Special Issue "Neuroprotective Strategies"

Guest Editor
Dr. Katalin Prokai-Tatrai
Department of Pharmacology & Neuroscience, University of North Texas Health Science Center, 3500 Camp Bowie Blvd, Fort Worth, TX 76107, USA
Website: http://www.hsc.unt.edu/faculty/biography.cfm?id=538
E-Mail:
Interests: Medicinal chemistry: drug design of central nervous system agents; neuropeptides and peptidomimetics; prodrugs for CNS delivery; oxidative stress; estrogens and other phenolic antioxidants; protein carbonylation

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 Molecules

Submission

All manuscripts should be submitted to ijms@mdpi.org with a copy to the Guest Editor. Manuscripts can be submitted until the deadline. Papers will be published continuously (as soon as accepted) and will be listed together on the special issue website. Research articles, review articles as well as communications are invited. For planned papers, a title and short abstract (about 100 words) can be sent to the Editorial Office for announcement on this website.

Submitted manuscripts should not have been published previously, nor be under consideration for publication elsewhere (except conference proceedings papers). All manuscripts are refereed through a peer-review process. A guide for authors and other relevant information for submission of manuscripts is available on the Instructions for Authors page. The International Journal of Molecular Sciences is an international peer-reviewed Open Access monthly journal published by MDPI.

Please visit the Instructions for Authors page before submitting a manuscript. The Article Processing Charge (APC) for publication in this Open Access journal is 1000 CHF per accepted paper.

aging, Alzheimer's disease, amyotrophic lateral sclerosis, anti-apoptotic drugs, antioxidants, apoptosis, axon damage, bioavailability, blood-brain barrier, caspases, cognition, excitotoxicity, free radicals, GABA agonists, glaucoma, growth factors, hydroxyl radical, hypothermia, hypoxia, inflammation, ion channels, iron chelators, ischemia, ischemic optic neuropathy, lipid peroxidation, MEK/ERK signaling pathway, mitochondria, necrosis, neurogenesis, neurotrophic factors, nitric oxide synthase, nitrosative/oxidative stress, NMDA agonist, nutraceuticals, Parkinson’s disease, peripheral neurons, peroxinitrite, posttranslational modification, protein aggregates, proteomics, redox-active metals, retinal ganglion cells, spinal cord injury, stem cell, steroids, stroke, superoxide dismutase, therapeutic window, traumatic brain injury

Feature Papers

Type of Paper: Article
Title: A Novel Parp-Inhibitor L-2286 in a Rat Model of Impact Acceleration Head Injury: Immunhistochemical and Behavioral Study
Authors: E. Kovesdi ¹, P. Bukovics ¹, V. C. Besson ², J. Luckl ¹, J. Pal ¹, B. Sumegi ³, T. Doczi ¹, I. Hernadi ⁴ and A. Buki ^1,*
Affiliations: ¹ Department of Neurosurgery, Clinical Centre, University of Pecs, Hungary
² Laboratoire de Pharmacologie de la Circulation Cerebrale, UPRES EA 2510, Universite Rene Descartes, Paris, France
³ Department of Biochemistry and Medical Chemistry, Medical School of Pecs, University of Pecs, Hungary
⁴ Department of Experimental Zoology and Neurobiology, University of Pecs, Hungary
* Author to whom correspondence should be addressed; E-mail: andras.buki@aok.pte.hu
Abstract: INTRODUCTION: Poly (ADP-ribose) polymerase-1 (PARP) is a nuclear enzyme, converting nicotinamide adenine dinucleotide (NAD+) to nicotinamide and ADP-ribose unit that is attached to either PARP itself or other proteins. While PARP- inhibitors exert neuroprotective effect in various animal models of experimental brain injury their potential on behavioral outcome is less extensively investigated. L-2286 is a novel PARP-1 inhibitor that has recently been identified through structure-based drug design.
METHODS: The aim of the study was to determine the optimal post-injury dosage of intracerebroventricularly (icv.) administered PARP-inhibitor L-2286 (2-[(2-piperidin-1-yletil)thio]quinazolin-4(3H)-one) in a rat model of severe impact acceleration brain injury by means of immunhistochemical analysis, and to examine its neuroprotective effect in various time-points post-injury applying specific immunhistochemical markers associated with traumatic brain injury, as well as behavioral tests (beam-balance, open-field and elevated plus-maze).
RESULTS: Both immediate and 30 minutes post-injury administration of 100 µg L-2286 significantly reduced the density of APP and RMO-14–immunoreactive (IR) axon profiles in the corticospinal tract (CSpT), and in the medial longitudinal fasciculus (MLF). Behavioral tests proved that the drug 30 minutes post-injury significantly improved the motor functions in beam-balance test compared to vehicle treated animals. In open-field test L-2286 significantly altered the number of grooming. Elevated plus-maze revealed that L-2286 treated rats perform in most of the examined parameters almost as sham injured do.
CONCLUSION: Our results indicate that L-2286 exerts neuroprotective effect and inhibits diffuse axonal injury (DAI) after impact acceleration injury in rats also reflected in significant improvement of motor-behavioral outcome. PARP-inhibitors including L-2286 should be considered potential subjects for further experimental evaluation and candidates for clinical studies in TBI.

