大剂量维生素C和维生素E对急性颅脑损伤病人神经损伤、神经营养及氧化应激的影响

目的 探讨大剂量维生素C和维生素E对急性颅脑损伤病人神经损伤、神经营养及氧化应激的影响。方法 2018年1月至2018年11月前瞻性收集84例急性颅脑损伤并随机分为对照组（n=42,接受常规治疗）和观察组（n=42,接受大剂量维生素C和维生素E联合常规治疗）。治疗前、治疗后4、7 d,采用酶联免疫吸附法测定血清神经损伤指标[包括神经元特异性烯醇化酶（NSE）、S100蛋白、脑红蛋白（NGB）、泛素羧基末端水解酶L1（UCH-L1））、神经营养指标[包括神经营养因子-α（NTF-α）、脑源性神经营养因子（BDNF）、神经生长因子（NGF）、胰岛素样生长因子-1（IGF-I）,采用放射免疫沉淀法测定氧化应激指标[包括超氧化物歧化酶（SOD）、谷胱甘肽过氧化物酶（GPx）、过氧化氢酶（CAT）、丙二醛（MDA）、晚期氧化蛋白产物（AOPP）]。结果 治疗后4、7 d,两组血清NSE、S100B、NGB、UCH-L1、MDA、AOPP含量均显著降低（P<0.05）,血清NTF-α、BDNF、NGF、IGF-I、SOD、GPx、CAT含量均显著增高（P<0.05）,而且,观察组均明显优于对照组（P<0.05）。结论 大剂量维生素C和维生素E治疗能够减轻急性颅脑损伤病人神经损伤程度、氧化应激反应并改善神经营养状态。     

Therapeutic effect analysis of acute traumatic brain injuries

OBJECTIVE: To explore the factors determining the prognosis of acute traumatic brain injury (TBI) by retrospectively analysing the clinical data. METHODS: During the last 5 years, 2500 acute TBI cases were admitted into our department. We analysed the survival and mortality rates to evaluate the therapeutic outcome, the effect of emergency operation and the effect of intracranial pressure monitoring (ICPM) on the mortality of severe TBI. RESULTS: The mortalities of TBI in the severe (GCS3 weeks). Of all the patients who became deceased in this study, approximately 80% was due to intractable intracranial hypertension during the acute phase, nearly 20% was due to multiple organ failure (including the lungs, kidneys, and heart), and <2% was due to chronic body consumption. A different therapeutic focus must be emphasized in each of the three phases. Emergency operation and ICPM could decrease the mortality to 32 and 36%, respectively. CONCLUSION: Recognition of clinical features during different phases is the key for the neurosurgeon to establish an early and appropriate treatment (including emergency operation and ICPM) to reduce the mortality.     

Reversible visual evoked potential abnormalities in vitamin E deficiency

A patient with cystic fibrosis and cirrhosis developed a progressive neurological syndrome associated with ataxia, proximal weakness, and ophthalmoplegia. Profound deficiencies of vitamins A, D, and E were present. Visual acuity and results of retinal funduscopy were normal. The pattern reversal visual evoked potential was initially abnormal (P100 latency, 136 and 130 ms from left and right eyes, respectively) but became normal (less than 3 standard deviations from mean control P100 latency) over a two-month period when vitamin E was administered. This case documents a potentially reversible visual evoked potential abnormality in a visually asymptomatic patient with vitamin E deficiency.     

神经干细胞在创伤性脑损伤中的治疗作用

长期以来,人们一直认为中枢神经系统的神经细胞没有再生能力,损伤后死亡的细胞不能像上皮组织那样由再生的细胞替补.但是,近年来的研究发现,在中枢神经系统中也存在有干细胞,即神经干细胞(neural stem cells, NSCs).     

The potential role of mitochondria in pediatric traumatic brain injury

Mitochondria play a central role in cerebral energy metabolism, intracellular calcium homeostasis and reactive oxygen species generation and detoxification. Following traumatic brain injury (TBI), the degree of mitochondrial injury or dysfunction can be an important determinant of cell survival or death. Literature would suggest that brain mitochondria from the developing brain are very different from those from mature animals. Therefore, aspects of developmental differences in the mitochondrial response to TBI can make the immature brain more vulnerable to traumatic injury. This review will focus on four main areas of secondary injury after pediatric TBI, including excitotoxicity, oxidative stress, alterations in energy metabolism and cell death pathways. Specifically, we will describe what is known about developmental differences in mitochondrial function in these areas, in both the normal, physiologic state and the pathologic state after pediatric TBI. The ability to identify and target aspects of mitochondrial dysfunction could lead to novel neuroprotective therapies for infants and children after severe TBI.     

