Molecular Mechanism In Brain Damage Research Articles

Targeting the Multiple Complex Processes of Hypoxia-Ischemia to Achieve Neuroprotection

Hypoxic-ischemic encephalopathy (HIE) is a major cause of newborn brain damage stemming from a lack of oxygenated blood flow in the neonatal period. Twenty-five to fifty percent of asphyxiated infants who develop HIE die in the neonatal period, and about sixty percent of survivors develop long-term neurological disabilities. From the first minutes to months after the injury, a cascade of events occurs, leading to blood-brain barrier (BBB) opening, neuronal death and inflammation. To date, the only approach proposed in some cases is therapeutic hypothermia (TH). Unfortunately, TH is only partially protective and is not applicable to all neonates. This review synthesizes current knowledge on the basic molecular mechanisms of brain damage in hypoxia-ischemia (HI) and on the different therapeutic strategies in HI that have been used and explores a major limitation of unsuccessful therapeutic approaches.

COVID-19: Cellular and Molecular Mechanisms of Brain Damage

The most common clinical manifestation of COVID-19 is bilateral pneumonia, a diffuse, alveolar injury with severe microangiopathy. Systemic infection is accompanied by an increase in circulating chemokines and interleukins in the blood, which penetrate the blood–brain barrier (BBB) and enter the brain. Clinical materials indicate lesions of the brain and peripheral nervous system, as well as neurodegenerative and mental disorders. Due to violations of the cerebral endothelium system and changes in the balance of ACE2-coupled cytochemical processes, coagulopathy develops, leading to microthrombosis and vascular occlusion. The concept of SARS-CoV-2 “neurotropism” is discussed as a rationale for the penetration by the virus into the brain. Infection can occur as axonal transport through the bulbar zone and the olfactory area of the cerebral cortex. Even more common is the “hematogenous pathway” of viral transfection, which includes damage to the vascular endothelium and a violation of the protective role of the BBB. Another concept that explains the mechanism of brain damage relates to the phenomenon of neuroinflammation. Astrocytes and microglia are considered potential targets of the SARS-CoV-2 coronavirus. The dissonance of the biochemical processes of the axis ACE2/ACE and changes in the functions of angiotensin peptides leads to the activation of astroglia with the development of neurodestructive processes in COVID-19.

Integrated transcriptomic and proteomic analysis indicated that neurotoxicity of rats with chronic fluorosis may be in mechanism involved in the changed cholinergic pathway and oxidative stress

BackgroundTo reveal the underling molecular mechanism in brain damage induced by chronic fluorosis, the neurotoxicity and its correlation were investigated by transcriptomics and proteomics. MethodsSprague-Dawley rats were treated with fluoride at different concentrations (0, 5, 50 and 100 ppm, prepared by NaF) for 3 months. Spatial learning and memory were evaluated by Morris water maze test; neuronal morphological change in the hippocampus was observed using Nissl staining; and the level of oxidative stress including reactive oxygen species (ROS), malondialdehyde (MDA) and superoxide dismutase (SOD) were detected by biological methods. The high-throughput transcriptome sequencing (RNA-Seq) and tandem mass tag (TMT) proteomic sequencing were performed to detect the expression of differentially expressed genes and proteins, respectively. ResultsThe results showed that compared with control group, rats exposed to high-dose fluoride exhibited declined abilities of learning and memory, decreased SOD activity and increased ROS and MDA levels, with lighter colored Nissl bodies. A total of 28 important differentially expressed genes (DEGs) were screened out by transcriptomics. Then, functional enrichment analyses showed that upregulated proteins enriched in cellular transport, while downregulated proteins enriched in synapse-related pathways. Thirteen corresponding DEGs and DAPs (cor-DEGs-DAPs) were identified by differential expressions selected with positively correlated genes/proteins, most of which were related to neurodegenerative changes and oxidative stress response. ConclusionThese results provide new omics evidence that rats chronically exposed to high-dose fluoride can induce neurotoxicity in the brains through changes in the cholinergic pathway and oxidative stress.

