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There is abundant evidence that extracellular ATP has an important role in pain signaling at both the periphery and in the CNS. The focus of attention now is on the possibility that ATP and its receptor system might play important roles in chronic pathological pain states, particularly in neuropathic pain. Neuropathic pain is often a consequence of nerve injury through surgery, bone compression, diabetes, or infection. This type of pain can be so severe that even light touching can be intensely painful. Unfortunately, this state is generally resistant to currently available treatments. In this review, we summarize the role of ATP receptor P2X4 and P2X7 in spinal microglia in neuropathic pain. The activated microglia express P2X4 after nerve injury, which can be stimulated by endogenous ATP, resulting in the release of brain-derived neurotrophic factor that is one of key molecules involving in neuropathic pain. The stimulation of microglial P2X7 releases cytokines including TNF-α and IL- 1β. Understanding the key roles of these ATP receptors may lead to new strategies for the management of intractable chronic pain. [ABSTRACT FROM AUTHOR]

Neurogenesis occurs in the adult hippocampus and subventricular zone. It provides an exciting potential inroad to new treatments for slow neurodegenerative disorders. Changes in neurogenesis in human degenerative diseases may also teach us something about the underlying disease mechanisms. In the present chapter, we review data from clinical and experimental studies concerning neurogenesis in Alzheimer's, Huntington's and Parkinson's diseases. In brief, the clinical data have not clearly shown whether the rate of neurogenesis is changed by the pathogenesis in these three diseases. Whether neurogenesis occurs at all in the adult substantia nigra under baseline conditions remains controversial. Studies on animal models of the three neurodegenerative conditions provide a mixed picture, with disease/ damage to the brain being associated both decreases and increases in neurogenesis in the different studied brain regions. In conclusion, this exciting research field is still in its infancy. It is too early to say whether neurogenesis in the adult brain can be targeted by novel therapies and be used to reduce functional deficits in slow neurodegenerative diseases. [ABSTRACT FROM AUTHOR]

Myelination in the central nervous system (CNS) is carried out by oligodendrocytes. These cells produce myelin, a lipid-rich biological membrane, which forms multilamellar, spirally wrapped sheets around axons. Myelination allows rapid saltatory conduction of action potentials, and contributes to the maintenance of axonal integrity. The devastating neurological effects caused by demyelinating CNS diseases illustrate the importance of the process. [ABSTRACT FROM AUTHOR]

Polyglutamine expansion diseases are inherited neurodegenerative disorders caused by the expansion of CAG repeat mutations in the coding region of genes encoding for specific proteins, mostly of unknown function. One example is Machado-Joseph disease (MJD) or spinocerebellar ataxia 3, which was described in people of Portuguese descendents and is caused by expanded ataxin-3, a polyubiquitin-binding protein. Like other neurodegenerative diseases, MJD exhibits gradual progression of symptoms that finally result in the death of the patients. Despite the identification of the genetic defects, the molecular mechanisms by which the mutant protein initiates the pathogenic process remain to be elucidated. This chapter resumes some of the most important features of polyglutamine expansion diseases with a special emphasis on MJD pathogenesis. Particular relevance is given to ataxin-3 structure and function, the formation of aggregates of mutant ataxin-3, the characteristics of current disease animal models and the most recent therapeutic strategies proposed for the treatment of MJD. [ABSTRACT FROM AUTHOR]

In this chapter, we review the role of glial cells in hippocampal neurogenesis under normal conditions, in aging and in the epileptic brain. Astrocytes or astrocyte-like cells are emerging as key components of the neurogenic niche in health and disease, with roles ranging from being stem cells to regulating almost all aspects of neurogenesis and synaptic integration of the newly generated neurons. It is likely that astrocytes and microglial cells are key sensors of local environmental changes, modulating neurogenesis appropriately. This is likely to be a fruitful area of research for extending our understanding of the role of stem cells in the normal and diseased brain. [ABSTRACT FROM AUTHOR]

Mesial temporal lobe epilepsy (TLE) represents the most frequent type of focal epilepsies. The most prominent neuropathological characteristics of TLE are severe neurodegenerations in the hippocampus (termed Ammon's horn sclerosis) and in related brain areas such as the amygdala and entorhinal cortex. Within the hippocampus, pyramidal cells of the areas CA1 and CA3 and interneurons of the dentate hilus are most vulnerable, whereas granule cells of the dentate gyrus, CA2 pyramidal cells and the subiculum are comparatively preserved. [ABSTRACT FROM AUTHOR]

The role of metal ions in the evolution and progression of Alzheimer's disease (AD) is becoming increasingly apparent. Indeed, the interactions of age-associated increases in metals with the amyloid precursor protein (APP) and its proteolytic enzymes and subsequent proteolytic fragments (such as -amyloid (A )) are well characterized. Likewise, the metal associated and age-related formation of free radicals, the subsequent generation of oxidative stress and its interactions on process whose dysfunction may contribute to the development of AD have also been highly characterized. Metal dyshomeostasis may thus initiate, and propogate, the development of AD. As science continues to gain greater resolution into the molecular underpinnings of AD, the potential for the use of metal-modulation in the treatment of this disorder is gaining greater acceptance. [ABSTRACT FROM AUTHOR]