Therapeutic potential of brain-derived neurotrophic factor(BDNF) and a small molecular mimics of BDNF for traumatic brain injury

Traumatic brain injury(TBI) is a major health problem worldwide.Following primary mechanical insults,a cascade of secondary injuries often leads to further neural tissue loss.Thus far there is no cure to rescue the damaged neural tissue.Current therapeutic strategies primarily target the secondary injuries focusing on neuroprotection and neuroregeneration.The neurotrophin brain-derived neurotrophic factor(BDNF) has significant effect in both aspects,promoting neuronal survival,synaptic plasticity and neurogenesis.Recently,the flavonoid 7,8-dihydroxyflavone(7,8-DHF),a small Trk B agonist that mimics BDNF function,has shown similar effects as BDNF in promoting neuronal survival and regeneration following TBI.Compared to BDNF,7,8-DHF has a longer half-life and much smaller molecular size,capable of penetrating the blood-brain barrier,which makes it possible for non-invasive clinical application.In this review,we summarize functions of the BDNF/Trk B signaling pathway and studies examining the potential of BDNF and 7,8-DHF as a therapy for TBI.     

Therapeutic options in dementia

Dementia is the final common path of various pathogenetic mechanisms that may lead to a number of different clinical forms, with primary degenerative and vascular dementias accounting for more than 80% of cases. Dementia is a complex clinical condition that includes cognitive, personality, and behavioral changes. Therefore a therapeutic approach to dementia should be based from the beginning on a comprehensive intervention plan, both pharmacological and nonpharmacological. This should not be aimed at obtaining a complete (impossible) recover but at achieving the best day-to-day management of a chronic, progressive, disabling disease involving numerous domains and showing impairments with varying rates of progression. Deterioration in functional abilities of daily living has a major impact on the quality of life of those suffering from dementia, and this is a critical predictor for institutionalization. Increasingly necessary for optimizing intervention strategies are studies to: (a) measure changes in functional abilities over the course of dementia (namely Alzheimer's disease), (b) evaluate the relationship between functional abilities and cognition, and (c) quantify the effect of various therapeutic approaches on functional decline. Symptomatic drugs affecting cognitive abilities and psychoactive drugs for behavioral disturbances should be considered. For the cognitive domain positive results have been obtained with acetylcholinesterase inhibitors. Among the psychoactive drugs indicated for behavioral disorders, significant improvement in terms of both efficacy and tolerability can be expected from the use of new antipsychotic drugs.     

Lack of awareness and its impact in traumatic brain injury

Research suggests that up to 45% of individuals with moderate to severe TBI demonstrate reduced awareness or complete lack of awareness of their deficits. We describe dimensions and distinctions within the concept of lack of awareness - including whether an individual has knowledge of a specific deficit, the emotional response an individual manifests to a specific deficit, the ability to comprehend the impact or consequences of the deficit on day to day life, and how an individual explains or accounts for any deficits - and various methods of assessing for lack of awareness in this population. Finally, a review of the literature studying lack of awareness in TBI, its relationship to injury severity, the impact of lack of awareness on outcome, and intervention approaches is presented.     

The potential of neural transplantation for brain repair and regeneration following traumatic brain injury

Traumatic brain injury is a major health problem worldwide. Currently, there is no effective treatment to improve neural structural repair and functional recovery of patients in the clinic. Cell transplantation is a potential strategy to repair and regenerate the injured brain. This review article summarized recent de-velopment in cell transplantation studies for post-traumatic brain injury brain repair with varying types of cell sources. It also discussed the potential of neural transplantation to repair/promote recovery of the injured brain following traumatic brain injury.     

Insulin-like growth factor-1 and its derivatives: potential pharmaceutical application for ischemic brain injury

