Asiatic acid exerts neuroprotective effect against hypoxicischemic brain injury in neonatal rats via inhibition of oxidative damage

Purpose: To investigate the effect of asiatic acid on hypoxic ischemia-induced injury in neonatal rats, and the underlying mechanism of action.Methods: Hypoxic-ischemia (HI) neonatal rat model was established via permanent ligation of the carotid artery, followed by hypoxia (exposure to 8 % oxygen and 92 % nitrogen) for 24 h. Immunofluorescence, using fluorescence microscope, was used for the determination of expressions of p-TAK1, NeuN and GFAP. Western blotting was used for assaying protein expression levels, while TUNEL assay was employed for the measurement of apoptosis.Results: Treatment of rats with asiatic acid prior to HI effectively prevented up-regulation of pTAK1 and decreased the count of p-TAK1-containing astrocytes. The proportion of NeuN containing p-TAK1 in HI rat brain cortex was significantly reduced by asiatic acid (p < 0.05). Treatment of rats with asiatic acid suppressed HI- induced up-regulation of pJNK expression. The HI-induced increase in the expression levels of caspase-3, p53 and p-c-Jun in rat brain cortex were reversed by asiatic acid (p < 0.05). The HImediated up-regulation of expressions of p- JNK, caspase-3, p53 and p-c-Jun in rat brain cortex were inhibited significantly by NG25. Asiatic acid treatment also significantly alleviated HI-mediated increase in apoptosis of neurons in rat brain cortex, when compared to model group (p < 0.05).Conclusion: These findings suggest that asiatic acid prevents HI-induced brain injury in neonatal rats via inhibition of neuronal apoptosis. Moreover, it inhibits TAK1 activation, suppresses p-JNK expression and targets pro-apoptotic factors in brain cortex. Therefore, asiatic acid may be a therapeutic agent for the management of HI-induced brain injury.

Secondary hypoxic ischemia alters neurobehavioral outcomes, neuroinflammation, and oxidative stress in mice exposed to controlled cortical impact

Objective Hypoxic ischemia (HI) is a secondary insult that can cause fatal neurologic outcomes after traumatic brain injury (TBI), ranging from mild cognitive deficits to persistent vegetative states. We here aimed to unravel the underlying pathological mechanisms of HI injury in a TBI mouse model.Methods Neurobehavior, neuroinflammation, and oxidative stress were assessed in a mouse model of controlled cortical impact (CCI) injury followed by HI. Mice underwent CCI alone, CCI followed by HI, HI alone, or sham operation. HI was induced by one-vessel carotid ligation with 1 hour of 8% oxygen in nitrogen. Learning and memory were assessed using the novel object recognition test, contextual and cued fear conditioning, and Barnes maze test. Brain cytokine production and oxidative stress-related components were measured.Results Compared to TBI-only animals, TBI followed by HI mice exhibited significantly poorer survival and health scores, spatial learning and memory in the Barnes maze test, discrimination memory in the novel object recognition test, and fear memory following contextual and cued fear conditioning. Malondialdehyde levels were significantly lower, whereas glutathione peroxidase activity was significantly higher in TBI followed by HI mice compared to TBI-only and sham counterparts, respectively. Interleukin-6 levels were significantly higher in TBI followed by HI mice compared to both TBI-only and sham animals.Conclusion Post-traumatic HI aggravated deficits in spatial, fear, and discrimination memory in an experimental TBI mouse model. Our results suggest that increased neuroinflammation and oxidative stress contribute to HI-induced neurobehavioral impairments after TBI.

Predictive value of early amplitude integrated electroencephalogram (aEEG) in sleep related problems in children with perinatal hypoxic-ischemia (HIE)

Background While great attention has been paid to motor and cognitive impairments in children with neonatal Hypoxic-Ischemic Encephalopathy (HIE), sleep related circadian rhythm problems, although commonly present, are often neglected. Subsequently, no early clinical indicators have been reported to correlate with sleep-related circadian dysfunction during development. Methods In this study, we first analyzed patterns of the amplitude integrated electroencephalogram (aEEG) in a cohort of newborns with various degrees of HIE. Next, during follow-ups, we collected information of sleep and circadian related problems in these patients and performed correlation analysis between aEEG parameters and different sleep/circadian disorders. Results A total of 101 neonates were included. Our results demonstrated that abnormal aEEG background pattern is significantly correlated with circadian rhythmic (r = 0.289, P = 0.01) and breathing issues during sleep (r = 0.237, P = 0.037). In contrast, the establishment of sleep–wake cycle (SWC) showed no correlation with sleep/circadian problems. Detailed analysis showed that summation of aEEG score, along with low base voltage (r = 0.272, P = 0.017 and r = -0.228, P = 0.048, respectively), correlates with sleep circadian problems. In contrast, background pattern (BP) score highly correlates with sleep breathing problem (r = 0.319, P = 0.004). Conclusion Abnormal neonatal aEEG pattern is correlated with circadian related sleep problems. Our study thus provides novel insights into predictive values of aEEG in sleep-related circadian problems in children with HIE.

