Challenges in developing therapeutic strategies for mild neonatal encephalopathy

There is increasing evidence that infants with mild neonatal encephalopathy(NE) have significant risks of mortality, brain injury and adverse neurodevelopmental outcomes. In the era of therapeutic hypothermia, infants need to be diagnosed within 6 hours of birth, corresponding with the window of opportunity for treatment of moderate to severe NE, compared to the retrospective grading over 2 to 3 days, typically with imaging and formal electroencephalographic assessment in the pre-hypothermia era. This shift in diagnosis may have increased the apparent prevalence of brain damage and poor neurological outcomes seen in infants with mild NE in the era of hypothermia. Abnormal short term outcomes observed in infants with mild NE include seizures, abnormal neurologic examination at discharge, abnormal brain magnetic resonance imaging and difficulty feeding. At 2 to 3 years of age, mild NE has been associated with an increased risk of autism, language and cognitive deficits. There are no approved treatment strategies for these infants as they were not included in the initial randomized controlled trials for therapeutic hypothermia. However, there is already therapeutic creep, with many centers treating infants with mild NE despite the limited evidence for its safety and efficacy. The optimal duration of treatment and therapeutic window of opportunity for effective treatment need to be specifically established for mild NE as the evolution of injury is likely to be slower, based on preclinical data. Randomized controlled trials of therapeutic hypothermia for infants with mild NE are urgently required to establish the safety and efficacy of treatment. This review will examine the evidence for adverse outcomes after mild NE and dissect some of the challenges in developing therapeutic strategies for mild NE, before analyzing the evidence for therapeutic hypothermia and other strategies for treatment of these infants.     

Neuroprotective mechanisms and translational potential of therapeutic hypothermia in the treatment of ischemic stroke

Stroke is a leading cause of disability and death,yet effective treatments for acute stroke has been very limited.Thus far,tissue plasminogen activator has been the only FDA-approved drug for thrombolytic treatment of ischemic stroke patients,yet its application is only applicable to less than 4–5% of stroke patients due to the narrow therapeutic window( 4.5 hours after the onset of stroke) and the high risk of hemorrhagic transformation.Emerging evidence from basic and clinical studies has shown that therapeutic hypothermia,also known as targeted temperature management,can be a promising therapy for patients with different types of stroke.Moreover,the success in animal models using pharmacologically induced hypothermia(PIH) has gained increasing momentum for clinical translation of hypothermic therapy.This review provides an updated overview of the mechanisms and protective effects of therapeutic hypothermia,as well as the recent development and findings behind PIH treatment.It is expected that a safe and effective hypothermic therapy has a high translational potential for clinical treatment of patients with stroke and other CNS injuries.     

Neuron-specific enolase in cerebrospinal fluid as a biomarker of brain damage in infants with hypoxic-ischemic encephalopathy

Neonatal encephalopathy resulting from an asphyxial episode occurring perinatally is a major cause of death and of permanent neurological disabilities worldwide. Therapeutic hypothermia(TH) started within 6 hours of life and maintained for 72 hours is now well established as standard treatment for infants with moderate-to-severe hypoxicischemic encephalopathy(HIE).     

Neuroprotective and neuroregenerative potential of pharmacologically-induced hypothermia with D-alanine D-leucine enkephalin in brain injury

Neurovascular disorders, such as traumatic brain injury and stroke, persist as leading causes of death and disability – thus, the search for novel therapeutic approaches for these disorders continues. Many hurdles have hindered the translation of effective therapies for traumatic brain injury and stroke primarily because of the inherent complexity of neuropathologies and an inability of current treatment approaches to adapt to the unique cell death pathways that accompany the disorder symptoms. Indeed, developing potent treatments for brain injury that incorporate dynamic and multiple disorder-engaging therapeutic targets are likely to produce more effective outcomes than traditional drugs. The therapeutic use of hypothermia presents a promising option which may fit these criteria. While regulated temperature reduction has displayed great promise in preclinical studies of brain injury, clinical trials have been far less consistent and associated with adverse effects, especially when hypothermia is pursued via systemic cooling. Accordingly, devising better methods of inducing hypothermia may facilitate the entry of this treatment modality into the clinic. The use of the delta opioid peptide D-alanine D-leucine enkephalin(DADLE) to pharmacologically induce temperature reduction may offer a potent alternative, as DADLE displays both the ability to cause temperature reduction and to confer a broad profile of other neuroprotective and neuroregenerative processes. This review explores the prospect of DADLE-mediated hypothermia to treat neurovascular brain injuries, emphasizing the translational steps necessary for its clinical translation.     