Type of Paper: Review
Title: Stem Cells and Neuroprotection: Understanding the Players
Author: Virginia Pearce
Affiliation: Department of Pharmacology and Neuroscience, University of North Texas Health Science Center, Fort Worth, TX 76107, USA; E-Mail: vpearce@hsc.unt.edu
Abstract: The use of neuroprotective therapies begs the question of how such therapies could effect preexisting stem cell populations within the host, as well as those introduced through cell-replacement therapy. Multiple mechanisms may mediate stem cell responses to neuroprotectants such as host/donor age and gender, cellular lineage/differentiation status, and mitochondrial dynamics. Current therapeutic sources for stem cells are embryonic, somatic, or induced pluripotent, with very little known about the effects of gender, age, cell type, and mitochondrial dynamics. With the advent of therapies to stimulate and recruit endogenous stem cells or transplant donor cells into damage areas in the hopes of recuperative regeneration of lost neurons, it is important to discuss mechanisms that dictate the winning players in the neuroprotection game.

Regular Papers

Type of Paper: Review
Title: Neuroprotective Effects of Peptide Agonists of the FGF-receptor
Authors: Shizong Li, Lanjun Zhang, Vladimir Berezin and Elisabeth Marianne Bock *
Affiliations: Københavns Universitet, Det Sundhedsvidenskabelige Fakultet, Institut for Neurovidenskab og Farmakologi, Blegdamsvej 3B, 2200 København N, Denmark; * Author to whom correspondence should be addressed; E-mail: bock@sund.ku.dk
Abstract: Fibroblast growth factor receptor (FGFR) has been proposed to interact with the cognate ligands, FGFs, as well as a number of cell adhesion molecules such as the neural cell adhesion molecule (NCAM) and L1, mediating a wide range of events in the development and maintenance of the nervous system. Structural and biological studies have resulted in the identification of FGFR binding peptides mimicking FGFs, NCAM and L1 as regards neuroprotective effects. We focus on recently developed peptide agonists of FGFR derived from the fibronectin type III modules of NCAM and L1, as well as from the β loops of FGFs.

Type of Paper: Review
Title: The Yin and Yang of VEGF and PEDF: Multifaceted Neurotrophic Factors and Their Potential in the Treatment of Parkinson’s Disease
Authors: Torsten Falk *, Robert T. Gonzalez and Scott J. Sherman
Affiliations: Department of Neurology, College of Medicine, University of Arizona, Tucson, AZ 85724, USA; * Author to whom correspondence should be addressed; E-mail: tfalk@email.arizona.edu
Abstract: Over the last few decades, vascular endothelial growth factor (VEGF) and pigment epithelium-derived factor (PEDF) have emerged as multifaceted players in not only the pathogenesis, but potential treatment, of numerous diseases. Recent work with the two factors indicates that the activity of one growth factor is often directly related to the action of the other. Their respective neuroprotective effects, in particular, raise important questions regarding the treatment of neurodegenerative disorders.

