Special Issue "Neuroprotective Strategies"
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A special issue of Molecules (ISSN 1420-3049). This special issue belongs to the section "Medicinal Chemistry".
Deadline for manuscript submissions: closed (15 August 2010)
Special Issue Editor
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: kprokai@hsc.unt.edu
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
Special Issue Information
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
Submission
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Keywords
- 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
Published Papers (17 papers)
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Received: 27 July 2009; in revised form: 14 August 2009 / Accepted: 1 September 2009 / Published: 3 September 2009
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Abstract: 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.
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Received: 12 November 2009; in revised form: 30 November 2009 / Accepted: 4 December 2009 / Published: 7 December 2009
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Abstract: 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.
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Received: 20 October 2009; in revised form: 26 November 2009 / Accepted: 4 December 2009 / Published: 9 December 2009
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Abstract: 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.
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Received: 5 November 2009; in revised form: 18 December 2009 / Accepted: 28 December 2009 / Published: 30 December 2009
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Abstract: 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.
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Received: 9 December 2009; in revised form: 12 January 2010 / Accepted: 1 February 2010 / Published: 10 February 2010
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Abstract: 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.
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Received: 31 December 2009; in revised form: 5 February 2010 / Accepted: 2 March 2010 / Published: 3 March 2010
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Abstract: 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.
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Received: 31 December 2009; in revised form: 17 February 2010 / Accepted: 2 March 2010 / Published: 3 March 2010
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Abstract: 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.
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Received: 22 February 2010; in revised form: 13 April 2010 / Accepted: 26 April 2010 / Published: 27 April 2010
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Abstract: 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.
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Received: 21 February 2010; in revised form: 31 March 2010 / Accepted: 6 May 2010 / Published: 14 May 2010
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Abstract: 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.
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Received: 30 April 2010; in revised form: 15 July 2010 / Accepted: 19 July 2010 / Published: 20 July 2010
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Abstract: Unmanaged sudden withdrawal from the excessive consumption of alcohol (ethanol) adversely alters neuronal integrity in vulnerable brain regions such as the cerebellum, hippocampus, or cortex. In addition to well known hyperexcitatory neurotransmissions, ethanol withdrawal (EW) provokes the intense generation of reactive oxygen species (ROS) and the activation of stress-responding protein kinases, which are the focus of this review article. EW also inflicts mitochondrial membranes/membrane potential, perturbs redox balance, and suppresses mitochondrial enzymes, all of which impair a fundamental function of mitochondria. Moreover, EW acts as an age-provoking stressor. The vulnerable age to EW stress is not necessarily the oldest age and varies depending upon the target molecule of EW. A major female sex steroid, 17β-estradiol (E2), interferes with the EW-induced alteration of oxidative signaling pathways and thereby protects neurons, mitochondria, and behaviors. The current review attempts to provide integrated information at the levels of oxidative signaling mechanisms by which EW provokes brain injuries and E2 protects against it.
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Received: 14 July 2010; in revised form: 28 July 2010 / Accepted: 30 July 2010 / Published: 2 August 2010
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Abstract: Physical exercise has been shown to be beneficial in stroke patients and animal stroke models. However, the exact mechanisms underlying this effect are not yet very clear. The present study investigated whether pre-ischemic treadmill training could induce brain ischemic tolerance (BIT) by inhibiting the excessive glutamate release and event-related kinase 1/2 (ERK1/2) activation observed in rats exposed to middle cerebral artery occlusion (MCAO). Sprague–Dawley rats were divided into three groups (n = 12/group): sham surgery without prior exercise, MCAO without prior exercise and MCAO following three weeks of exercise. Pre-MCAO exercise significantly reduced brain infarct size (103.1 ± 6.7 mm3) relative to MCAO without prior exercise (175.9 ± 13.5 mm3). Similarly, pre-MCAO exercise significantly reduced neurological defects (1.83 ± 0.75) relative to MCAO without exercise (3.00 ± 0.63). As expected, MCAO increased levels of phospho-ERK1/2 (69 ± 5%) relative to sham surgery (40 ± 5%), and phospho-ERK1/2 levels were normalized in rats exposed to pre-ischemic treadmill training (52 ± 6%) relative to MCAO without exercise (69% ± 5%). Parallel effects were observed on striatal glutamate overflow. This study suggests that pre-ischemic treadmill training might induce neuroprotection by inhibiting the phospho-ERK1/2 over-activation and reducing excessive glutamate release.
