;原位末端标记技术检测脑组织细胞凋亡;荧光免疫组化法检测脑组织中caspase-3表达水平。结果假手术组小鼠脑组织未见梗死灶,脑组织细胞排列致密整齐,TUNEL阳性细胞数[(18.57±4.98)个]和caspase-3阳性细胞数[(9.17±2.14)个]明显低于NHIE模型组的TUNEL阳性细胞数[(209.57±41.27)个]和caspase-3阳性细胞数[(63.33±16.22)个];与假手术组相比,NHIE模型组小鼠的右侧半球可见梗死灶,脑组织细胞大量坏死脱落、周围组织间隙变大。结论 NHIE模型鼠出现的脑组织损伤可能与caspase-3表达增加、脑组织细胞凋亡增加有关。展开更多
Perinatal encephalopathy remains a major cause of disability, such as cerebral palsy. Therapeutic hypo- thermia is now well established to partially reduce risk of disability in late preterm/term infants. However, new...Perinatal encephalopathy remains a major cause of disability, such as cerebral palsy. Therapeutic hypo- thermia is now well established to partially reduce risk of disability in late preterm/term infants. However, new and complementary therapeutic targets are needed to further improve outcomes. There is increasing evidence that glia play a key role in neural damage after hypoxia-ischemia and infection/inflammation. In this review, we discuss the role of astrocytic gap junction （connexin） hemichannels in the spread of neural injury after hypoxia-ischemia and/or infection/inflammation. Potential mechanisms of hemichannel medi- ated injury likely involve impaired intraceUular calcium handling, loss of blood-brain barrier integrity and release of adenosine triphosphate （ATP） resulting in over-activation of purinergic receptors. We propose the hypothesis that inflammation-induced opening of connexin hemichannels is a key regulating event that initiates a vicious cycle of excessive ATP release, which in turn propagates activation of purinergic receptors on microglia and astrocytes. This suggests that developing new neuroprotective strategies for preterm infants will benefit from a detailed understanding of glial and connexin hemichannel responses.展开更多
基金supported by The Health Research Council of New Zealand(grant No.16/003,17/601)the Marsden Fund(grant No.17-UOA232)a Sir Charles Hercus Fellowship from the Health Research Council of New Zealand(grant No.16/003)
文摘Perinatal hypoxic-ischemic encephalopathy is a leading cause of neonatal death and disability.Therapeutic hypothermia significantly reduces death and major disability associated with hypoxic-ischemic encephalopathy;however,many infants still experience lifelong disabilities to movement,sensation and cognition.Clinical guidelines,based on strong clinical and preclinical evidence,recommend therapeutic hypothermia should be started within 6 hours of birth and continued for a period of 72 hours,with a target brain temperature of 33.5 ±0.5℃ for infants with moderate to severe hypoxic-ischemic encephalopathy.The clinical guidelines also recommend that infants be re warmed at a rate of 0.5℃ per hour,but this is not based on strong evidence.There are no randomized controlled trials investigating the optimal rate of rewarming after therapeutic hypothermia for infants with hypoxic-ischemic encephalopathy.Preclinical studies of rewarming are conflicting and results were confounded by treatment with sub-optimal durations of hypothermia.In this review,we evaluate the evidence for the optimal start time,duration and depth of hypothermia,and whether the rate of rewarming after treatment affects brain injury and neurological outcomes.
文摘目的观察半胱氨酸天冬氨酸蛋白酶(caspase)-3在新生儿缺氧缺血性脑病(NHIE)小鼠模型脑组织中表达的变化。方法选取7 d CD1新生小鼠30只,按随机数字表法分为假手术组(9只)和NHIE模型组(21只),后者制备NHIE动物模型。用TTC染色法检查2组的脑组织梗死面积;DAPI染色观察脑组织病理变化;原位末端标记技术检测脑组织细胞凋亡;荧光免疫组化法检测脑组织中caspase-3表达水平。结果假手术组小鼠脑组织未见梗死灶,脑组织细胞排列致密整齐,TUNEL阳性细胞数[(18.57±4.98)个]和caspase-3阳性细胞数[(9.17±2.14)个]明显低于NHIE模型组的TUNEL阳性细胞数[(209.57±41.27)个]和caspase-3阳性细胞数[(63.33±16.22)个];与假手术组相比,NHIE模型组小鼠的右侧半球可见梗死灶,脑组织细胞大量坏死脱落、周围组织间隙变大。结论 NHIE模型鼠出现的脑组织损伤可能与caspase-3表达增加、脑组织细胞凋亡增加有关。
基金supported by the Health Research Council of New Zealand(grant 17/601)the Auckland Medical Research Foundation+1 种基金National Health and Medical Research Council CJ Martin Early Career Fellowship(grant No.1090890 to RG)the Victorian Government Operational Infrastructure Support Program
文摘Perinatal encephalopathy remains a major cause of disability, such as cerebral palsy. Therapeutic hypo- thermia is now well established to partially reduce risk of disability in late preterm/term infants. However, new and complementary therapeutic targets are needed to further improve outcomes. There is increasing evidence that glia play a key role in neural damage after hypoxia-ischemia and infection/inflammation. In this review, we discuss the role of astrocytic gap junction （connexin） hemichannels in the spread of neural injury after hypoxia-ischemia and/or infection/inflammation. Potential mechanisms of hemichannel medi- ated injury likely involve impaired intraceUular calcium handling, loss of blood-brain barrier integrity and release of adenosine triphosphate （ATP） resulting in over-activation of purinergic receptors. We propose the hypothesis that inflammation-induced opening of connexin hemichannels is a key regulating event that initiates a vicious cycle of excessive ATP release, which in turn propagates activation of purinergic receptors on microglia and astrocytes. This suggests that developing new neuroprotective strategies for preterm infants will benefit from a detailed understanding of glial and connexin hemichannel responses.
