Biochemical Aspects of Neuroinflammation

Abstract

Neuroinflammation is a complex host defense mechanism that isolates the damaged brain tissue from uninjured area, destroys injured cells, and repairs the extracellular matrix (Minghetti et al. 2005). Neuroinflammation is orchesterated by microglia and astrocytes to re-establish homeostasis in the brain after injury-mediated disequi-librium of normal physiology. Microglial cells dynamically express distinct arrays of functions during the course of neuroinflammation and depending on neurological condition, such as neurotraumatic diseases (stroke, spinal cord injury (SCI), and traumatic head injury (TBI)), neurodegenerative diseases (Alzheimer disease (AD), Parkinson disease (PD), and amyotrophic lateral sclerosis (ALS), and neuropsy-chiatric diseases (depression, Schizophrenia, and biopolar disorders) (Colton 2009; Farooqui and Horrocks 2007; Farooqui 2010). Age is a major risk factor for stroke, AD, and PD. Although, normal aging is accompanied with increase in neuroin-flammation in the hippocampus (Lynch 1998; Gemma and Bickford 2007), but the intensity of neuroinflammation is markedly increased in stroke, AD, and PD. There are two types of neuroinflammation (a) acute inflammation and (b) chronic inflam-mation. Stroke involves acute neuroinflammation and oxidative stress whereas AD and PD are associated with chronic neuroinflammation and oxidative stress (see below) (Farooqui et al. 2007; Farooqui 2010). Recently the role of inflammation in brain health has become a major focal point of studies related with aging and age-related neurological disorders (Farooqui 2010). Activation of inflammatory pathways in the brain has been increasingly emphasized as a major risk factor for the initiation, development, and progression of pathogenesis of stroke, AD, and PD (Farooqui 2010). Epidemiological studies on humans have indicated that long-term use of anti-inflammatory drugs not only protects brain from inflammation, but also delays the onset of cognitive decline (Launer et al. 1998; Arvanitakis et al. 2008). These studies are supported by animal studies, which provide additional support to the hypothesis that inflammation may contribute to the pathogenesis of stroke, AD, and PD (Lim et al. 2000; Heneka and O'Banion 2007). However, clinical studies on the treatment of stroke, AD, and PD with antiinflammatory drugs once the disease is clinically apparent have been largely unsuccessful (Aisen 2008; Meinert et al. A. A. Farooqui, Inflammation and Oxidative Stress in Neurological Disorders, DOI 10.1007/978-3-319-04111-7_2, © Springer International Publishing Switzerland 2014 44 2 Biochemical Aspects of Neuroinflammation 2009; Breitner et al. 2009). Based on these observations it is suggested that the timing of anti-inflammatory treatment for neurological disorders is crucial, and that attenuation of inflammation is particularly important prior to clinical manifestation of stroke, AD, and PD. Astrocytes are complex, highly differentiated cells of the brain. They play sev-eral important roles, such as regulating the external environment of neurons, partici-pating in the physical structuring of the brain, providing metabolites to neurons, and maintaining the blood brain barrier (BBB) integrity. The cell body and the major processes of astrocytes are enriched with glial fibrillary acidic protein (GFAP) that forms intermediate filaments, whose recognition by Golgi staining is the reason for the classically star-shaped appearance of astrocytes (Bushong et al. 2002). Astro-cytes outnumber neurons by over fivefold and play important role in the brain. It is well known that microvascular beds consist of endothelial cells, basal lamina, and astrocyte (Zoppo and Hallenbeck 2000). Astrocytes enwrap the vessel wall with a large number of end feet and support the formation of BBB, a neurovascular unit composed of endothelial cells, pericytes, astrocytes, and neurons (Hawkins and Davis 2005). An anatomical particularity of the BBB is that brain microvessel endothelial cells are connected by strong tight junctions that direct plasma sub-stances into transcellular routes and reduce the paracellular diffusion of solutes and macromolecules (Benarroch 2011). However, the exact role of astrocytes in the BBB formation is poorly understood (Zoppo and Hallenbeck 2000). The tight orga-nization of astrocytes around the vasculature is thought to be due to the necessity of glucose to reach neurons. In fact, it is hypothesized that astrocytes take up glucose since they express a large number of glucose transporters, convert it to lactate, and then deliver lactate to neurons (Takano et al. 2006). Astrocytes not only maintain BBB, regulate cerebral blood flow, and modulate synaptic function and plasticity, but also maintain the extracellular balance of ions, modulate neurotransmitter (glutamate) trafficking and recycling, and provide nutrient support for neurons (Fig. 2.1) (Nedergaard et al. 2003; Seifert et al. 2006). Another transmitter released 0RGXODWLRQRIFHUHEUDO EORRGIORZV