Neurogenesis and inflammation after ischemic stroke: what is known and where we go from here

Abstract

This review covers the pathogenesis of ischemic stroke and future directions regarding therapeutic options after injury. Ischemic stroke is a devastating disease process affecting millions of people worldwide every year. The mechanisms underlying the pathophysiology of stroke are not fully understood but there is increasing evidence demonstrating the contribution of inflammation to the drastic changes after cerebral ischemia. This inflammation not only immediately affects the infarcted tissue but also causes long-term damage in the ischemic penumbra. Furthermore, the interaction between inflammation and subsequent neurogenesis is not well understood but the close relationship between these two processes has garnered significant interest in the last decade or so. Current approved therapy for stroke involving pharmacological thrombolysis is limited in its efficacy and new treatment strategies need to be investigated. Research aimed at new therapies is largely about transplantation of neural stem cells and using endogenous progenitor cells to promote brain repair. By understanding the interaction between inflammation and neurogenesis, new potential therapies could be developed to further establish brain repair mechanisms.

Figure 1

Inflammatory cascade leading to secondary brain inflammation and cell death after ischemic injury. Cerebral ischemia alone leads to both an initial cell necrosis and generation of reactive oxygen species (ROS) and proinflammatory molecules like interleukin-1 beta (IL-1β) and tumor necrosis factor-alpha (TNF-α) from injured neurons as well as inducing blood–brain barrier (BBB) dysfunction with loosening of cell-to-cell tight junctions between endothelial cells and upregulation of endothelial cell expression of various cell adhesion molecules (e.g., vascular cell adhesion molecules (VCAM), intracellular adhesions molecule-1 (ICAM-1)). This increase causes adherence, migration, and extravasation of circulating leukocytes into the brain parenchyma. When in the brain, leukocytes and activated microglia generate a variety of proinflammatory molecules like inducible nitric oxide synthase (iNOS), matrix metalloproteinases (MMPs), IL-1β and TNF-α, and continue to generate ROS. These events lead to secondary brain injury, increased inflammation, and ultimately cell death. ECM, extracellular matrix; NO, nitric oxide.

Figure 2

Adult neurogenesis in rodents. Coronal sections of the rodent show the neurogenic environments of the adult brain: the subventricular zone (SVZ; left panel) and the subgranular layer (SGL; right panel). The SVZ contains type B neural stem cells (NSCs), which give rise to transit-amplifying type C cells followed by type A migrating neuroblasts. These cells migrate along the rostral migratory stream (RMS) toward the olfactory bulb before terminal differentiation. The SGL contains type I NSCs, which are similar to the type B cells in the SVZ. Type I NSCs give rise to type II NPCs (or intermediate progenitors; IP), which can be further classified as type IIa and type IIb. These type IIb cells are early committed neuronal progenitor cells, which give rise to type III neuroblasts, which migrate into the granular cell layer where they exit the cell cycle and become mature neurons. All cell types described here can be identified based on a unique set of molecular and morphologic markers, as described in the cell population column. GCL, granular cell layer; GFAP, glial fibrillary acidic protein.

Figure 3

Adult neurogenesis in humans. Coronal sections of the human brain show the neurogenic environments of the adult brain: the subventricular zone (SVZ; left panel) and the dentate gyrus (DG) of the hippocampus (right panel). Cell types unique to these regions as well as the fate of these cells are listed. Cell types described here can be identified based on a unique set of molecular and morphologic markers, as noted in the cell population column. GCL, granular cell layer; LV, lateral ventricle; SGL, subgranular layer.