Neuropathophysiology of Brain Injury

Abstract

Every year in the United States, millions of individuals incur ischemic brain injury from stroke, cardiac arrest, or traumatic brain injury (TBI). These forms of acquired brain injury can lead to death, or in many cases long-term neurologic and neuropsychological impairments. The mechanisms of ischemic and traumatic brain injuries that lead to these deficiencies result from a complex interplay of multiple interdependent molecular pathways that include excitotoxicity, acidotoxicity, ionic imbalance, oxidative stress, inflammation, and apoptosis. This article briefly reviews several of the traditional, well-known mechanisms of brain injury and then discusses more recent developments and newer mechanisms. Although much is known concerning mechanisms of injury and the manipulation of these mechanisms to result in protection of neurons and increased behavioral performance in animal models of injury, it has been difficult to translate these effects to humans. Attention is given to why this is so and newer outcome measures of injury are discussed.

Inhibition of MiRNA-125b Decreases Cerebral Ischemia/Reperfusion Injury by Targeting CK2α/NADPH Oxidase Signaling

“…Neuronal cell apoptosis is a critical part of cerebral stroke pathophysiology [12], and current evidence has suggested a pivotal role of miRNAs in regulating neuronal death during cerebral ischemic stroke [13]. For instance, miR-134 regulates I/R injury-induced neuronal cell death by regulating CREB signaling [14].…”

Ischemic Stroke Mechanisms, Prevention, and Treatment: The Anesthesiologist’s Perspective

“…Apoptosis involves the organized dismantling of cells to minimize damage to neighboring cells, while necrosis leads to release of intracellular debris which can stimulate inflammatory responses and damage surrounding cells through various mechanisms, for example, by generating excess ROS (54,55). We now understand there is considerable overlap between these pathways, and that necrotic cell death can be regulated (termed necroptosis, programmed necrosis, or caspase-independent programmed cell death) (11,(54)(55)(56)(57)(58)(59)(60). Autophagy, a lysosomal processes of cellular component recycling, is intimately associated with both cell death and survival mechanisms in ischemia (58,59,(61)(62)(63)(64)(65)(66).…”

“…After an ischemic insult, several key transcriptional factors, such as hypoxia inducible factor 1 (HIF-1), nuclear factor-κB (NF-κB), interferon regulatory factor 1 (IRF1), and STAT3, are up-regulated via calcium-induced signaling pathways, increased oxygen free radicals, and hypoxia (30)(31)(32). These transcriptional factors induce the expression of numerous pro-inflammatory genes, including tumor necrosis factor α (TNFα), interleukin 1α (IL-1α) and 1β (IL-1β), intercellular adhesion molecule 1 (ICAM-1), and selectins (11,30,33). Circulating leukocytes interact with these adhesion molecules to adhere to brain endothelium, transmigrate through the vascular wall, and enter the brain parenchyma.…”

“…Necrosis is caused by overwhelming stress (i.e. acute hypoxia in stroke), resulting in unregulated cellular demise (11,54,57,60,68). Nuclei appear swollen, ROS are generated, and cellular membranes begin to disintegrate to allow the release of inflammatory cellular contents into the extracellular space (54,55,60,63).…”

“…Concurrently, presynaptic reuptake of glutamate is reduced due to the lack of energy needed to activate ion pumps, which further exacerbates the increased extracellular glutamate concentration. The excess glutamate binds AMPA (α-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid) and NMDA (Nmethyl-D -aspartate) receptors to increase the influx of water, sodium, and calcium into neurons, inducing a host of signaling events that cause cell swelling, activation of catabolic activity, and eventual cell death (11,12 cium influx initiates a series of cytoplasmic, nuclear, and mitochondrial events that directly contribute to the development of tissue damage, for example, via activation of proteases (13). Uncontrolled activation of calcium-dependent enzymes leads to further ATP depletion and accelerates cell death.…”