Pathophysiologic molecular mechanisms as possible therapeutic targets for prevention and correction of secondary brain damage in severe craniocerebral trauma

Abstract

Severe craniocerebral trauma (SCT) leads to a cascade of cellular reactions due to mitochondrial dysfunction and partly due to microglia activation. Simultaneously, the structure of the blood-brain barrier (BBB) is disrupted. Understanding the molecular mechanisms that control the function and integrity of neurons, microglia, and vascular wall elements in the norm is a prerequisite for finding new therapeutic targets in PMT. My-tochondrial dysfunction as a major factor in the development of secondary brain damage after PMT triggers a cascade of the following events: oxidative stress, apoptosis, autophagy, local disruption of blood supply and GEB, glial dysfunction, cell edema and inflammatory reactions of microglia and astrocytes. It is important to identify the role of more than one specific molecular mechanism to allow paralleling between them and finding common points of application. Caspases play a role in cell apoptosis, which affects the Hippo signaling pathway. The anti-apoptosis pathway RSMT1/ Mst1 is formed, which increases Bax expression but decreases Bcl2 expression, all of which leads to caspase-3 activation and provokes enhanced triggering of apoptosis via the mitochondrial pathway. Conversely, miR-21 increases Bcl2 expression but inhibits Bax and caspase-3 expression. Thus suppressing apoptosis and increasing the time of therapeutically potent drug and the ability to accelerate repair mechanisms of secondary cellular damage after tCMT. P53 and mRNA are upregulated after exposure to PMT. Hippo directly acts through p53 and mRNA to control proliferation and expression of pro-apoptotic genes, which will help control all of the above processes. Microglia, or rather the identification of its morphological variants, is of particular interest. Currently, three variants are distinguished: branched, activated (deramified) and amoeba-like. The bacillary microglia, which some authors consider as a special morphology of activated microglia, stands apart. Accurate identification of microglia populations is key to understanding therapeutic approaches that modify the microglial response to PMT and improve long-term outcome measures. Determining which markers or combinations of markers each microglia variant engages is important. The latter has historically been categorized similarly to macrophages by M1 and M2 activation profiles. But there is increasing evidence that individual morphological variants of microglia express specific markers whose activation is realized in a different time frame from M1 and M2. Edema is considered to be one of the important patho-physiological characteristics after severe traumatic injury and an intractable clinical problem. In this review, we described the effects of non-mRNA representatives, including circular RNAs, and AQP on edema.