Neurotoxic and cytoprotective mechanisms in the ischemic neocortex

Abstract

Neuronal damage in ischemic stroke occurs due to permanent imbalance between the metabolic needs of the brain and the ability of the blood-vascular system to maintain glucose delivery and adequate gas exchange. Oxidative stress and excitotoxicity trigger complex processes of neuroinflammation, necrosis, and apoptosis of both neurons and glial cells. This review summarizes data on the structural and chemical changes in the neocortex and main cytoprotective effects induced by focal ischemic stroke. We focus on the expression of neurotrophins (NT) and molecular and cellular changes in neurovascular units in ischemic brain. We also discuss how these factors affect the apoptosis of cortical cells. Ischemic damage involves close interaction of a wide range of signaling molecules, each acting as an efficient marker of cell state in both the ischemic core and penumbra. NTs play the main regulatory role in brain tissue recovery after ischemic injury. Heterogeneous distribution of the BDNF, NT-3, and GDNF immunoreactivity is concordant with the selective response of different types of cortical neurons and glia to ischemic injury and allows mapping the position of viable neurons. Astrocytes are the central link in neurovascular coupling in ischemic brain by providing other cells with a wide range of vasotropic factors. The NT expression coincides with the distribution of reactive astrocytes, marking the boundaries of the penumbra. The development of ischemic stroke is accompanied by a dramatic change in the distribution of GDNF reactivity. In early ischemic period, it is mainly observed in cortical neurons, while in late one, the bulk of GDNF-positive cells are various types of glia, in particular, astrocytes. The proportion of GDNF-positive astrocytes increases gradually throughout the ischemic period. Some factors that exert cytoprotective effects in early ischemic period may display neurotoxic and pro-apoptotic effects later on. The number of apoptotic cells in the ischemic brain tissue correlates with the BDNF levels, corroborating its protective effects. Cytoprotection and neuroplasticity are two lines of brain protection and recovery after ischemic stroke. NTs can be considered an important link in these processes. To develop efficient pharmacological therapy for ischemic brain injury, we have to deepen our understanding of neurochemical adaptation of brain tissue to acute stroke.

Keywords: Apoptosis; Hypoxia; Ischemic cortex; Neurochemical adaptation; Neurotrophin; Oxidative stress; Selective neuroprotection.