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:
Phone: +1 871 735-0617
Fax: +1 817 735 2118
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 IJMS

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• 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

Manuscript ID: Molecules- Neupro-20091002- Linseman-us
Type of Paper: Review
Title: Nutraceutical Antioxidants as Novel Neuroprotective Agents
Authors: Natalie A. Kelsey¹ and Daniel A. Linseman^1,2,3
Affiliations: ¹Department of Biological Sciences and Eleanor Roosevelt Institute, University of Denver, Denver, Colorado, USA; E-Mail: daniel.linseman@du.edu
²Research Service, Veterans Affairs Medical Center, Denver, Colorado, USA
³Division of Clinical Pharmacology and Toxicology, Department of Medicine, University of Colorado Denver, Denver, Colorado, USA
Abstract: A variety of antioxidant compounds derived from natural products (nutraceuticals) have demonstrated neuroprotective activity in either ro or in vivo models of neuronal cell death or neurodegeneration, respectively. These natural antioxidants fall into several distinct groups based on their chemical structures: 1) flavonoid polyphenols like epigallocatechin 3-gallate (EGCG) from green tea and quercetin from apples; 2) non-flavonoid polyphenols such as curcumin from tumeric and resveratrol from grapes; 3) phenolic acids or phenolic diterpenes such as rosmarinic acid or carnosic acid, respectively, both from rosemary; and 4) organosulfur compounds including the isothiocyanate, L-sulforaphane, from broccoli and the thiosulfonate, allicin, from garlic. All of these compounds are generally considered to be antioxidants. They may be classified this way either because they directly scavenge free radicals or they indirectly increase endogenous cellular antioxidant defenses, for example, via activation of the nuclear factor erythroid-derived 2-related factor 2 (Nrf2) transcription factor pathway. Alternative mechanisms of action have also been suggested for the neuroprotective effects of these compounds such as modulation of signal transduction cascades or effects on gene expression. Here, we will review the literature pertaining to these various classes of nutraceutical antioxidants and discuss their potential therapeutic value in neurodegenerative diseases.

Manuscript ID: Molecules-Neupro-20091118-Prokai-us
Type of Paper: Review
Title: Current Trends in Neuroprotection by Estrogen Therapy
Authors: Istvan Merchenthaler ¹ and Laszlo Prokai ²
Affiliations: ¹ Department of Epidemiology and Anatomy/Neurobiology, University of Maryland at Baltimore, School of Medicine, 10 S. Pine Str. MSTF Room 9-00F, Baltimore, MD 21201, USA; E-Mail: imerchen@epi.umaryland.edu (I.M.)
² Department of Molecular Biology and Immunology, University of North Texas Health Science Center, 3500 Camp Bowie Boulevard, Fort Worth, TX 76107, USA; E-Mail: lprokai@hsc.unt.edu (L.P.)
Abstract: As the human population ages, women spend half of their lives in a post-menopausal, estrogen-deprived state. Demographics projects a devastating increase in the prevalence of neurodegenerative diseases reinforcing thereby the need for developing novel and safe remedies, including estrogen therapy (ERT) and/or hormone (estrogen plus progestin) therapy (HT). Besides their function as female sex hormones, estrogens also exhibit neurotrophic properties and protect neurons from a variety of harmful insults. All the current estrogen products approved for ERT/HT non-selectively bind to and regulate the two isoforms of the estrogen receptor (ER), ERα and ERβ. However, the activation of ERα, the predominant form in the periphery, by estrogens causes the proliferation of cells, which increases the risk of breast and endometrial cancer. Focusing on protection against hypoxia-induced neurodegeneration and implicating other related maladies such as Alzheimer’s disease and menopausal symptoms, this review summarizes recent strategies for the development of safer estrogen therapies that would have beneficial effects in the central nervous system (CNS) without exhibiting significant side effects in the periphery. Initial efforts to develop non-feminizing estrogens moved toward developing neuro-selective estrogen receptor modulators (neuro-SERMs). Agents that selectively activate ERβ are particularly attractive alternative for ERT/HT, because ERβ acts as a tumor suppressor that inhibits the growth of breast cancer cells and does not exhibit any proliferative effects on the mammary glands and uterus of rodents. Several in vitro and in vivo studies suggest that either synthetic ERβ ligands or some soy isoflavone products, particularly S-equol, may fulfill the criteria to become qualified neuro-SERMs. Another strategy to concentrate the effect of estrogens on the CNS is based on the prodrug approach. CNS-targeting estrogen prodrugs are expected to distribute into or retained preferentially by the CNS where they are converted via an enzyme-catalyzed mechanism to the neuroprotective estrogens reducing thereby peripheral exposure to estrogen. Therefore, the use of these prodrugs for ERT/HT would reduce or eliminate uterotrophic and mammotrophic liabilities currently associated with conventional therapies.

