http://www.mdpi.com/journal/molecules/special_issues/neuroprotec-strateg/ Dear Colleagues, This special issue is aimed at both the basic science and clinical aspects of neuroprotective approaches to acute (e.g., brain or spinal cord trauma, stroke), and chronic neurodegenerative (e.g., Alzheimer's and Parkinson's diseases, age-related macular degeneration) diseases. Potential and existing interventions, either as reviews or original papers, to prevent neuronal cell death in the CNS and in the periphery are welcome to this special issue. The concept of neuroprotection in therapeutic terms may be best described by Shouldon (Science, 1998; 282:1072) as "pharmacological interventions that produce enduring benefits by favorably influencing underlying etiology or pathogenesis and thereby forestalling onset of disease or clinical decline." Our life span has increased and it brought about a significant increase in the incidence of neurodegenerative diseases. While each neurodegenerative disease has its own characteristics and clinical manifestations, some common markers have been recognized. Among others, increased levels of oxidative/nitrosative damage to DNA, RNA, mitochondria, membranes, and proteins, etc. have been detected in connection with situations of neuronal damage. The wide variety of approaches to rescue neurons includes free radical scavenging antioxidants, ion channel modulators, excitatory amino acid antagonists and neurotrophic factors. Stem-cell based approaches may also represent a new opportunity to treat neurodegenerative diseases. I wish to thank all the authors for their contribution to this special issue. Katalin Prokai-Tatrai, Ph. D. Guest Editor Related Special Issues in other Journals Neuroprotective Strategies in IJMS {snippet name="submission_info"} http://www.mdpi.com/1420-3049/15/7/4984/ http://www.mdpi.com/1420-3049/15/7/4984/ Tue, 20 Jul 2010 00:00:00 CEST Molecules 2010-07-20 15 7 Review 4984 5011 1420-3049 Alcohol Withdrawal and Brain Injuries: Beyond Classical Mechanisms 2010-07-20 doi: 10.3390/molecules15074984 Marianna E. Jung Daniel B. Metzger http://www.mdpi.com/1420-3049/15/5/3517/ Plant secondary metabolites include an array of bioactive constituents form both medicinal and food plants able to improve human health. The exposure to these phytochemicals, including phenylpropanoids, isoprenoids and alkaloids, through correct dietary habits, may promote health benefits, protecting against the chronic degenerative disorders mainly seen in Western industrialized countries, such as cancer, cardiovascular and neurodegenerative diseases. In this review, we briefly deal with some plant foods and herbs of traditional medicines and diets, focusing on their neuroprotective active components. Because oxidative stress and neuroinflammation resulting from neuroglial activation, at the level of neurons, microglial cells and astrocytes, are key factors in the etiopathogenesis of both neurodegenerative and neurological diseases, emphasis will be placed on the antioxidant and anti-inflammatory activity exerted by specific molecules present in food plants or in remedies prescribed by herbal medicines. http://www.mdpi.com/1420-3049/15/5/3517/ Fri, 14 May 2010 00:00:00 CEST Molecules 2010-05-14 15 5 Review 3517 3555 1420-3049 Neuroprotective Herbs and Foods from Different Traditional Medicines and Diets 2010-05-14 doi: 10.3390/molecules15053517 Iriti Vitalini Fico Faoro http://www.mdpi.com/1420-3049/15/5/3038/ The calpain inhibitor MDL-28710 blocks the early local pro-inflammatory cytokine gene expression in mice after chronic constriction nerve injury (CCI). One-hundred-thirteen wild type mice of C57Bl/6J background received CCI of the right sciatic nerve. Mechanical paw withdrawal thresholds and thermal withdrawal latencies were investigated at baseline and at 1, 3, and 7 days after CCI. Three application regimens were used for MDL-28170: a) single injection 40 min before CCI; b) serial injections of MDL-28170 40 min before and up to day three after CCI; c) sustained application via intraperitoneal osmotic pumps. The control animals received the vehicle DMSO/PEG 400. The tolerable dose of MDL-28170 for mice was 30 mg/kg body weight, higher doses were lethal within the first hours after application. Mechanical withdrawal thresholds and thermal withdrawal latencies were reduced after CCI and did not normalize after single or serial injections, nor with application of MDL-28170 via osmotic pumps. Although the calpain inhibitor MDL-28170 inhibits the early local cytokine upregulation in the sciatic nerve after CCI, pain behavior is not altered. This finding implies that local cytokine upregulation after nerve injury alone is only one factor in the induction and maintenance of neuropathic pain. http://www.mdpi.com/1420-3049/15/5/3038/ Tue, 27 Apr 2010 00:00:00 CEST Molecules 2010-04-27 15 5 Article 3038 3047 1420-3049 MDL-28170 Has No Analgesic Effect on CCI Induced Neuropathic Pain in Mice 2010-04-27 doi: 10.3390/molecules15053038 Üçeyler Biko Sommer http://www.mdpi.com/1420-3049/15/3/1196/ Epidemiological evidence indicates that nutritionally-derived polyphenols such as resveratrol (RES) have