Brain ischemia induces the IGF-1 system in damaged regions, and exogenous administration of IGF-1 after injury is neuroprotective and improves long-term neurological function. The short treatment window can be extended by mild hypothermia, probably due to delayed apoptosis. Nevertheless, the poor central uptake of IGF-1 and its mitogenic potential preclude clinical application. The N-terminal tripeptide of IGF-1 (glycine-proline-glutamate, GPE) is neuroprotective after central administration. Central uptake of GPE is injury dependent, and it is rapidly degraded in the plasma. Intravenous infusion of GPE prevents brain injury and improves long-term functional recovery, with a broad effective dose range and a 3-7 hour therapeutic window. GPE does not interact with IGF receptors. G-2meth-PE, a GPE analogue with improved stability, has a prolonged plasma half life and is neuroprotective after ischemic injury. Neuroprotection by GPE and its analogue may involve modulating inflammation, promoting astrocytosis and inhibiting apoptosis, and the analogue may have a vascular effect. Cyclo-glycyl-proline (cGP) is an endogenous diketopiperazine possibly derived from GPE. Cyclic GP and its analogue cyclo-L-glycyl-L-2-allylproline (cG-2allylP) are neuroprotective after ischemic injury. cG-2allylP crosses the BBB independent of injury and remains detectable several hours after a single administration. Repeated peripheral administration of cG-2allyP improves somatosensory-motor function and long-term histological outcome.     

The potential of endogenous neurogenesis for brain repair and regeneration following traumatic brain injury

Traumatic brain injury （TBI） is the leading cause of death and disability of persons under 45 years old in the United States, affecting over 1.5 million individtials each year. It had been th ought that recovery from such injuries is severely limited due to the inability of the adult bra in to replace damaged neurons. However, recent studies indicate that the mature mammalian central nervous system （CNS） has the potential to replenish damaged neurons by proliferation and neuronal differentiation of adult neural stem/progenitor cells residing in the neurogenic regions in the brain. Furthermore, increasing evidence indicates that these endogenous stem/ progenitor cells may play regenerative and reparative roles in response to CNS injuries or diseases. In support of this notion, heightened levels of cell proliferation and neurogenesis have been ob- served in response to brain trauma or insults suggesting that the brain has the inherent potential to restore populations of damaged or destroyed neurons. This review will discuss the potential functions of adult neurogenesis and recent development of strategies aiming at harnessing this neurogenic capacity in order to repopulate and repair the injured brain.     

Oxidation of vitamin E and vitamin C and inhibition of brain mitochondrial oxidative phosphorylation by peroxynitrite

The effects of peroxynitrite (PN; product of the reaction between nitric oxide and superoxide) on mitochondrial respiration as well as oxidation of alpha-tocopherol and ascorbic acid were studied. Mitochondria were isolated from brain hemispheres of 4-month-old male Fisher rats by standard centrifugation procedures utilizing Ficoll gradients. Treatment of brain mitochondria with PN caused a concentration-dependent impairment of oxidative phosphorylation and depletion of the endogenous antioxidants alpha-tocopherol and ascorbic acid. PN-induced mitochondrial dysfunction was characterized by 1) decreases in state 3 respiration and oxidative phosphorylation, 2) loss of respiratory control [ratio of ADP-stimulated (state 3) to basal (state 4) respiration], and 3) uncoupling of oxidative phosphorylation. PN did not function as a pure uncoupler, insofar as the increase in state 4 respiration was accompanied by a larger decrease in state 3 respiration. This contrasts with the uncoupling action of the protonophore carbonyl cyanide m-chlorophenylhydrozone, which increases both state 3 and state 4 respiration. PN-induced reduction in respiratory control and oxidative phosphorylation closely paralleled the oxidation of membrane tocopherol and were preceded by loss of ascorbate. alpha-Tocopherol (the most potent biological lipid antioxidant) may have a unique role in protecting mitochondrial membranes from oxidative stress. The two antioxidant nutrients alpha-tocopherol and ascorbate (which interact with each other and glutathione) may be intimately involved in protecting mitochondria in situations in which excessive release of superoxide and nitric oxide occurs under normal and/or pathological conditions.     

Association of vitamin E and C supplement use with cognitive function and dementia in elderly men

OBJECTIVE: To determine whether use of vitamin E and C supplements protects against subsequent development of dementia and poor cognitive functioning. METHODS: The Honolulu-Asia Aging Study is a longitudinal study of Japanese-American men living in Hawaii. Data for this study were obtained from a subsample of the cohort interviewed in 1982, and from the entire cohort from a mailed questionnaire in 1988 and the dementia prevalence survey in 1991 to 1993. The subjects included 3,385 men, age 71 to 93 years, whose use of vitamin E and C supplements had been ascertained previously. Cognitive performance was assessed with the Cognitive Abilities Screening Instrument, and subjects were stratified into four groups: low, low normal, mid normal, and high normal. For the dementia analyses, subjects were divided into five mutually exclusive groups: AD (n = 47), vascular dementia (n = 35), mixed/other types of dementia (n = 50), low cognitive test scorers without diagnosed dementia (n = 254), and cognitively intact (n = 2,999; reference). RESULTS: In a multivariate model controlling for other factors, a significant protective effect was found for vascular dementia in men who had reported taking both vitamin E and C supplements in 1988 (odds ratio [OR], 0.12; 95% CI, 0.02 to 0.88). They were also protected against mixed/other dementia (OR, 0.31; 95% CI, 0.11 to 0.89). No protective effect was found for Alzheimer's dementia (OR, 1.81; 95% CI, 0.91 to 3.62). Among those without dementia, use of either vitamin E or C supplements alone in 1988 was associated significantly with better cognitive test performance at the 1991 to 1993 examination (OR, 1.25; 95% CI, 1.04 to 1.50), and use of both vitamin E and C together had borderline significance (OR, 1.18; 95% CI, 0.995 to 1.39). CONCLUSIONS: These results suggest that vitamin E and C supplements may protect against vascular dementia and may improve cognitive function in late life.     

