Eugene Gusev

Microglial Activation, Cytokine Production, and Local Inflammation in Focal Brain Ischemia

Studies of Baron et al. [11], Chen et al. [29], and Fisher and Garcia [46] demonstrated that within the first hours after the onset of stroke there are neurons with structure and functions changed to different extent in the damaged brain area, and the extent of these changes decreases from the central zone of the ischemic core towards the peripheral parts of the penumbra. Regularities in the distribution of these structural and functional changes throughout the penumbra determine the final size of the brain infarction formed by the 3rd to 5th days after stroke onset. These changes must be studied to establish the basis for developing effective neuroprotective therapeutic approaches [7, 46, 80, 148, 149, 158].

Energy Failure Induced by Brain Ischemia

Decrease in brain perfusion is accompanied by decrease in oxygen delivery to brain tissue, where oxygen is involved in aerobic generation of energy as a substrate for cytochrome oxidase, the terminal enzyme of the respiratory chain. The resulting state of hypoxia is the consequence of a complicated multi-stage process involving sequential changes in the properties of the mitochondrial enzyme complexes [27].

The Glutamate—Calcium Cascade

When glutamate is released from presynaptic terminals, it diffuses to the postsynaptic terminals where it binds to glutamate receptors, allowing Na+ influx that depolarizes the membrane. This opens Ca2+ channels allowing Ca2+ to enter the postsynaptic cell. Under ischemic conditions, this process becomes excessive—the “glutamate-calcium cascade”.

Molecular Mechanisms of Post-Ischemic Reparation Events

When effective blood flow is recovered before irreversible necrotic damage forms, a stereotype reparative process will have been started in the brain tissue.

Programmed Cell Death. Apoptosis in Focal Brain Ischemia

Until the 1980s it was believed that neuronal death in acute brain ischemia occurred only by the mechanism of necrosis. However, later studies elucidated the role of apoptosis, another pathway to infarction, which is a variant of programmed cell death.

Autoimmune Mechanisms of Trophic Dysfunction and Ischemic Brain Damage

The nervous, immune, and endocrine systems function together to support the dynamic homeostasis of the human body. As components of a unified system, they interact via mutual regulation involving neuromediators, neuropeptides, cytokines, trophic factors, and hormones and the corresponding receptor systems [95]. Mutual regulation of the nervous, endocrine, and immune systems determines the reliability of their common functioning. However, this entails the risk of systemic dysfunction when any one component of the whole system is affected. Such disorders can be defined as under-regulation pathology, the pathogenesis of which may be connected with primarily nervous or endocrine and/or immune mechanisms [83].

Delayed Neuronal Death Following Acute Focal Brain Ischemia

The major part of a brain infarction is formed within the first 3–6 h of the first clinical signs of strake (Fig. 6.1). However, the temporal evolution of infarction and its “up-formation” are connected with secondary brain cell damage which takes place in hours to days after the initial vascular event.

Metabolic Acidosis and Ischemic Damage

One of the primary responses of brain tissue to decrease in CBF is acidosis. Decrease in ATP content in the ischemized brain area leads to compensatory activation of anaerobic glycolysis and to increased production of lactate and H+ that causes the development of lactic acidosis. Modest increase in H+ concentration in early stages of ischemia plays a compensatory and adaptive role as it promotes the improvement of perfusion in the penumbral area [2]. Significant elevation of lactate level within the first hours of ischemic stroke leads to decrease in pH to 6.4–6.7 [11] and appears to be an unfavorable prognostic sign [5, 12, 19, 20].

Strategies and Prospects for Development of Neuroprotective Therapy for Brain Ischemia

Much new information about processes of extra- and intraceIlular signaling, interactions between neuronal and glial cells, and mechanisms of ischemic damage to brain tissue on the genetic, molecular, biochemical, immune, and cellular levels, as well as about processes of brain cell survival and post-ischemic regeneration and reparation has become available in recent years. This information provides the basis for further development of neuroprotective strategies.

Modern Therapeutic Approaches to Acute Focal Brain Ischemia. Basic Strategies for Neuroprotection

Modern scientific and technological advances give reason to revise the previous pessimistic opinion about the therapeutic possibilities for acute focal brain ischemia, i.e. ischemic stroke.