The Potential Relationship Between HIF-1α and Amino Acid Metabolism After Hypoxic Ischemia and Dual Effects on Neurons

Hypoxia inducible factor (HIF) is one of the major transcription factors through which cells and tissues adapt to hypoxic-ischemic injury. However, the specific mechanism by which HIF regulates amino acid metabolism and its effect on neurons during hypoxic ischemia (HI) have remained unclear. This study analyzed the changes in cerebral metabolism of amino acids after HI by using 1H-MRS and investigated the relationship between the changes in cerebral metabolism of amino acids and HIF-1α as well as the potential effects on neurons. Newborn pigs were used as an HI model in this study. Twenty-eight newborn Yorkshire pigs (male, 1.0–1.5 kg) aged 3–5 days were selected and randomly divided into experimental groups tested at 0–2 h (n = 4), 2–6 h (n = 4), 6–12 h (n = 4), 12–24 h (n = 4), 24–48 h (n = 4), and 48–72 h (n = 4) after HI, and a control group (n = 4). After the modeling was completed, 1H-MRS imaging was conducted, followed by immunohistochemical staining of HIF-1α, NeuN, and doublecortin (DCX), and immunofluorescence of glutamic oxaloacetic transaminase (GOT)-1, GOT2, glutathione synthase (GS), glutamate-cysteine ligase catalytic subunit (GCLC), and glutamate-cysteine ligase modifier subunit (GCLM) in brain tissues. The expression of HIF-1α exhibited two increases after HI injury. The first time was opposite to the trends of change of GOT2, aspartic acid, and the number of neurons, while the second was consistent with these trends, suggesting that HIF-1α may have a two-way induction effect on neurons by regulating GOT2 after HI. HIF-1α was closely related to GCLM expression, and GSH level was correlated with the number of hippocampal neurons, indicating that HIF-1α may regulate GCLM to promote GSH synthesis and additionally play a neuroprotective role.

A Review on Chitosan in Drug Delivery for the Treatment of Neurological and Psychiatric Disorders

: Neurological diseases are known as global health problems with a growing number of patients annually. Neurodegenerative diseases, such as Alzheimer’s disease and Parkinson’s disease as well as spinal cord injury, hypoxic ischemia injury, epilepsy, depression etc., are some examples of neurological diseases. One of the main problems in the treatment of these diseases is the delivery of drugs across the blood-brain barrier (BBB). These days, researchers have tended to find non-invasive and non-toxic strategies for solving this problem. As a non-toxic, safe, and potential agent, chitosan has attracted attention for use in drug delivery systems. Recently, numerous studies have designed drug delivery systems by using chitosan for the treatment of various neurological diseases. In this paper, the latest developments of chitosan and its derivatives and their utilization in the drug delivery systems for the treatment of different neurological and psychiatric diseases were reviewed.

Deficiency in Neuroserpin Exacerbates CoCl2 Induced Hypoxic Injury in the Zebrafish Model by Increased Oxidative Stress

Protective strategy against hypoxic-ischemic (H/I) induced injury has been intensively discussed. Neuroserpin, an inhibitor for tissue plasminogen activator (tPA), has been proved a vital neuroprotective agent in cerebral ischemia mouse model and oxygen-glucose deprivation and reoxygenation (OGD/R) cell model. Neuroserpin is a promising therapeutic hint for neonatal hypoxic-ischemia injury. Here, we established a neuroserpin deficient zebrafish to study its role in CoCl2 chemically induced hypoxic injury. CoCl2 exposure was beginning at the embryonic stage. Development defects, neuronal loss, and vascular malformation was assessed by imaging microscopy. Neuroserpin deficient zebrafish showed more development defects, neuronal loss and vascular malformation compared to wide-type. Apoptosis and oxidative stress were evaluated to further identify the possible mechanisms. These findings indicate that neuroserpin could protective against CoCl2 induced hypoxic injury by alleviating oxidative stress.

The Roles of High Mobility Group Box 1 in Cerebral Ischemic Injury

High mobility group box 1 (HMGB1) is a ubiquitous nuclear protein that plays an important role in stabilizing nucleosomes and DNA repair. HMGB1 can be passively released from necrotic neurons or actively secreted by microglia, macrophages/monocytes, and neutrophils. Cerebral ischemia is a major cause of mortality and disability worldwide, and its outcome depends on the number of neurons dying due to hypoxia in the ischemic area. HMGB1 contributes to the pathogenesis of cerebral ischemia via mediating neuroinflammatory responses to cerebral ischemic injury. Extracellular HMGB1 regulates many neuroinflammatory events by interacting with its different cell surface receptors, such as receptors for advanced glycation end products, toll-like receptor (TLR)-2, and TLR-4. Additionally, HMGB1 can be redox-modified, thus exerting specific cellular functions in the ischemic brain and has different roles in the acute and late stages of cerebral ischemic injury. However, the role of HMGB1 in cerebral ischemia is complex and remains unclear. Herein, we summarize and review the research on HMGB1 in cerebral ischemia, focusing especially on the role of HMGB1 in hypoxic ischemia in the immature brain and in white matter ischemic injury. We also outline the possible mechanisms of HMGB1 in cerebral ischemia and the main strategies to inhibit HMGB1 pertaining to its potential as a novel critical molecular target in cerebral ischemic injury.