载脂蛋白E基因多态性和急性脑损伤的关联研究

背景 急性脑损伤及其预后的影响因素是多方面的,如年龄、损伤程度与患者体质情况等,但其对外伤性脑损伤的预后结局仅作部分预测.近年来,有关遗传因素对脑损伤的影响和其预后的报道开始增多,关于载脂蛋白E在颅脑外伤预后中所起作用已引起人们的关注.在国外以往的研究中,关于载脂蛋白E基因多态性和脑损伤预后的研究结果也不相同.本研究初步探讨有关我国急性脑损伤及其预后与APOE基因之间的关系.方法 采用病例对照研究,选取94名车祸脑损伤患者和正常人作为研究对象,采用聚合酶链式反应(PCR)限制性片段长度多态性(RFLP)方法鉴定载脂蛋白E(APOE)基因型,探讨其等位基因及基因型同车祸脑损伤及其预后的关系.结果 车祸脑损伤患者中其等位基因ε2频率为0.1010,其基因型ε2/ε3的频率为0.1596明显高于正常人群ε2等位基因频率0.0050,及ε2/ε3基因型的频率0.0100(P＜0.05).同时,患者中,其未愈死亡组中ε2等位基因频率为0.1970及ε2/ε3基因型的频率为0.2727,明显高于好转治愈组ε2等位基因频率0.0508及ε2/ε3基因型的频率0.1017(P＜0.05),有统计学意义.结论 APOE基因的等位基因ε2基因型ε2/ε3初步可作为预示不良的预后参数.     

重型颅脑损伤与继发性脑梗死的预防及治疗

目的分析重型颅脑损伤继发脑梗死的原因，探讨重型颅脑损伤继发脑梗死的预防及治疗。方法回顾我院1996～2004年收治的重型颅脑损伤病人在救治中继发脑梗死的临床特点及预后。结果480例重型颅脑损伤的病人继发脑梗死42例．继发脑梗死的发生率占8．8％，其中成人组432例发生脑梗死34例，占7．9％；儿童组病例48例，发生继发脑梗死8例，占17％。儿童组病例继发脑梗死的例数明显高于成人组。结论重型颅脑损伤病人由于脑损伤的病理生理过程继发脑梗死外，在治疗过程中一些治疗因素也可引发脑梗死。脑梗死的发生加重脑组织的损伤，影响预后。     

脑损伤修复与功能重建干预策略

脑是人体的生命中枢,脑功能损害将严重影响人的生存与健康.脑损伤是造成脑功能损害的直接原因,具有发病率高,致死、致残率高的特点.无论是脑创伤、脑部缺血或出血,其共同病理特点都是神经元严重受损、缺失或死亡,造成神经功能障碍,患者出现偏瘫、失语、视力丧失、智力及意识障碍等症状,严重影响患者生活质量.在临床上,脑损伤主要包括颅脑损伤和卒中,前者因机械性损伤所致,后者因脑血管梗死或出血引起,其中缺血性卒中(缺血性脑损伤)最为多见,占80%[1].     

脑损伤修复与功能重建干预策略

脑是人体的生命中枢,脑功能损害将严重影响人的生存与健康.脑损伤是造成脑功能损害的直接原因,具有发病率高,致死、致残率高的特点.无论是脑创伤、脑部缺血或出血,其共同病理特点都是神经元严重受损、缺失或死亡,造成神经功能障碍,患者出现偏瘫、失语、视力丧失、智力及意识障碍等症状,严重影响患者生活质量.在临床上,脑损伤主要包括颅脑损伤和卒中,前者因机械性损伤所致,后者因脑血管梗死或出血引起,其中缺血性卒中(缺血性脑损伤)最为多见,占80%[1].