Mild hypothermia combined with neural stem cell transplantation for hypoxic-ischemic encephalopathy： neuroprotective effects of combined therapy

Neural stem cell transplantation is a useful treatment for ischemic stroke, but apoptosis often occurs in the hypoxic-ischemic environment of the brain after cell transplantation. In this study, we determined if mild hypothermia(27–28°C) can increase the survival rate of neural stem cells(1.0 × 105 /μL) transplanted into neonatal mice with hypoxic-ischemic encephalopathy. Long-term effects on neurological functioning of the mice were also examined. After mild hypothermia combined with neural stem cell transplantation, we observed decreased expression levels of inflammatory factor nuclear factor-kappa B and apoptotic factor caspase-3, reduced cerebral infarct volumes, increased survival rate of transplanted cells, and marked improvements in neurological function. Thus, the neuroprotective effects of mild hypothermia combined with neural stem cell transplantation are superior to those of monotherapy. Moreover, our findings suggest that the neuroprotective effects of mild hypothermia combined with neural stem cell transplantation on hypoxic-ischemic encephalopathy are achieved by anti-inflammatory and anti-apoptotic mechanisms.     

Interleukin-1:an important target for perinatal neuroprotection?

Perinatal inflammation is a significant risk factor for lifelong neurodevelopmental impairments such as cerebral palsy.Extensive clinical and preclinical evidence links the severity and pattern of perinatal inflammation to impaired maturation of white and grey matters and reduced brain growth.Multiple pathways are involved in the pathogenesis of perinatal inflammation.However,studies of human and experimental perinatal encephalopathy have demonstrated a strong causative link between perinatal encephalopathy and excessive production of the pro-inflammatory effector cytokine interleukin-1.In this review,we summarize clinical and preclinical evidence that underpins interleukin-1 as a critical factor in initiating and perpatuating systemic and central nervous system inflammation and subsequent perinatal brain injury.We also highlight the important role of endogenous interleukin-1 receptor antagonist in mitigating interleukin-1-driven neuroinflammation and tissue damage,and summarize outcomes from clinical and mechanistic animal studies that establish the commercially available interleukin-1 receptor antagonist,anakinra,as a safe and effective therapeutic intervention.We reflect on the evidence supporting clinical translation of interleukin-1 receptor antagonist for infants at the greatest risk of perinatal inflammation and impaired neurodevelopment,and suggest a path to advance interleukin-1 receptor antagonist along the translational path for perinatal neuroprotection.     

High mobility group box-1 protein as a therapeutic target in perinatal hypoxic-ischemic brain injury

Perinatal hypoxic-ischemic(HI)brain injury is a leading cause of morbidity and longstanding disability in newborns(Millar et al.,2017).Improved neonatal intensive care has increased survival in infants with pregnancy and birth related complications.Nonetheless,many surviving neonates exhibit neurological abnormalities that can persist throughout life(Millar et al.,2017).Early neuroprotective strategies have the potential to improve neurological outcomes and attenuate developmental delay in neonates.However,hypothermia is the only currently approved intervention for HI encephalopathy in fullterm infants,which is only partially protective(Millar et al.,2017).Findings in preterm and full-term infants suggest that elevations in proinflammatory cytokines are important in the pathogenesis of HI-related brain injury(Millar et al.,2017).The high mobility group box-1(HMGB1),a representative damage associatedmolecular pattern(DAMP)protein,has been reported to be implicated in a variety of brain related inflammatory diseases including traumatic brain injury,epilepsy,and stroke(Nishibori et al.,2019).Anti-HMGB1 therapies have gained increasing interest to treat inflammation related disorders in the brain(Nishibori et al.,2019).However,there is a paucity of information regarding the pathology of HMGB1 in HI-related brain injury during the perinatal period.The current perspective discusses the potential contributions of HMGB1 to HI-related brain injury during the perinatal period and also addresses the potential of HMGB1 as a therapeutic target of the brain injury.Furthermore,this perspective emphasizes the potential for combinational therapeutics for hypothermia with anti-HMGB1 monoclonal antibodies(mAb)in perinatal HI brain injury.     

