Central Nervous System Agents in Medicinal Chemistry (Formerly Current Medicinal Chemistry - Central Nervous System Agents) - Volume 10, Issue 4, 2010

Science is progressing constantly, and this evolution is often difficult to follow if we consider the rapid and massive advance in every field of research. The study of molecules positively and negatively modulating the function of the Nervous System is not an exception. Recently, our knowledge on the actions that different chemical molecules exert modulating the Nervous System has been expanded with the help of a variety of molecular tools. In turn, these approaches have served to improve our understanding regarding how this System works, how vulnerable can be to the actions of neuroactive molecules, and by which mechanisms is affected, but mostly, how we can prevent or ameliorate some of its alterations through the design of therapeutic strategies based on chemical agents designed to either reduce or potentiate some functions in the brain. In this thematic issue of Central Nervous System Agents - Medicinal Chemistry, which is devoted to the general topic “Chemical Agents Positively and Negatively Affecting the Central Nervous System”, we have compiled the reviews of several colleagues with expertise in different themes related with the actions of chemical agents, either endogenous or exogenous, that modulate diverse functions of the Nervous System. These authors offer the state-of-the-art on their respective topics, thus bringing a valuable update to follow as referential works for all those colleagues doing biomedical and clinical research. First, Diaz- Munoz and Salin-Pascual make an updated approach to the role of agents such as adenosine, ATP and caffeine - all known purines - as hypnogenic factors and their relevance for future paradigms. Campos-Esparza and Torres-Ramos offer an interesting insight into the role of the antioxidant molecules, polyphenols, and their mechanisms of action in the brain. Tobon- Velasco and coworkers revisit the hard topic of Parkinson's disease and those molecules serving as biomarkers in this disorder and related animal models. Limon-Pacheco and Gonsebatt describe a compilation of evidence supporting a regulatory role of melatonin in the glutathione system in the Nervous System. Rubio and coworkers pay special attention to those molecules used up to date to produce experimental models of epilepsy under in vivo conditions. Aztatzi-Santillan and coworkers develop the topic of the protective properties of heme oxygenase-1 in cerebral ischemia with a molecular perspective. Following the issue of ischemia, Espinoza-Rojo and coworkers describe the relevance of glucose transporters as therapeutic targets by different modulators for possible treatment of this condition. Saenz and coworkers discuss the role of regulatory T cells and their chemical modulation in the Nervous System under different conditions. Finally, Montes de Oca-Balderas brings us an interesting approach to the regulated intracellular proteolysis and ectodomain shedding in the Nervous System by chemical signaling. We hope this broad spectrum of topics covered in this thematic issue can be considered a useful tool for colleagues, students, physicians, and in general terms professionals of health sciences around the world as a guide to get introduced in all thesefascinating themes.

Purines are ubiquitous molecules with important roles in the regulation of metabolic networks and signal transduction events. In the central nervous system, adenosine and ATP modulate the sleep-wake cycle, acting as ligands of specific transmembrane receptors and as allosteric effectors of key intracellular enzymes for brain energy expenditure. Two types of adenosine receptors seem to be relevant to the sleep function, A1 and A2A. Caffeine, an antagonist of adenosine receptors, has been used as a tool in some of the studies reviewed in the present chapter. Possible changes in adenosine functioning due to the aging process have been observed in animal models and abnormalities in the adenosine system could also explain primary insomnia or the reduced amount of delta sleep and increased sensitivity to caffeine in some subjects with sleep deficits. Caffeine is a methylated-derivate of xanthine with profound effects on the onset and quality of sleep episodes. This purine acts principally as an antagonist of the A2A receptors. Adenosine and ATP in the nervous system are the bridge between metabolic activity, recovery function, and purinergic transmission that underlies the daily wake-sleep cycle in mammals. Modulators of purine actions have the potential to alleviate insomnia and other sleep disorders based on their physiopathological role during the sleep process.