Alzheimer's disease (AD) and prion-related encephalopathies (PRE) are neurodegenerative disorders linked to the aberrant extracellular deposition of amyloidogenic proteins, amyloid-beta (A ), and pathogenic scrapie prion (PrPSc), respectively. In both disorders, cerebral amyloid deposits are associated with a local inflammatory response, which is initiated by the activation of microglia and recruitment of astrocytes. Activated microglia, particularly those in the vicinity of amyloid deposits can produce and release proinflammatory cytokines, chemokines, complement proteins, acute-phase proteins, and reactive oxygen and nitrogen species that can damage the neighboring neurons. [ABSTRACT FROM AUTHOR]

Infection with the human immunodeficiency virus-1 (HIV-1) and acquired immunodeficiency syndrome (AIDS) pose a persistent health problem worldwide. Infected peripheral immune-competent cells, in particular macrophages, appear to infiltrate the central nervous system (CNS) and provoke a neuropathological and inflammatory response involving all cell types in the brain. In fact, HIV-1 seems to enter the brain very soon after infection and can subsequently induce severe and debilitating neurological problems that range from mild behavioral abnormalities and motor dysfunction to frank dementia. [ABSTRACT FROM AUTHOR]

Familial amyloidotic polyneuropathy (FAP) is an autosomal dominant neurodegenerative disorder related to the systemic deposition of mutated transthyretin (TTR) amyloid fibrils, particularly in peripheral nervous system (PNS). Recently, evidence for the presence of toxic non-fibrillar TTR aggregates early in FAP nerves constituted a first step to unravel molecular signaling related to neurodegeneration in FAP. The toxic nature of TTR non-fibrillar aggregates, and not mature TTR fibrils, was evidenced by their ability to induce the expression of oxidative stress and inflammation-related molecules in neuronal cells, driving them into apoptotic pathways. How these TTR aggregates exert their effects is debatable; interaction with cellular receptors, namely the receptor for advanced glycation endproducts is a probable candidate mechanism. The pathology and the yet unknown molecular signaling mechanisms responsible for neurodegeneration in FAP will be discussed. [ABSTRACT FROM AUTHOR]

Neuronal loss occurs with aging or dementia, and an extended concept of neuroprotection assumes that the administration of a drug, or a procedure, is able to reverse or prevent neuronal damage. Neuroprotective strategies have been classified according to the mechanisms of neuronal death, and this chapter will deal mainly with neuroinflammation and related processes that occur in aging, cognitive decline, and dementia. The evidence for inflammatory phenomena in dementia, especially in Alzheimer's disease (AD), is impressive, and the role of inflammatory cells and mediators has been extensively studied. Furthermore, anti-inflammatory drugs (specially the nonsteroidal anti-inflammatory drugs (NSAIDs)) have been shown to attenuate these phenomena in preclinical studies. [ABSTRACT FROM AUTHOR]

Cumulating evidence suggest that Zn2+ dys/homeostasis can play a major role in promoting brain injury in excitotoxic syndromes. Zn2+ homeostasis in the brain is regulated through highly dynamic pathways and is deeply connected with other major signaling pathways, such as NO- and MAP kinase-dependent systems. Zn2+ signaling in neurons and glia also interplays with proton and Ca2+ homeostasis. Zn2+ appears to promote injury with greater potency compared to Ca2+ and as such the cation may be an underappreciated mediator of excitotoxicity, which for many years has been described mainly as a Ca2+- dependent phenomenon. [ABSTRACT FROM AUTHOR]

Mitochondria play an important role as ATP producers through the activity of the citric acid cycle and oxidative phosphorylation, as regulators of intracellular calcium homeostasis, and producers of endogenous reactive oxygen species (ROS). Mitochondria also regulate cell death, marking the point of no return in necrosis and apoptosis. Many evidences have been raised implicating mitochondria defects as crucial mechanisms in the pathogenesis of several neurodegenerative diseases, as well as in aging. This chapter resumes some of the findings that provide evidence for the role of mitochondria in neurodegeneration associated with Parkinson's disease (PD) and Huntington's disease (HD), two neurodegenerative disorders that cause movement disturbances. [ABSTRACT FROM AUTHOR]

Glial cell line-derived neurotrophic factor (GDNF) is a potent survival factor for dopaminergic neurons of the nigrostriatal pathway that degenerate in Parkinson's disease (PD). In animal models of PD, GDNF delivery has been shown to both protect dopaminergic neurons against toxin-induced injury and to rescue damaged neurons, promoting recovery of the motor deficit. GDNF may act both as a target-derived neurotrophic factor in the striatum, and as a local neurotrophic factor at the level of neuronal cell bodies in the substantia nigra. The neuroprotective and regenerative effects of GDNF are mediated by increases in the activity of antioxidant enzymes and induction of antiapoptotic proteins and cell adhesion molecules. [ABSTRACT FROM AUTHOR]

