The miR-9-5p/CXCL11 pathway is a key target of hydrogen sulfide-mediated inhibition of neuroinflammation in hypoxic ischemic brain injury

We previously showed that hydrogen sulfide(H2S)has a neuroprotective effect in the context of hypoxic ischemic brain injury in neonatal mice.However,the precise mechanism underlying the role of H2S in this situation remains unclear.In this study,we used a neonatal mouse model of hypoxic ischemic brain injury and a lipopolysaccharide-stimulated BV2 cell model and found that treatment with L-cysteine,a H2S precursor,attenuated the cerebral infarction and cerebral atrophy induced by hypoxia and ischemia and increased the expression of miR-9-5p and cystathionineβsynthase(a major H2S synthetase in the brain)in the prefrontal cortex.We also found that an miR-9-5p inhibitor blocked the expression of cystathionineβsynthase in the prefrontal cortex in mice with brain injury caused by hypoxia and ischemia.Furthermore,miR-9-5p overexpression increased cystathionine-β-synthase and H2S expression in the injured prefrontal cortex of mice with hypoxic ischemic brain injury.L-cysteine decreased the expression of CXCL11,an miR-9-5p target gene,in the prefrontal cortex of the mouse model and in lipopolysaccharide-stimulated BV-2 cells and increased the levels of proinflammatory cytokines BNIP3,FSTL1,SOCS2 and SOCS5,while treatment with an miR-9-5p inhibitor reversed these changes.These findings suggest that H2S can reduce neuroinflammation in a neonatal mouse model of hypoxic ischemic brain injury through regulating the miR-9-5p/CXCL11 axis and restoringβ-synthase expression,thereby playing a role in reducing neuroinflammation in hypoxic ischemic brain injury.

Exosomes derived from microglia overexpressing miR-124-3p alleviate neuronal endoplasmic reticulum stress damage after repetitive mild traumatic brain injury

We previously reported that miR-124-3p is markedly upregulated in microglia-derived exosomes following repetitive mild traumatic brain injury.However,its impact on neuronal endoplasmic reticulum stress following repetitive mild traumatic brain injury remains unclear.In this study,we first used an HT22 scratch injury model to mimic traumatic brain injury,then co-cultured the HT22 cells with BV2 microglia expressing high levels of miR-124-3p.We found that exosomes containing high levels of miR-124-3p attenuated apoptosis and endoplasmic reticulum stress.Furthermore,luciferase reporter assay analysis confirmed that miR-124-3p bound specifically to the endoplasmic reticulum stress-related protein IRE1α,while an IRE1αfunctional salvage experiment confirmed that miR-124-3p targeted IRE1αand reduced its expression,thereby inhibiting endoplasmic reticulum stress in injured neurons.Finally,we delivered microglia-derived exosomes containing miR-124-3p intranasally to a mouse model of repetitive mild traumatic brain injury and found that endoplasmic reticulum stress and apoptosis levels in hippocampal neurons were significantly reduced.These findings suggest that,after repetitive mild traumatic brain injury,miR-124-3 can be transferred from microglia-derived exosomes to injured neurons,where it exerts a neuroprotective effect by inhibiting endoplasmic reticulum stress.Therefore,microglia-derived exosomes containing miR-124-3p may represent a novel therapeutic strategy for repetitive mild traumatic brain injury.

Chlorogenic acid alleviates hypoxic-ischemic brain injury in neonatal mice

Recent studies have shown that chlorogenic acid(CGA),which is present in coffee,has protective effects on the nervous system.However,its role in neonatal hypoxic-ischemic brain injury remains unclear.In this study,we established a newborn mouse model of hypoxic-ischemic brain injury using a modified Rice-Vannucci method and performed intraperitoneal injection of CGA.We found that CGA intervention effectively reduced the volume of cerebral infarct,alleviated cerebral edema,restored brain tissue structure after injury,and promoted axon growth in injured brain tissue.Moreover,CGA pretreatment alleviated oxygen-glucose deprivation damage of primary neurons and promoted neuron survival.In addition,changes in ferroptosis-related proteins caused by hypoxic-ischemic brain injury were partially reversed by CGA.Furthermore,CGA intervention upregulated the expression of the key ferroptosis factor glutathione peroxidase 4 and its upstream glutamate/cystine antiporter related factors SLC7A11 and SLC3A2.In summary,our findings reveal that CGA alleviates hypoxic-ischemic brain injury in neonatal mice by reducing ferroptosis,providing new ideas for the treatment of neonatal hypoxic-ischemic brain injury.