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Received: 18 June 2010; in revised form: 24 August 2010 / Accepted: 30 August 2010 / Published: 31 August 2010
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Abstract: Cognitive function is multidimensional and complex, and research in multiple species indicates it is considerably impacted by age and gonadal hormone milieu. One domain of cognitive function particularly susceptible to age-related decrements is spatial memory. Gonadal hormones can alter spatial memory, and they are potent modulators of brain microstructure and function in many of the same brain areas affected by aging. In this paper, we review decades of animal and human literature to support a tertiary model representing interactions between gonadal hormones, spatial cognition and age given that: 1) gonadal hormones change with age, 2) age impacts spatial learning and memory, and 3) gonadal hormones impact spatial learning and memory. While much has been discovered regarding these individual tenets, the compass for future aging research points toward clarifying the interactions that exist between these three points, and understanding mediating variables. Indeed, identifying and aligning the various components of the complex interactions between these tenets, including evaluations using basic science, systems, and clinical perspectives, is the optimal approach to attempt to converge the many findings that may currently appear contradictory. In fact, as discoveries are being made it is becoming clear that the findings across studies that appear contradictory are not contradictory at all. Rather, there are mediating variables that are influencing outcome and affecting the extent, and even the direction, of the effects that gonadal hormones have on cognition during aging. These mediating variables are just starting to be understood. By aligning basic scientific discoveries with clinical interpretations, we can maximize the opportunities for discoveries and subsequent interventions to allow individuals to “optimize their aging” and find their own map to cognitive health as aging ensues.
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Received: 16 August 2010; in revised form: 10 September 2010 / Accepted: 14 September 2010 / Published: 20 September 2010
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Abstract: Injury to the central nervous system initiates complex physiological, cellular and molecular processes that can result in neuronal cell death. Of interest to this review is the activation of the kinin family of neuropeptides, in particular bradykinin and substance P. These neuropeptides are known to have a potent pro-inflammatory role and can initiate neurogenic inflammation resulting in vasodilation, plasma extravasation and the subsequent development of edema. As inflammation and edema play an integral role in the progressive secondary injury that causes neurological deficits, this review critically examines kinin receptor antagonists as a potential neuroprotective intervention for acute brain injury, and more specifically, traumatic brain and spinal cord injury and stroke.
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Received: 11 August 2010; in revised form: 16 September 2010 / Accepted: 19 September 2010 / Published: 28 September 2010
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Abstract: Huntington´s disease, one of the so-called poly-glutamine diseases, is a dominantly inherited movement disorder characterized by formation of cytosolic and nuclear inclusion bodies and progressive neurodegeneration. Recently, we have shown that Bcl-2-associated athanogene-1 (BAG1), a multifunctional co-chaperone, modulates toxicity, aggregation, degradation and subcellular distribution in vitro and in vivo of the disease-specific mutant huntingtin protein. Aiming at future small molecule-based therapeutical approaches, we further analysed structural demands for these effects employing the C-terminal deletion mutant BAGDC. We show that disruption of the BAG domain known to eliminate intracellular heat shock protein 70 (Hsp70) binding and activation also precludes binding of Siah-1 thereby leaving nuclear huntingtin translocation unaffected. At the same time BAGDC fails to induce increased proteasomal huntingtin turnover and does not inhibit intracellular huntingtin aggregation, a pre-requisite necessary for prevention of huntingtin toxicity.
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Received: 19 August 2010; in revised form: 6 September 2010 / Accepted: 8 September 2010 / Published: 8 October 2010
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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 aggregated protein species that are cytotoxic. Misfolded proteins may also form aberrant, non-physiological protein-protein interactions leading to the sequestration of other normal proteins essential for 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, and the 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 diseases, highlighting their functional classification, regulation, and therapeutic potential for such diseases.
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Received: 15 October 2010 / Accepted: 20 October 2010 / Published: 3 November 2010
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Abstract: A variety of antioxidant compounds derived from natural products (nutraceuticals) have demonstrated neuroprotective activity in either in vitro 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 review the literature pertaining to these various classes of nutraceutical antioxidants and discuss their potential therapeutic value in neurodegenerative diseases.
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Received: 29 October 2010; in revised form: 29 November 2010 / Accepted: 8 December 2010 / Published: 10 December 2010
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Abstract: It is important to understand the molecular mechanisms underlying neuron death following stroke in order to develop effective neuroprotective strategies. Since studies on human stroke are extremely limited due to the difficulty in collecting post-mortem tissue at different time points after the onset of stroke, brain ischaemia research focuses on information derived from in-vitro models of neuronal death through ischaemic injury [1]. This review aims to provide an update on the different in-vitro stroke models with brain microvascular endothelial cells that are currently being used. These models provide a physiologically relevant tool to screen potential neuroprotective drugs in stroke and to study the molecular mechanisms involved in brain ischaemia.
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Last update: 5 February 2013