neuroprotective properties. Administration of RES to culture media protects a wide variety of neuronal cell types from stress-induced death. Dietary supplementation of RES can ameliorate neuronal damage and death resulting from both acute and chronic stresses in rodents. The specific molecular mechanisms by which RES acts at the cellular level remain incompletely understood. However, many experimental data indicate that RES reduces or prevents the occurrence of oxidative damage. Here we discuss possible mechanisms by which RES might exert protection against oxidative damage and cell death. Evidence suggesting that RES’s chemical antioxidant potential is not sufficient explanation for its effects is discussed. Putative biological activities, including interactions with estrogen receptors and sirtuins are critically discussed. We provide a synthesis of how RES’s phytoestrogenic properties might mediate the neuronal stress resistance underlying its observed neuroprotective properties. http://www.mdpi.com/1420-3049/15/3/1196/ Wed, 03 Mar 2010 00:00:00 CET Molecules 2010-03-03 15 3 Review 1196 1212 1420-3049 trans-Resveratrol as A Neuroprotectant 2010-03-03 doi: 10.3390/molecules15031196 Ellen L. Robb Jeffrey A. Stuart http://www.mdpi.com/1420-3049/15/3/1168/ Both acute and chronic degenerative diseases of the nervous system reduce the viability and function of neurons through changes in intracellular calcium signaling. In particular, pathological increases in the intracellular calcium concentration promote such pathogenesis. Disease involvement of numerous regulators of intracellular calcium signaling located on the plasma membrane and intracellular organelles has been documented. Diverse groups of chemical compounds targeting ion channels, G-protein coupled receptors, pumps and enzymes have been identified as potential neuroprotectants. The present review summarizes the discovery, mechanisms and biological activity of neuroprotective molecules targeting proteins that control intracellular calcium signaling to preserve or restore structure and function of the nervous system. Disease relevance, clinical applications and new technologies for the identification of such molecules are being discussed. http://www.mdpi.com/1420-3049/15/3/1168/ Wed, 03 Mar 2010 00:00:00 CET Molecules 2010-03-03 15 3 Review 1168 1195 1420-3049 Control of Intracellular Calcium Signaling as a Neuroprotective Strategy 2010-03-03 doi: 10.3390/molecules15031168 R. Scott Duncan Daryl L. Goad Michael A. Grillo Simon Kaja Andrew J. Payne Peter Koulen http://www.mdpi.com/1420-3049/15/2/878/ Huntington’s disease (HD) is an inheritable autosomal-dominant disorder whose causal mechanisms remain unknown. Experimental models have begun to uncover these pathways, thus helping to understand the mechanisms implicated and allowing for the characterization of potential targets for new therapeutic strategies. 3-Nitropropionic acid is known to produce in animals behavioural, biochemical and morphologic changes similar to those occurring in HD. For this reason, this phenotypic model is gaining attention as a valuable tool to mimick this disorder and further developing new therapies. In this review, we will focus on the past and present research of this molecule, to finally bring a perspective on what will be next in this promising field of study. http://www.mdpi.com/1420-3049/15/2/878/ Wed, 10 Feb 2010 00:00:00 CET Molecules 2010-02-10 15 2 Review 878 916 1420-3049 3-Nitropropionic Acid as a Tool to Study the Mechanisms Involved in Huntington’s Disease: Past, Present and Future 2010-02-10 doi: 10.3390/molecules15020878 Isaac Túnez Inmaculada Tasset Verónica Pérez-De La Cruz Abel Santamaría http://www.mdpi.com/1420-3049/15/1/114/ Hypoxia is an established factor of neurodegeneration. Nowadays, attention is directed at understanding how alterations in the expression of stress-related signaling proteins contribute to age dependent neuronal vulnerability to injury. The purpose of this study was to investigate how Hif-1α, a major neuroprotective factor, and JNK signaling, a key pathway in neurodegeneration, relate to hypoxic injury in young (6DIV) and adult (12DIV) neurons. We could show that in young neurons as compared to mature ones, the protective factor Hif-1α is more induced while the stress protein phospho-JNK displays lower basal levels. Indeed, changes in the expression levels of these proteins correlated with increased vulnerability of adult neurons to hypoxic injury. Furthermore, we describe for the first time that treatment with the D-JNKI1, a JNK-inhibiting peptide, rescues adult hypoxic neurons from death and contributes to Hif-1α upregulation, probably via a direct interaction with the Hif-1α protein. http://www.mdpi.com/1420-3049/15/1/114/ Wed, 30 Dec 2009 00:00:00 CET Molecules 2009-12-30 15 1 Article 114 127 1420-3049 JNK Contributes to Hif-1α Regulation in Hypoxic Neurons 2009-12-30 doi: 10.3390/molecules15010114 Xanthi Antoniou Alessandra Sclip Cristina Ploia Alessio Colombo Gautier Moroy Tiziana Borsello http://www.mdpi.com/1420-3049/14/12/5115/ Calcium-induced, calpain-mediated proteolysis (CMSP) has recently been implicated to the pathogenesis