Title: Modulation of Huntingtin Toxicity by BAG1 is Dependent on an Intact BAG Domain
Authors: Jan Liman, K. Sroka, C. Dohm, S. Deeg, M. Bähr and P. Kermer
Affiliation: Dept. of Neurology and DFG-Research Center Molecular Physiologie of the Brain (Dept. of Neurodegeneration and –restoration), University of Göttingen, Germany; E-Mail: pkermer@gwdg.de (P.K.)
Abstract: Recently, we have shown that Bcl-2-associated athanogene-1 (BAG1), a multifunctional co-chaperone, modulates mutant huntingtin (htt) toxicity, aggregation, degradation and subcellular distribution in vitro and in vivo. Aiming at future small molecule approaches, we further analysed structural demands for these effects employing the C-terminal deletion mutant BAGΔC. We show that disruption of the BAG domain known to eliminate intracellular HSP70 binding and activation also precludes binding of Siah-1 thereby leaving nuclear huntingtin translocation unaffected. At the same time BAGΔC fails to induce increased proteasomal htt turnover and does not inhibit intracellular htt aggregation, a pre-requisite necessary for prevention of htt toxicity.

Type of Paper: Review
Title: Emerging Biological Importance of Brain Lanthionines
Author: Kenneth Hensley
Affiliation: The University of Toledo, 2801 W. Bancroft, Toledo, OH, USA; E-Mail: Kenneth.Hensley@utoledo.edu
Abstract: Lanthionine (Lan), the mono-sulfide analog of cysteine, is a natural but nonproteogenic amino acid thought to form in mammals mainly through promiscuous reactivity of the transulfuration enzyme cystathionine-ß-synthase (CßS). Lanthionine exists at appreciable concentrations in mammalian brain, wherein Lan undergoes aminotransferase conversions to yield unusual cyclic thioether ketimines. Recently one of these Lan metabolites, lanthionine ketimine (LK) was discovered to possess neuritigenic and anti-inflammatory activities. Moreover both LK and the ubiquitous redox regulator glutathione (g-glutamyl-cysteine-synthase) bind to mammalian lanthionine synthetase-like protein-1 (LanCL1). These findings begin to suggest that Lan and its downstream metabolites may be biologically important substances rather than mere metabolic waste products.

Type of paper: Review
Title: The Biochemical Basis of Hydroxymethylglutaryl-CoA Reductase Inhibitors as a Neuroprotective Agent in Aneurysmal Subarachnoid Haemorrhage
Authors: George Kwok-Chu Wong and Wai Sang Poon
Affiliation: Division of Neurosurgery, The Chinese University of Hong Kong, Hong Kong, China; E-Mail: georgewong@surgery.cuhk.edu.hk (G.K.-C.W.)
Abstract: Aneurysmal subarachnoid haemorrhage (SAH) has the highest morbidity and mortality rates among all types of stroke. Many aneurysmal SAH patients still suffer from significant neurological morbidity and mortality directly related to delayed cerebral ischaemia. Pilot clinical studies on Hydroxymethylglutaryl-CoA Reductase Inhibitors (statins) in aneurysmal SAH patients have reported reduction in delayed cerebral ischemia and trend towards better clinical outcome. Here we review statins’ biochemical effects on endothelium vascular function, glutamate-mediated neurotoxicity, inflammatory changes, and oxidative injuries, with reference to its possible neuroprotective effects in aneurysmal SAH.

Title: Dealing with Misfolded Proteins: Examining the Neuroprotective Role of Molecular Chaperones in Aging and Neurodegeneration
Authors: Ali Y. ¹, Kitay B.M. ^1,2,3 and Zhai R.G. ^2,3
Affiliations: ¹ Department of Molecular and Cellular Pharmacology, University of Miami, USA
² Neuroscience Graduate Program, University of Miami, USA; gzhai@med.miami.edu (Z.R.G.)
³ M.D./Ph.D. Program, University of Miami, USA
Abstract: Human neurodegenerative diseases arise from a wide array of genetic and environmental factors. Despite the diversity in etiology, many of these diseases are considered "conformational" in nature characterized by the accumulation of pathological, misfolded proteins. These misfolded proteins can induce cellular stress by overloading the proteolytic machinery, ultimately resulting in the accumulation and deposition of protein aggregates that are cytotoxic and may also form aberrant, non-physiological protein-protein interactions leading to the sequestration of proteins required for normal cellular functions. The progression of such disease may therefore be viewed as a failure of normal protein homeostasis, a process that involves a network of molecules regulating the synthesis, folding, translocation and clearance of proteins. Molecular chaperones are highly conserved proteins involved in the folding of nascent proteins, as well as the maintenance and repair of proteins that have lost their typical conformations. These functions have therefore made molecular chaperones an active area of investigation within the field of conformational diseases. This review will discuss the role of molecular chaperones in neurodegenerative disease progression, highlighting their functional classifications, regulation, and potential for therapeutics for these diseases.