HOXA11-AS aggravates microglia-induced neuroinflammation after traumatic brain injury

Long noncoding RNAs(lnc RNAs)participate in many pathophysiological processes after traumatic brain injury by mediating neuroinflammation and apoptosis.Homeobox A11 antisense RNA(HOXA11-AS)is a member of the lnc RNA family that has been reported to participate in many inflammatory reactions;however,its role in traumatic brain injury remains unclear.In this study,we established rat models of traumatic brain injury using a weight-drop hitting device and injected LV-HOXA11-AS into the right lateral ventricle 2 weeks before modeling.The results revealed that overexpression of HOXA11-AS aggravated neurological deficits in traumatic brain injury rats,increased brain edema and apoptosis,promoted the secretion of proinflammatory factors interleukin-1β,interleukin-6,and tumor necrosis factorα,and promoted the activation of astrocytes and microglia.Microglia were treated with 100 ng/m L lipopolysaccharide for 24 hours to establish in vitro cell models,and then transfected with pc DNA-HOXA11-AS,mi R-124-3 p mimic,or sh-MDK.The results revealed that HOXA11-AS inhibited mi R-124-3 p expression and boosted MDK expression and TLR4-nuclear factor-κB pathway activation.Furthermore,lipopolysaccharide enhanced potent microglia-induced inflammatory responses in astrocytes.Forced overexpression of mi R-124-3 p or downregulating MDK repressed microglial activation and the inflammatory response of astrocytes.However,the mi R-124-3 p-mediated anti-inflammatory effects were reversed by HOXA11-AS.These findings suggest that HOXA11-AS can aggravate neuroinflammation after traumatic brain injury by modulating the mi R-124-3 p-MDK axis.This study was approved by the Animal Protection and Use Committee of Southwest Medical University(approval No.SMU-2019-042)on February 4,2019.

8-hydroxy-2-(di-n-propylamino)tetralin intervenes with neural cell apoptosis following diffuse axonal injury

Previous studies have reported a neuroprotective effect of 8-hydroxy-2-（di-n-propylamino）tetralin （8-OH-DPAT） against traumatic brain injury. In accordance with the Marmarou method, rat models of diffuse axonal injury were established. 8-OH-DPAT was intraperitoneally injected into model rats. 8-OH-DPAT treated rats maintained at constant temperature served as normal temperature controls TUNEL results revealed that neural cell swelling, brain tissue necrosis and cell apoptosis occurred around the injured tissue. Moreover, the number of Bax-, Bcl-2- and caspase-3-positive cells increased at 6 hours after diffuse axonal injury, and peaked at 24 hours. However, brain injury was attenuated, the number of apoptotic cells reduced, Bax and caspase-3 expression decreased, and Bcl-2 expression increased at 6, 12, 24, 72 and 168 hours after diffuse axonal injury in normal temperature control and in 8-OH-DPAT-intervention rats. The difference was most significant at 24 hours. All indices in 8-OH-DPAT-intervention rats were better than those in the constant temperature group. These results suggest that 8-OH-DPAT inhibits Bax and caspase-3 expression, increases Bcl-2 expression, and reduces neural cell apoptosis, resulting in neuroprotection against diffuse axonal injury. This effect is associated with a decrease in brain temperature.

5-lipoxygenase expression in a brain damage model induced by chronic oral administration of aluminum

A preliminary study has found that the 5-lipoxygenase inhibitor, caffeic acid, has a marked protective effect on acute brain injury induced by intracerebroventricular microinjection of aluminum. In this experiment, chronic brain injury and neuronal degeneration model was established in rats by chronic oral administration of aluminum, and then intervened using caffeic acid. Results showed that caffeic acid can downregulate chronic aluminum overload-induced 5-1ipoxygenase mRNA and protein expression, and repair the aluminum overload-induced hippocampal neuronal damage and spatial orientation impairment. It is suggested that direct intervention of 5-lipoxygenase expression has a neuroprotective role in the degeneration induced by chronic aluminum overload brain injury model.

1,6-二磷酸果糖对颅脑损伤炎症介质浓度的影响和预后观察

目的观察1,6-二磷酸果糖(FDP)对重度颅脑创伤患者炎症介质浓度变化及预后的影响。方法选择2008年4月～2010年6月入住笔者所在医院ICU的急性重症颅脑创伤患者100例,随机分为两组,两组均按常规重型颅脑创伤治疗原则处理,治疗组(50例)入院当日给予1,6-二磷酸果糖(FDP)10 g/d,静脉点滴,对照组(50例)按常规重型颅脑创伤治疗原则处理。两组入院1、3、5、7 d分别检测脑引流液和血清肿瘤坏死因子-α(TNF-α)、白细胞介素-1β(IL-1β)、IL-6、IL-10的浓度。统计两组患者GCS评分、APACHEⅡ评分、入住ICU时间、呼吸机使用时间及死亡率。结果两组入院时GCS评分、APACHEⅡ评分和TNF-α、IL-1β、IL-6、IL-10浓度比较差异无统计学意义(P>0.05)。治疗组3 d后炎症介质浓度即较对照组明显降低,比较差异有统计学意义(P<0.05)。治疗组GCS评分明显改善,呼吸机使用时间和ICU住院时间明显缩短,与对照组相比差异有统计学意义(P均<0.05),28 d死亡率有所降低,但差异无统计学意义(P>0.05)。结论早期使用FDP可以通过对神经细胞能量代谢的改善,稳定细胞内环境和膜功能,降低炎症介质浓度,以缩短呼吸机使用时间和ICU住院时间。