Neuroprotective effects of bloodletting atJing points combined with mild induced hypothermia in acute severe traumatic brain injury

Bloodletting at Jing points has been used to treat coma in traditional Chinese medicine. Mild induced hypothermia has also been shown to have neuroprotective effects. However, the therapeutic effects of bloodletting at Jing points and mild induced hypothermia alone are limited. Therefore, we investigated whether combined treatment might have clinical effectiveness for the treatment of acute severe traumatic brain injury. Using a rat model of traumatic brain injury, combined treatment substantially alleviated cerebral edema and bloodbrain barrier dysfunction. Furthermore, neurological function was ameliorated, and cellular necrosis and the inflammatory response were lessened. These findings suggest that the combined effects of bloodletting at Jing points(20 μL, twice a day, for 2 days) and mild induced hypothermia(6 hours) are better than their individual effects alone. Their combined application may have marked neuroprotective effects in the clinical treatment of acute severe traumatic brain injury.     

Effect of erythropoietin combined with hypothermia on serum tau protein levels and neurodevelopmental outcome in neonates with hypoxic-ischemic encephalopathy

Although hypothermia therapy is effective to treat neonatal hypoxic-ischemic encephalopathy, many neonatal patients die or suffer from severe neurological dysfunction. Erythropoietin is considered one of the most promising neuroprotective agents. We hypothesized that erythropoietin combined with hypothermia will improve efficacy of neonatal hypoxic-ischemic encephalopathy treatment. In this study, 41 neonates with moderate/severe hypoxic-ischemic encephalopathy were randomly divided into a control group (hypothermia alone for 72 hours, n = 20) and erythropoietin group (hypothermia + erythropoietin 200 IU/kg for 10 days, n = 21). Our results show that compared with the control group, serum tau protein levels were lower and neonatal behavioral neurological assessment scores higher in the eryth-ropoietin group at 8 and 12 days. However, neurodevelopmental outcome was similar between the two groups at 9 months of age. Thesefindings suggest that erythropoietin combined with hypothermia reduces serum tau protein levels and improves neonatal behavioral neu-rology outcome but does not affect long-term neurodevelopmental outcome.     

Hyperbaric oxygen treatment promotes neural stem cell proliferation in the subventricular zone of neonatal rats with hypoxic-ischemic brain damage

Hyperbaric oxygen therapy for the treatment of neonatal hypoxic-ischemic brain damage has been used clinically for many years, but its effectiveness remains controversial. In addition, the mechanism of this potential neuroprotective effect remains unclear. This study aimed to investigate the influence of hyperbaric oxygen on the proliferation of neural stem cells in the subventricular zone of neonatal Sprague-Dawley rats (7 days old) subjected to hypoxic-ischemic brain damage. Six hours after modeling, rats were treated with hyperbaric oxygen once daily for 7 days. Immunohistochemistry revealed that the number of 5-bromo-2′-deoxyuridine positive and nestin positive cells in the subventricular zone of neonatal rats increased at day 3 after hypoxic-ischemic brain damage and peaked at day 5. After hyperbaric oxygen treatment, the number of 5-bromo-2′- deoxyuridine positive and nestin positive cells began to increase at day 1, and was significantly higher than that in normal rats and model rats until day 21. Hematoxylin-eosin staining showed that hyperbaric oxygen treatment could attenuate pathological changes to brain tissue in neonatal rats, and reduce the number of degenerating and necrotic nerve cells. Our experimental findings indicate that hyperbaric oxygen treatment enhances the proliferation of neural stem cells in the subventricular zone of neonatal rats with hypoxic-ischemic brain damage, and has therapeutic potential for promoting neurological recovery following brain injury.     

