Traumatic brain injury (TBI) is a principal cause of death and disability worldwide. Melatonin, a hormone made by the pineal gland, is known to have anti-inflammatory and antioxidant properties. In ...this study, using a weight-drop model of TBI, we investigated the protective effects of ramelteon, a melatonin MT1/MT2 receptor agonist, and its underlying mechanisms of action. Administration of ramelteon (10 mg/kg) daily at 10:00 a.m. alleviated TBI-induced early brain damage on day 3 and long-term neurobehavioral deficits on day 28 in C57BL/6 mice. Ramelteon also increased the protein levels of interleukin (IL)-10, IL-4, superoxide dismutase (SOD), glutathione, and glutathione peroxidase and reduced the protein levels of IL-1β, tumor necrosis factor, and malondialdehyde in brain tissue and serum on days 1, 3, and 7 post-TBI. Similarly, ramelteon attenuated microglial and astrocyte activation in the perilesional cortex on day 3. Furthermore, ramelteon decreased Keap 1 expression, promoted nuclear factor erythroid 2-related factor 2 (Nrf2) nuclear accumulation, and increased levels of downstream proteins, including SOD-1, heme oxygenase-1, and NQO1 on day 3 post-TBI. However, in Nrf2 knockout mice with TBI, ramelteon did not decrease the lesion volume, neuronal degeneration, or myelin loss on day 3; nor did it mitigate depression-like behavior or most motor behavior deficits on day 28. Thus, timed ramelteon treatment appears to prevent inflammation and oxidative stress via the Nrf2-antioxidant response element pathway and might represent a potential chronotherapeutic strategy for treating TBI.
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•Ramelteon provided marked neuroprotection after TBI.•Ramelteon activated the Nrf2-ARE pathway in the brain after TBI.•The protection by ramelteon was partially lost in Nrf2-/- mice with TBI.
Opinion statement
Autophagy is a physiological process that occurs in normal tissues. Under external environmental pressure or internal environmental changes, cells can digest part of their contents ...through autophagy in order to reduce metabolic pressure or remove damaged organelles. In cancer, autophagy plays a paradoxical role, acting as a tumor suppressor—by removing damaged organelles and inhibiting inflammation or by promoting genome stability and the tumor-adaptive responses—as a pro-survival mechanism to protect cells from stress. In this article, we review the autophagy-dependent mechanisms driving childhood central nervous system tumor cell death, malignancy invasion, chemosensitivity, and radiosensitivity. Autophagy inhibitors and inducers have been developed, and encouraging results have been achieved in autophagy modulation, suggesting that these might be potential therapeutic agents for the treatment of pediatric central nervous system (CNS) tumors.
Ferroptosis is an iron-dependent form of cell death that is characterized by early lipid peroxidation and different from other forms of regulated cell death in terms of its genetic components, ...specific morphological features, and biochemical mechanisms. Different initiation pathways of ferroptosis have been reported, including inhibition of system X
, inactivation of glutathione-dependent peroxidase 4, and reduced glutathione levels, all of which ultimately promote the production of reactive oxygen species, particularly through enhanced lipid peroxidation. Although ferroptosis was first described in cancer cells, emerging evidence now links mechanisms of ferroptosis to many different diseases, including cerebral ischemia and brain hemorrhage. For example, neonatal brain injury is an important cause of developmental impairment and of permanent neurological deficits, and several types of cell death, including iron-dependent pathways, have been detected in the process of neonatal brain damage. Iron chelators and erythropoietin have both shown neuroprotective effects against neonatal brain injury. Here, we have summarized the potential relation between ferroptosis and neonatal brain injury, and according therapeutic intervention strategies.
Iron is important for a remarkable array of essential functions during brain development, and it needs to be provided in adequate amounts, especially to preterm infants. In this review article, we ...provide an overview of iron metabolism and homeostasis at the cellular level, as well as its regulation at the mRNA translation level, and we emphasize the importance of iron for brain development in fetal and early life in preterm infants. We also review the risk factors for disrupted iron metabolism that lead to high risk of developing iron deficiency and subsequent adverse effects on neurodevelopment in preterm infants. At the other extreme, iron overload, which is usually caused by excess iron supplementation in iron-replete preterm infants, might negatively impact brain development or even induce brain injury. Maintaining the balance of iron during the fetal and neonatal periods is important, and thus iron status should be monitored routinely and evaluated thoroughly during the neonatal period or before discharge of preterm infants so that iron supplementation can be individualized.
Perinatal asphyxia induces neuronal cell death and brain injury, and is often associated with irreversible neurological deficits in children. There is an urgent need to elucidate the neuronal death ...mechanisms occurring after neonatal hypoxia-ischemia (HI). We here investigated the selective neuronal deletion of the Atg7 (autophagy related 7) gene on neuronal cell death and brain injury in a mouse model of severe neonatal hypoxia-ischemia. Neuronal deletion of Atg7 prevented HI-induced autophagy, resulted in 42% decrease of tissue loss compared to wild-type mice after the insult, and reduced cell death in multiple brain regions, including apoptosis, as shown by decreased caspase-dependent and -independent cell death. Moreover, we investigated the lentiform nucleus of human newborns who died after severe perinatal asphyxia and found increased neuronal autophagy after severe hypoxic-ischemic encephalopathy compared to control uninjured brains, as indicated by the numbers of MAP1LC3B/LC3B (microtubule-associated protein 1 light chain 3)-, LAMP1 (lysosomal-associated membrane protein 1)-, and CTSD (cathepsin D)-positive cells. These findings reveal that selective neuronal deletion of Atg7 is strongly protective against neuronal death and overall brain injury occurring after HI and suggest that inhibition of HI-enhanced autophagy should be considered as a potential therapeutic target for the treatment of human newborns developing severe hypoxic-ischemic encephalopathy.