Dynamic changes in cerebral microcirculation and hypoxia in the early stages of diffuse axonal injury

This study demonstrated that damage to the cerebral microvasculature, the formation of microthrombi and swelling of vascular endothelial cells occur early and peak 12 hours after injury in a rat model of diffuse axonal injury. Moreover, these pathological changes were most evident in the cerebral cortex. Cerebral microcirculatory dysfunction peaked later and had a shorter duration than axonal injury. In addition, the radioactive imaging agent, 99Tcm-4, 9-diaza-2, 3, 10, 10- tetramethyldodecan-2, 11 -dione dioxime, was used to visualize the dynamic changes that occur in tissue with cerebral hypoxia. The results demonstrated that cerebral hypoxia occurs at an early stage in diffuse axonal injury. Cerebral hypoxia was evident 12 hours after injury and declined slightly 24 hours after injury, but was significantly higher than in the control group. The pathological changes that underpin microcirculatory dysfunction did not occur at the same time as axonal injury, but did occur simultaneously with neuronal injury. Cerebral hypoxia plays a key role in promoting the secondary brain injury that occurs after diffuse axonal injury.

颅脑损伤后同期颅骨修补及脑室-腹腔分流术的治疗体会

目的研究颅脑损伤后颅骨修补及脑室-腹腔分流术治疗体会。方法收集整理2006年1月～2010年3月本院收治的符合条件(颅脑损伤后颅骨缺损合并脑积水)的38例患者的临床资料,要求所有患者都有明确的致伤史和影像诊断。所有的患者都采用相同的手术方法(同期颅骨修补、脑室-腹腔分流术)。结果所有患者手术都获得成功,手术中没有出现死亡的现象,手术结束后8～14d时进行拆线,平均拆线时间为11d。手术结束2周时复查颅部CT发现,患者颅骨修补都固定牢固,脑室没有发现扩大的现象。结论颅脑缺损并发脑积水患者同期行颅骨修补术和脑室-腹腔分流术是一种有效可行的治疗方法,值得在临床推广。

1,6-二磷酸果糖治疗重型颅脑损伤96例

目的:观察1,6-二磷酸果糖治疗重型颅脑损伤的效果。方法:将重型颅脑损伤96例随机分为A、B两组,A组在常规治疗基础上加用1,6-二磷酸果糖,B组按常规治疗。按GCS评分进行临床观察。结果:A、B两组的抢救成功率分别为80.8％、68.2％,A组较B组GCS≤14分维持时间明显缩短。结论:1,6-二磷酸果糖能改善脑细胞的能量供应,提高脑细胞ATP浓度,减轻脑水肿,切断脑水肿的恶性循环,促进病人苏醒,较大幅度地提高重型颅脑损伤的抢救成功率,减少致死致残,并缩短受损脑组织恢复时间。

Study on the value of exogenous bFGF in the treatment of brain injury

Objective: To investigate the relation between necrosis and apoptosis in the hippocampus of exogenous bFGF on this process. Methods: With Marmarous method we produced a severe diffuse brain injury and studied the changes in the hippocampus by adapting a modified TdT mediated dUTP biotin nick end labeling (TUNEL) method. At the same time we observed the effect of exogenous bFGF on neuronal necrosis and apoptosis. Results: We found that together with cell necrosis there was an increase in the number of apoptotic neurons in the hippocampus CA2 3 sectors as early as 4 h after injury, with numbers reaching a maximum at 7 d. Exogenous bFGF resulted in a definite reduction in the amount of necrosis and apoptosis. Conclusions: Neuronal necrosis and apoptosis occur in combination after brain injury and that one of the causes may be the insufficience expression of the bFGF gene in the hippocampus after severe injury. Exogenous bFGF and similar substance may prove clinically useful after brain injury by reducing cell necrosis and apoptosis.

陆路交通事故中颅脑损伤1028例临床分析

本文对陆路交通事故所致颅脑损伤1028例作回顾性分析。总死亡率为21．79％诊断特别要注意询问受伤方式，仔细检查着力点、意识状态、瞳孔、呼吸和其他生命体征，辅以物理学检查包括颅脑摄片，CT扫描和脑血管造影等，以明确颅脑损伤类型。GlasgowComaScale（GCS）评分结合瞳孔改变是早期诊断及判断预后的一个有价值的指标。积极抗休克治疗和维持呼吸道通畅，对降低颅脑损伤病人的病死率和致残率有着重要意义。