Expression of Clock genes in the pineal glands of newborn rats with hypoxic-ischemic encephalopathy

Clock genes are involved in circadian rhythm regulation, and surviving newborns with hypoxic-ischemic encephalopathy may present with sleep-wake cycle reversal. This study aimed to determine the expression of the clock genes Clock and Bmal1, in the pineal gland of rats with hypoxic-ischemic brain damage. Results showed that levels of Clock mRNA were not significantly changed within 48 hours after cerebral hypoxia and ischemia. Expression levels of CLOCK and BMAL1 protein were significantly higher after 48 hours. The levels of Bmal1 mRNA reached a peak at 36 hours, but were significantly reduced at 48 hours. Experimental findings indicate that Clock and Bmal1 genes were indeed expressed in the pineal glands of neonatal rats. At the initial stage (within 36 hours) of hypoxic-ischemic brain damage, only slight changes in the expression levels of these two genes were detected, followed by significant changes at 36-48 hours. These changes may be associated with circadian rhythm disorder induced by hypoxic-ischemic brain damage.     

重型颅脑损伤患者亚低温治疗的临床研究

Objective To compare the prognoses of patients with severe brain injury receiving mild hypothermia and normothermia interventions and evaluate the brain protective effect of mild hypothermia. Methods Seventy-six patients with severe head injury (Glaseow Coma Score≤8) were divided into mild hypothermia group (36 cases) and normothermia group (40 cases). The patients in the normothermia group were managed with measures for reducing the intracranial pressure and controlling the hemorrhage and gastric acid, with also administration of neurotrophic treatment and nutritional support. In addition to these conventional interventions, the patients in mild hypothermia group received mild hypothermia treatment administered using a water blanket to reduce the core body temperature and brain temperature to 32-34℃, which was maintained for 3-14 days as needed. Results The patients receiving mild hypothermia therapy had significantly improved prognosis in comparison with those in normothermia group (P<0.05). Conclusion Mild hypothermia treatment has brain protective effect and improves the prognosis of patients with severe brain injury.     

重型颅脑损伤患者亚低温治疗的临床研究

Objective To compare the prognoses of patients with severe brain injury receiving mild hypothermia and normothermia interventions and evaluate the brain protective effect of mild hypothermia. Methods Seventy-six patients with severe head injury (Glaseow Coma Score≤8) were divided into mild hypothermia group (36 cases) and normothermia group (40 cases). The patients in the normothermia group were managed with measures for reducing the intracranial pressure and controlling the hemorrhage and gastric acid, with also administration of neurotrophic treatment and nutritional support. In addition to these conventional interventions, the patients in mild hypothermia group received mild hypothermia treatment administered using a water blanket to reduce the core body temperature and brain temperature to 32-34℃, which was maintained for 3-14 days as needed. Results The patients receiving mild hypothermia therapy had significantly improved prognosis in comparison with those in normothermia group (P<0.05). Conclusion Mild hypothermia treatment has brain protective effect and improves the prognosis of patients with severe brain injury.     

重型颅脑损伤患者亚低温治疗的临床研究

Objective To compare the prognoses of patients with severe brain injury receiving mild hypothermia and normothermia interventions and evaluate the brain protective effect of mild hypothermia. Methods Seventy-six patients with severe head injury (Glaseow Coma Score≤8) were divided into mild hypothermia group (36 cases) and normothermia group (40 cases). The patients in the normothermia group were managed with measures for reducing the intracranial pressure and controlling the hemorrhage and gastric acid, with also administration of neurotrophic treatment and nutritional support. In addition to these conventional interventions, the patients in mild hypothermia group received mild hypothermia treatment administered using a water blanket to reduce the core body temperature and brain temperature to 32-34℃, which was maintained for 3-14 days as needed. Results The patients receiving mild hypothermia therapy had significantly improved prognosis in comparison with those in normothermia group (P<0.05). Conclusion Mild hypothermia treatment has brain protective effect and improves the prognosis of patients with severe brain injury.     