Given the relatively low rate and limited publicly available data regarding children with SARS-CoV-2 infection, this knowledge gap should be addressed with urgency. This systematic review with ...meta-analysis aimed to evaluate the epidemiological spectrum and clinical characteristics of children infected with SARS-CoV-2. Relevant international and Chinese public databases were systematically searched to identify all case studies from January 1, 2020 to May 7, 2020. This study consisted of 96 studies involving 7004 cases. The mean age of pediatric cases was 6.48 years (95% CI 52.0–77.5), 90% had household contact, and 66% presented with mild to moderate clinical syndromes. The main symptoms were fever (47%, 95% CI 41–53%) and cough (42%, 95% CI 36–48%). About 23% of children were asymptomatic, 27% had comorbidity, and 29% had a co-infection. The pooled mean incubation period was 9.57 days (95% CI 7.70–11.44). The shedding of SARS-CoV-2 in the upper respiratory tract lasted 11.43 days, and 75% of patients had virus particles in their stool. A total of 34% of the children had neutropenia and 26% had lymphocytosis. Interferon-alpha (81%) was the most commonly used antiviral drug in the children. The discharge and death rates were 79 and 1%. In conclusion, the transmissibility of pediatric COVID-19 should be not ignored because of the relatively long incubation period, shedding duration, and mild clinical syndromes.
Isoflurane and related anesthetics are widely used to anesthetize children, ranging from premature babies to adolescents. Concerns have been raised about the safety of these anesthetics in pediatric ...patients, particularly regarding possible negative effects on cognition. The purpose of this study was to investigate the effects of repeated isoflurane exposure of juvenile and mature animals on cognition and neurogenesis. Postnatal day 14 (P14) rats and mice, as well as adult (P60) rats, were anesthetized with isoflurane for 35 mins daily for four successive days. Object recognition, place learning and reversal learning as well as cell death and cytogenesis were evaluated. Object recognition and reversal learning were significantly impaired in isoflurane-treated young rats and mice, whereas adult animals were unaffected, and these deficits became more pronounced as the animals grew older. The memory deficit was paralleled by a decrease in the hippocampal stem cell pool and persistently reduced neurogenesis, subsequently causing a reduction in the number of dentate gyrus granule cell neurons in isoflurane-treated rats. There were no signs of increased cell death of progenitors or neurons in the hippocampus. These findings show a previously unknown mechanism of neurotoxicity, causing cognitive deficits in a clearly age-dependent manner.
Preterm birth and associated brain injury are the primary cause of cerebral palsy and developmental disabilities and are among the most serious global health issues that modern society faces. Current ...therapy for infants suffering from premature brain injury is still mainly supportive, and there are no effective treatments. Thus there is a pressing need for comparative and translational studies on how to reduce brain injury and to increase regeneration and brain repair in preterm infants. There is strong supporting evidence for the use of umbilical cord blood (UCB)‐derived stem cell therapy for treating preterm brain injury and neurological sequelae. UCB‐derived stem cell therapy is effective in many animal models and has been shown to be feasible in clinical trials. Most of these therapies are still experimental, however. In this review, we focus on recent advances on the efficacy of UCB‐derived stem cell therapy in preterm infants with brain injury, and discuss the potential mechanisms behind their therapeutic effects as well as application strategies for future preclinical and clinical trials.
Autism spectrum disorder (ASD) is a neurological and developmental condition that begins in infancy or earlier and lasts through the individual's lifetime. The aetiology and mechanisms of ASD are not ...yet fully understood, and current treatment comprises mainly education and rehabilitation, without significant improvement in the core symptoms. Recent studies suggest that microbiota change in children with ASD after the ingestion of probiotics may improve the balance of microbiota and thus ASD symptoms.
The objectives of this study are to evaluate the efficacy of probiotics on the symptoms of children with ASD and the possible mechanisms involved.
This is a prospective controlled trial. A total of 160 children with ASD will be stratified and allocated to placebo and probiotics groups randomised according to the severity of their ASD symptoms. The probiotics group will be given probiotics supplements orally twice a day for 3 months and the control group will be given a placebo at the same amount, in addition to the baseline therapy of education and rehabilitation. All the children will be evaluated systematically by using different scales, questionnaires before, during, and after 3 months' treatment, as well as 3 months after discontinuation. The potential impact of probiotics on immunity and inflammation, metabolism, and metagenome will also be investigated.
Our previous study showed that the abundance of intestinal flora was greatly different in children with ASD, and that Bifidobacterium was associated with the severity of ASD. In the present study, we will investigate the impact of probiotics supplementation on the symptoms of Children with ASD, with the purpose of evaluating the possible therapeutic effects of additives on ASD and of providing a reference for clinical treatment. The results will help to disclose as yet unknown relationship between probiotics and ASD.
This study has been registered with Chinese Clinical Trial Registry (ChiCTR-2000037941).
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