Neurotrophins control survival, differentiation and maintenance of neurons and glial cells in the central and peripheral nervous system. Their biological functions are mediated by two distinct families of receptors, the Trk receptor tyrosine kinases (TrkA, TrkB and TrkC) and the p75 neurotrophin receptors (p75NTR with different signaling activity. Both receptor types convey trophic signals, but p75NTR activation may also cause apoptotic cell death. The abundance of neurotrophins and/or their receptors changes in various pathological conditions, contributing to cell death or cell survival, depending also on the receptors activated. This chapter focuses on the changes in the abundance of neurotrophins and neurotrophin receptors in diseases of the nervous system and how these changes affect neuronal survival. [ABSTRACT FROM AUTHOR]

There is now a significant body of evidence indicating that, with age, the brain is exposed to a number of stresses. One of these is a decrease in the concentration of antiinflammatory cytokines that exert significant neuroprotective effects. On the basis of recent findings, it seems reasonable to propose that among the most critical neuroprotective effects of IL-4 and IL-10 is maintenance of microglia in a quiescent state, preventing excessive release of proinflammatory cytokines like IL-1μ, which have been shown to negative impact on hippocampal plasticity. It must therefore be concluded that it is an imbalance between proinflammatory and anti-inflammatory cytokines that leads to age-related deficits in synaptic function and that strategies that restore the balance are likely to be beneficial in reducing the deterioration of function that accompanies age. [ABSTRACT FROM AUTHOR]

The functional activity in the brain is primarily composed of interplay between excitation and inhibition. In any given region the output is based upon a complex processing of incoming signals that require both excitatory and inhibitory units. Moreover, these units must be regulated and balanced such that an integrated and finely tuned response is generated. In each of these units or synapses, the activity depends on biosynthesis, release, receptor interaction, and inactivation of the neurotransmitters; thus, it is easily understood that each of these processes needs to be highly regulated and controlled. [ABSTRACT FROM AUTHOR]

Neural stem cells of the adult subventricular zone (SVZ) can be easily propagated in culture and give rise to a large number of glial cells and neuronal progenitors, offering promising perspectives for future cell-based therapies. Many factors able to modulate neuronal production have been identified but efficient differentiation into specific neuronal phenotypes is still a challenge. Animal models of brain diseases have been used in neuronal replacement studies in Huntington's and Parkinson's diseases, in stroke and trauma, contributing to highlight the potential of stem cell's therapy. [ABSTRACT FROM AUTHOR]

Adenosine is a homeostatic modulator in all cells, being produced from intracellular ATP as a consequence of increased workload or noxious stimuli. Extracellular adenosine can then afford tissue protection by a combination of effects operated by inhibitory A1 receptors, which refrain metabolism, and facilitatory A2A receptors, which cause vasodilatation and act as a potent "Off" signal of immune/inflammatory cells in the periphery. Adenosine also acts as a neuromodulator in the brain through A1 receptor-mediated inhibition of excitatory transmission. However, adenosine also aggravates brain damage in chronic neurodegenerative conditions by mechanisms that may involve an A2A receptor-mediated potentiation of neuroinflammation. We will now review the evidences suggesting that A2A receptor control neuroinflammation and discuss the possible mechanisms underlying the opposite modulation by A2A receptors of peripheral inflammation and neuroinflammation. [ABSTRACT FROM AUTHOR]

By studying the response of hippocampal microglia to anterograde axonal and terminal degeneration in the dentate gyrus we have identified several subsets of microglia, including immigrant bone marrow (BM)-derived and resident microglia, and resident microglia expressing different levels of CD34, of which the majority were induced to undergo proliferation upon injury. Based on the population kinetics elucidated until now, we have evidence that a subpopulation of microglial cells may undergo repeated proliferation upon injury while some microglial cells may not proliferate at all within the investigated period. Furthermore, resident cells in the mouse may be supplemented by BM-derived cells. A picture emerges where new cells are being born, while other cells, including the newly generated and recruited cells are beginning to be cleared from the site of lesion, at least partly by apoptotic mechanisms. Increased insight into basic microglial cell biology may improve diagnostic and therapeutic possibilities for patients suffering from conditions that are currently without real treatment options. [ABSTRACT FROM AUTHOR]

The fast growing research field of Neuroinflammation is challenging the traditional view of the Brain as an immune privileged organ. Our increasing understanding of the mechanisms involved in the close functional interaction between neurons and glia in health and disease is contributing to shed new light into the cellular and molecular mechanisms of neurodegeneration. The response of microglia and astrocytes to injury, releasing signaling molecules (specially, cytokines, chemokines, growth factors, reactive oxygen and nitrogen species), is central in neuroinflammation and in neuron death/survival. [ABSTRACT FROM AUTHOR]