重型颅脑损伤患者亚低温治疗的临床研究

Objective To compare the prognoses of patients with severe brain injury receiving mild hypothermia and normothermia interventions and evaluate the brain protective effect of mild hypothermia. Methods Seventy-six patients with severe head injury (Glaseow Coma Score≤8) were divided into mild hypothermia group (36 cases) and normothermia group (40 cases). The patients in the normothermia group were managed with measures for reducing the intracranial pressure and controlling the hemorrhage and gastric acid, with also administration of neurotrophic treatment and nutritional support. In addition to these conventional interventions, the patients in mild hypothermia group received mild hypothermia treatment administered using a water blanket to reduce the core body temperature and brain temperature to 32-34℃, which was maintained for 3-14 days as needed. Results The patients receiving mild hypothermia therapy had significantly improved prognosis in comparison with those in normothermia group (P<0.05). Conclusion Mild hypothermia treatment has brain protective effect and improves the prognosis of patients with severe brain injury.     

重型颅脑损伤患者亚低温治疗的临床研究

Objective To compare the prognoses of patients with severe brain injury receiving mild hypothermia and normothermia interventions and evaluate the brain protective effect of mild hypothermia. Methods Seventy-six patients with severe head injury (Glaseow Coma Score≤8) were divided into mild hypothermia group (36 cases) and normothermia group (40 cases). The patients in the normothermia group were managed with measures for reducing the intracranial pressure and controlling the hemorrhage and gastric acid, with also administration of neurotrophic treatment and nutritional support. In addition to these conventional interventions, the patients in mild hypothermia group received mild hypothermia treatment administered using a water blanket to reduce the core body temperature and brain temperature to 32-34℃, which was maintained for 3-14 days as needed. Results The patients receiving mild hypothermia therapy had significantly improved prognosis in comparison with those in normothermia group (P<0.05). Conclusion Mild hypothermia treatment has brain protective effect and improves the prognosis of patients with severe brain injury.     

Clinical observations on treating thalamic hemorrhage into ventricle

Objective To investigate the treatment of severe patients with thalamic hemorrhage into ventricles. Method 12 cases with thalamic hemorrhage into ventricular system were studied, 9 male, 3 femaie, with a mean age of 64 years. All patients were unconscious. The average size of hematoma was 65 ml. Besides general comprehensive care, they received ventricular puncture for ingertion of drainage tape into the cerebral ventricle, infusion with urokinase for clotlysis, lumbar puncture for letting out some cerebrospinal fluid and injection of dexemethasone. Result The patients' clinical symptoms and signs were obviously improved.. The CT scan also demonstrated that hematomas were removed faster. The effective rate was 83.3 per cent, with a murtality of 16.7 per cent. Cohclusion This kind of therapy can increase the clinical cure rate. decrease the disability rate and death rete.     

重型颅脑损伤患者亚低温治疗的临床研究

Objective To compare the prognoses of patients with severe brain injury receiving mild hypothermia and normothermia interventions and evaluate the brain protective effect of mild hypothermia. Methods Seventy-six patients with severe head injury (Glaseow Coma Score≤8) were divided into mild hypothermia group (36 cases) and normothermia group (40 cases). The patients in the normothermia group were managed with measures for reducing the intracranial pressure and controlling the hemorrhage and gastric acid, with also administration of neurotrophic treatment and nutritional support. In addition to these conventional interventions, the patients in mild hypothermia group received mild hypothermia treatment administered using a water blanket to reduce the core body temperature and brain temperature to 32-34℃, which was maintained for 3-14 days as needed. Results The patients receiving mild hypothermia therapy had significantly improved prognosis in comparison with those in normothermia group (P<0.05). Conclusion Mild hypothermia treatment has brain protective effect and improves the prognosis of patients with severe brain injury.