Polyphenols are the most abundant antioxidants in diet. These can be found in fruits, vegetables, beverages (tea, wine, juices, etc.), plants and some herbs. These compounds are capable of protecting neuronal cells in different in vivo and in vitro models through diverse intracellular targets. The focus of this review is aimed at presenting the role of some polyphenols on the molecular mechanism involved in neuroprotection throught different biological processes like oxidative stress, excitotoxicity, apoptotic neuronal death, regulation of the kinase signal cascade and modulation of Ubiquitin- Proteasome pathway. The study of the molecular mechanisms involved in neuroprotection and the molecular targets of natural polyphenols are important in the discovery of a valuable tool for new and more advanced therapy in neurodegenerative diseases.

One of the common features occurring in several experimental models of neurodegenerative disorders is oxidative/ nitrosative stress (OS/NS). This event induces a series of deleterious actions involving the primary formation of reactive oxygen and nitrogen species (ROS/RNS), affecting both the structure and function of different biological molecules, and leading to specific toxic processes that compromise cell redox status. Biomarkers are important indicators of normal and abnormal biological processes. Specific biochemical and genetic changes observed in different pathologies bring us comprehensive information regarding the nature of any particular disorder. Parkinson's disease (PD) is a chronic neurodegenerative disorder difficult to study, given the intricate events occurring in the pathology, and also because the resultant clinical phenotype fluctuates over time. At present, we have no definitive diagnostic test, and thus for clinicians there is still expectation that biomarkers will eventually help to diagnose symptomatic and presymptomatic disease, or provide surrogated end-points to demonstrate clinical efficacy of new treatments and neuroprotective therapies. In this review we explore current information on some potential biomarkers of OS/NS in PD models, with special emphasis on the mostrecent findings on this topic.

The glutathione system includes reduced (GSH) and oxidized (GSSG) forms of glutathione; the enzymes required for its synthesis and recycling, such as gamma-glutamate cysteine ligase (γ-GCL), glutathione synthetase (GS), glutathione reductase (GSR) and gamma glutamyl transpeptidase (γ-GGT); and the enzymes required for its use in metabolism and in mechanisms of defense against free radical-induced oxidative damage, such as glutathione s-transferases (GSTs) and glutathione peroxidases (GPxs). Glutathione functions in the central nervous system (CNS) include maintenance of neurotransmitters, membrane protection, detoxification, metabolic regulation, and modulation of signal transduction. A common pathological hallmark in various neurodegenerative disorders, such as amyotrophic lateral sclerosis and Alzheimer's and Parkinson's diseases, is the increase in oxidative stress and the failure of antioxidant systems, such as the decrease in the GSH content. The administration of exogenous neurohormone melatonin at pharmacological doses has been shown not only to be an effective scavenger of reactive oxygen and nitrogen species but also to enhance the levels of GSH and the expression and activities of the GSH-related enzymes including γ-GCL, GPxs, and GSR. The exact mechanisms by which melatonin regulates the glutathione system are not fully understood. The main purpose of this short review is to discuss evidence relating to the potential common modulation signals between the glutathione system and melatonin in the CNS. The potential regulatory mechanisms and interactions between neurons and non-neuronal cells are also discussed.

This study reviews the different in vivo experimental models that have been used for the study of epileptogenesis. In this review we will focus on how to replicate the different models that have led to the study of partial seizures, as well as generalized seizures and the status epilepticus. The main characteristics that participate in the processes that generate and modulate the manifestations of different models of epileptogenesis are described. The development of several models of experimental epilepsy in animals has clearly helped the study of specific brain areas capable of causing convulsions. The experimental models of epilepsy also have helped in the study the mechanisms and actions of epilepsy drugs. In order to develop experimental animal models of epilepsy, animals are generally chosen according to the kind of epilepsy that can be developed and studied. It is currently known that animal species can have epileptic seizures similar to those in humans. However, it is important to keep in mind that it has not been possible to entirely evaluate all manifestations of human epilepsy. Notwithstanding, these experimental models of epilepsy have allowed a partial understanding of most of the underlying mechanisms of this disease.