Dietary Protein Source Influences Brain Inflammation and Memory in a Male Senescence-Accelerated Mouse Model of Dementia.

Dementia is a pathological condition characterized by a decline in memory, as well as in other cognitive and social functions. The cellular and molecular mechanisms of brain damage in dementia are not completely understood; however, neuroinflammation is involved. Evidence suggests that chronic inflammation may impair cognitive performance and that dietary protein source may differentially influence this process. Dietary protein source has previously been shown to modify systemic inflammation in mouse models. Thus, we aimed to investigate the effect of chronic dietary protein source substitution in an ageing and dementia male mouse model, the senescence-accelerated mouse-prone 8 (SAMP8) model. We observed that dietary protein source differentially modified memory as shown by inhibitory avoidance testing at 4 months of age. Also, dietary protein source differentially modified neuroinflammation and gliosis in male SAMP8 mice. Our results suggest that chronic dietary protein source substitution may influence brain ageing and memory-related mechanisms in male SAMP8 mice. Moreover, the choice of dietary protein source in mouse diets for experimental purposes may need to be carefully considered when interpreting results.

Targeting High Mobility Group Box 1 in Subarachnoid Hemorrhage: A Systematic Review.

Aneurysmal subarachnoid hemorrhage (aSAH) is a complex and potentially deadly disease. Neurosurgical clipping or endovascular coiling can successfully obliterate ruptured aneurysms in almost every case. However, despite successful interventions, the clinical outcomes of aSAH patients are often poor. The reasons for poor outcomes are numerous, including cerebral vasospasm (CVS), post-hemorrhagic hydrocephalus, systemic infections and delayed cerebral ischemia. Although CVS with subsequent cerebral ischemia is one of the main contributors to brain damage after aSAH, little is known about the underlying molecular mechanisms of brain damage. This review emphasizes the importance of pharmacological interventions targeting high mobility group box 1 (HMGB1)-mediated brain damage after subarachnoid hemorrhage (SAH) and CVS. We searched Pubmed, Ovid medline and Scopus for “subarachnoid hemorrhage” in combination with “HMGB1”. Based on these criteria, a total of 31 articles were retrieved. After excluding duplicates and selecting the relevant references from the retrieved articles, eight publications were selected for the review of the pharmacological interventions targeting HMGB1 in SAH. Damaged central nervous system cells release damage-associated molecular pattern molecules (DAMPs) that are important for initiating, driving and sustaining the inflammatory response following an aSAH. The discussed evidence suggested that HMGB1, an important DAMP, contributes to brain damage during early brain injury and also to the development of CVS during the late phase. Different pharmacological interventions employing natural compounds with HMGB1-antagonizing activity, antibody targeting of HMGB1 or scavenging HMGB1 by soluble receptors for advanced glycation end products (sRAGE), have been shown to dampen the inflammation mediated brain damage and protect against CVS. The experimental data suggest that HMGB1 inhibition is a promising strategy to reduce aSAH-related brain damage and CVS. Clinical studies are needed to validate these findings that may lead to the development of potential treatment options that are much needed in aSAH.

Prospects for the studies of the cellular and molecular mechanisms of brain damage on a model system of cultured hippocampal slices

Using an immunohistochemistry technique, combined with light and electron microscopy,in vitro development of various cell elements in organotypic hippocampal rat slice culture were studied. It was shown that hippocampal neurons preserve their normal structure and function for a month of culturing. Astrocytes are activated and fulfill a protective function, and microglial cells show typical dynamics of the development in culture. After experimental hypoxia, progressive neuronal degradation and death, as well as microglial activation, are observed. The prospects for using hippocampal slice culture as a model system for studying cellular and molecular mechanisms of brain damage of different etiology are discussed.