of diffuse (traumatic) axonal injury (TAI). Some studies suggested that subaxolemmal CMSP may contribute to axolemmal permeability (AP) alterations observed in TAI. Seeking direct evidence for this premise we investigated whether subaxolemmal CMSP may contribute to axolemmal permeability alterations (APA) and pre-injury calpain-inhibition could reduce AP in a rat model of TAI. Horseradish peroxidase (HRP, a tracer that accumulates in axons with APA) was administered one hour prior to injury into the lateral ventricle; 30 min preinjury a single tail vein bolus injection of 30 mg/kg MDL-28170 (a calpain inhibitor) or its vehicle was applied in Wistar rats exposed to impact acceleration brain injury. Histological detection of traumatically injured axonal segments accumulating HRP and statistical analysis revealed that pre-injury administration of the calpain inhibitor MDL-28170 significantly reduced the average length of HRP-labeled axonal segments. The axono-protective effect of pre-injury calpain inhibition recently demonstrated with classical immunohistochemical markers of TAI was further corroborated in this experiment; significant reduction of the length of labeled axons in the drug-treated rats implicate CMSP in the progression of altered AP in TAI. http://www.mdpi.com/1420-3049/14/12/5115/ Wed, 09 Dec 2009 00:00:00 CET Molecules 2009-12-09 14 12 Article 5115 5123 1420-3049 Calpain Inhibition Reduces Axolemmal Leakage in Traumatic Axonal Injury 2009-12-09 doi: 10.3390/molecules14125115 Endre Czeiter András Büki Péter Bukovics Orsolya Farkas József Pál Erzsébet Kövesdi Tamás Dóczi János Sándor http://www.mdpi.com/1420-3049/14/12/5054/ Neurodegeneration is frequently associated with damage by free radicals. However, increases in reactive oxygen and nitrogen species, which may ultimately lead to neuronal cell death, do not necessarily reflect its primary cause, but can be a consequence of otherwise induced cellular dysfunction. Detrimental processes which promote free radical formation are initiated, e.g., by disturbances in calcium homeostasis, mitochondrial malfunction, and an age-related decline in the circadian oscillator system. Free radicals generated at high rates under pathophysiological conditions are insufficiently detoxified by scavengers. Interventions at the primary causes of dysfunction, which avoid secondary rises in radical formation, may be more efficient. The aim of such approaches should be to prevent calcium overload, to reduce mitochondrial electron dissipation, to support electron transport capacity, and to avoid circadian perturbations. l-Theanine and several amphiphilic nitrones are capable of counteracting excitotoxicity and/or mitochondrial radical formation. Resveratrol seems to promote mitochondrial biogenesis. Mitochondrial effects of leptin include attenuation of electron leakage. Melatonin combines all the requirements mentioned, additionally regulates anti- and pro-oxidant enzymes and is, with few exceptions, very well tolerated. In this review, the perspectives, problems and limits of drugs are compared which may be suitable for reducing the formation of free radicals. http://www.mdpi.com/1420-3049/14/12/5054/ Mon, 07 Dec 2009 00:00:00 CET Molecules 2009-12-07 14 12 Review 5054 5102 1420-3049 Neuroprotection by Radical Avoidance: Search for Suitable Agents 2009-12-07 doi: 10.3390/molecules14125054 Rüdiger Hardeland http://www.mdpi.com/1420-3049/14/9/3392/ Elevated serum glucocorticoid levels contribute to the progression of many diseases, including depression, Alzheimer’s disease, hypertension, and acquired immunodeficiency syndrome. Here we show that the benzamide derivative N-[2-(4-cyclopropanecarbonyl-3-methyl-piperazin-1-yl)-1-(tert-butyl-1H-indol-3-yl-methyl)-2-oxo-ethyl]-4-nitrobenzamide (SP-10) inhibits dibutyryl cyclic AMP (dbcAMP)-induced corticosteroid synthesis in a dose-dependent manner in Y-1 adrenal cortical mouse tumor cells, without affecting basal steroid synthesis and reduced stress-induced corticosterone increases in rats without affecting the physiological levels of the steroid in blood. SP-10 did not affect cholesterol transport and metabolism by the mitochondria but was unexpectedly found to increase 3-hydroxy-3-methylglutaryl-coenzyme A, low density lipoprotein receptor, and scavenger receptor class B type I (SR-BI) expression. However, it also markedly reduced dbcAMP-induced NBD-cholesterol uptake, suggesting that this is a compensatory mechanism aimed at maintaining cholesterol levels. SP-10 also induced a redistribution of filamentous (F-) and monomeric (G-) actin, leading to decreased actin levels in the submembrane cytoskeleton suggesting that SP-10-induced changes in actin distribution might prevent the formation of microvilli–cellular structures required for SRBI-mediated cholesterol uptake in adrenal cells. http://www.mdpi.com/1420-3049/14/9/3392/ Thu, 03 Sep 2009 00:00:00 CEST Molecules 2009-09-03 14 9 Article 3392 3410 1420-3049 Identification of a Benzamide Derivative that Inhibits Stress-Induced Adrenal Corticosteroid Synthesis 2009-09-03 doi: 10.3390/molecules14093392 Jing Xu Laurent Lecanu Matthew Tan Janet Greeson Vassilios Papadopoulos