Type of Paper: Review
Title: Voltage-Gated Potassium Channel Modifiers as Neuroprotective Agents
Author: Yuk-Man Leung
Affiliation: Graduate Institute of Neural and Cognitive Sciences, College of Life Sciences, China Medical University, Taichung 404, Taiwan; E-mail: ymleung@mail.cmu.edu.tw
Abstract: A manifestation in neurodegeneration is apoptosis of neurons. Neurons undergoing apoptosis may lose cytosolic K⁺ through a number of pathways including K⁺ efflux via voltage-gated K⁺ (Kv) channels. The consequent drop in cytosolic [K⁺] relieves inhibition of an array of pro-apoptotic caspases and nucleases. Blockers of Kv channels (Kv1, Kv2 and Kv3 family members) have been known to prevent neuronal apoptosis by preventing K⁺ efflux. Some neural diseases such as epilepsy are caused by neuronal hyperexcitability. Reduction in activities of A-type K⁺ channels and Kv7 family members is amongst the etiological causes, and enhancing the opening of these channels may offer opportunities of remedy. This review will discuss the potential therapeutic values of Kv channel modifiers.

Type of Paper: Article
Title: The Calpain Inhibitor MDL-28170 Has No Analgesic Effects after Nerve Injury
Authors: Nurcan Üçeyler, Lydia Biko and Claudia Sommer
Affiliation: Department of Neurology University of Würzburg, Josef-Schneider-Str. 11, 97080 Würzburg, Germany; E-mail: Ueceyler_N@klinik.uni-wuerzburg.de
Abstract: Background: The calpain inhibitor MDL-28170 blocks the early local pro-inflammatory cytokine gene expression in mice after chronic constrictive nerve injury (CCI).
Animals and methods: C57BL/6 mice received CCI of the right sciatic nerve. Mechanical withdrawal thresholds and thermal withdrawal latencies were investigated at baseline and at 1, 3, and 7 days after CCI. Three injection regimens were used for MDL-28170: a) single shot 45 minutes before CCI; b) serial injection of MDL-28170 45 minutes before and up to day three after CCI; c) implantation of intraperitoneal osmotic pumps. The control animals received DMSO-PEG 400 respectively.
Results: The tolerable dose of MDL-28170 for mice was 30 mg/kg body weight, higher doses were lethal within the first hour after CCI. Mechanical withdrawal thresholds and thermal withdrawal latencies were reduced after CCI and did not normalize neither by single shot nor by serial injections, nor by application of MDL-28170 via osmotic pumps after CCI.
Conclusion: 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 implicates that local cytokine upregulation after nerve injury alone is only one factor in the induction and maintenance of neuropathic pain.

Type of Paper: Review
Title: Programmed Cell Death Regulation Is a Component of Neuronal HSV Infection and the Treatment of Neurodegeneration by HSV Genes
Author: Laure Aurelian
Affiliation: Virology/Immunology Laboratories, Department of Pharmacology and Experimental Therapeutics, The University of Maryland, School of Medicine, Baltimore, Maryland 21201, USA; E-Mail: laurelia@umaryland.edu
Abstract: Herpes simplex virus (HSV) is neurotropic and infects the peripheral (PNS) and central (CNS) nervous systems. A major virus property is the establishment of latency, defined as virus persistence in infected neurons in a repressed state that is compatible with cell survival and is often accompanied by episodes of virus reactivation and clinical symptoms. The most common sites for latency establishment are respectively the trigeminal ganglia for HSV-1 and the sacral dorsal root ganglia for HSV-2. Latency is also established in the CNS, primarily the brain stem. The mechanisms of latency establishment and reactivation are still poorly understood, but the viral transcript LAT contributes to the pathogenesis of latency, apparently through apoptosis modulation. Despite an 83% overall sequence identity in the coding regions, the two HSV serotypes display distinct neurovirulence patterns, with encephalitis (HSV-induced encephalitis, HSE) being almost always caused by HSV-1. HSV-2 primarily causes aseptic meningitis. Virus infection is also associated with neurodegenerative disorders, notably HSV-1 with Alzheimer’s disease. This article reviews present understanding of the mechanisms of latency and CNS disease and underscores the role of programmed cell death (PCD) regulation in both phenomena. The use of different strategies by the two HSV serotypes is highlighted. Evidence is presented that PCD and related inflammatory responses are components of HSE pathogenesis. The potential contribution of innate immunity and bidirectional neuron-glia crosstalk is discussed. The use of molecularly altered HSV vectors and viral genes to treat neurodegenerative disorders or as oncolytic viruses to treat cancer is emphasized.