Cerebral ischemia is one of the leading causes of death and disability in industrialized countries, with no curative treatments to date. Identification of potential targets and elucidation of their physiological role under stress conditions may give support to the development of drugs and strategies to contend with this pathology. In the last years, Heme oxygenase- 1 (HO-1) has been recognized by many groups as a potential target in ischemic damage. HO-1 is the enzyme responsible for the conversion of the heme group to biliverdin, carbon monoxide and iron; a highly regulated cytoprotective enzyme able to respond to numerous chemical or physical stressors, many of which decrease oxygen availability and generate oxidative stress. The disruption of HO-1 activity has been widely associated with a bad outcome in many disorders, and a protective role through its heme catabolism products has been observed in transplantation, cardiac ischemia, limb ischemia/reperfusion and different alterations that involve ischemia and reperfusion events. Here, we review recent reports supporting the protective role of HO-1 in cerebral ischemia. Results on the endogenous HO-1 response, overexpression of HO-1 and compounds that reduce ischemic damage through the induction of HO-1 in cerebral ischemia in in vivo and in vitro models are analyzed.

Ischemic stroke is a major cause of death worldwide that provokes a high society cost. Deprivation of blood supply, with the subsequent deficiency of glucose and oxygen, triggers an important number of mechanisms (e.g. excitotoxicity, oxidative stress and inflammation) leading to irreversible neuronal injury. Consequently, ischemia increases the energy demand which is associated with profound changes in brain energy metabolism. Glucose transport activity may adapt to ensure the delivery of glucose to maintain normal cellular function, even at the low glucose levels observed in plasma during ischemia. In the brain, the main glucose transporters (GLUTs) are GLUT3 in neurons and GLUT1 in the microvascular endothelial cells of the blood brain barrier and glia. The intracellular signaling pathways involved in GLUT regulation in cerebral ischemia remain unclear; however, it has been established that ischemia induces changes in their expression. In this review, we describe the effect of glutamate-induced excitotoxicity, mitochondrial damage, glucose deprivation, and hypoxia on GLUTs expression in the brain. Additionally, we discuss the possible role of GLUTs as therapeutic target for ischemia. Despite of the intense research, current therapeutics options for stroke are very limited, therefore it is especially important to find new options. Few studies have examined the neuroprotective potential of GLUT upregulation in ischemic stroke; however, evidence suggests that augmented GLUTs could be related to a protective mechanism. Increased understanding of the beneficial effects of GLUTs activation provides the rationale for targeting GLUT in the development of new therapeutic strategies.

Regulatory T cells participate in several immune responses including autoimmune reactions inducing selftolerance, tumor immunity, transplantation tolerance and microbial infection. Nevertheless, regulatory T cells actions seem to be different when they are in the central nervous system (CNS), since they interact with resident cells of the CNS, according to the particular conditions elicited in this compartment. This review focuses on the role of regulatory T cells in health, autoimmune and other CNS diseases, pointing out their interactions with resident CNS cells.

The term Ectodomain Shedding (ES) refers to extracellular domain proteolytic release from cell membrane molecules. This proteolysis is mediated mainly by matrix metalloproteases (MMP) or disintegrin and metalloproteases (ADAM), although some other proteases may participate. Virtually, all functional categories of cell membrane molecules are subject of this kind of proteolysis, for this reason ES is involved in different cellular processes such as proliferation, apoptosis, migration, differentiation or pathologies such as inflammation, cancer and degeneration among others. ES releases membrane molecule's extracellular domain (or ectodomain) to the extracellular milieu where it can play different biological functions. ES of transmembrane molecules also generates membrane attached terminal fragments comprising transmembrane and intracellular domains that enable their additional processing by intracellular proteases, mechanism known as Regulated Intracellular Proteolysis (RIP). This second proteolytic cleavage delivers molecule's intracellular domain (ICD) that carries out intracellular functions. RIP is mediated by the group of intracellular cleaving proteases (i- CLiPs) that include presenilin from the γ-secretase complex. In the CNS the best well known ES is that of the Amyloid Precursor Protein, although many other membrane molecules expressed by cells of the CNS are also subject to ES and RIP. In this review, these molecules are summarized, and some meaningful examples are highlighted and described. In addition, ES and RIP implications in the context of cell biology are discussed. Finally, some considerations that rise from the study of ES and RIP are formulated in view of the unexpected roles of intracellular fragments.