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Topical Collection "Molecular Research in Neurotoxicology"

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A topical collection in International Journal of Molecular Sciences (ISSN 1422-0067). This collection belongs to the section "Molecular Toxicology".

Editor

Collection Editor
Dr. G. Jean Harry

Neurotoxicology Group, NIEHS and National Toxicology Program, National Institute of Environmental Health Sciences, P.O. Box 12233, Research Triangle Park, NC 27709, USA
Website | E-Mail
Phone: 919-967-7449
Fax: +1 919 541 4611
Interests: neurotoxicants; aging; development; inflammation; oxidative stress; signal transduction; hormones; neuropathology; pharmaceuticals; alternative models

Topical Collection Information

Dear Colleagues,

Alterations in nervous system functioning as a result of environmental factors, pharmaceuticals, genetic variability, and health status remain an issue of concern for human health. Recent advancements have been made in our understanding of common biological processes related to neurotoxicity associated with disease states and age-related or genetic vulnerabilities. These advances have been possible due to the ability to examine molecular aspects underlying neurodevelopment, neurodegeneration, and associated processes of neurotoxicity. The integration of this molecular data into the field of neurotoxicology, as it applies to the broad spectrum of environmental exposure now offers a mechanistic framework for understanding the dynamics of neurotoxicity. Further work on epigenetic mechanisms associated with nervous system functioning, e.g., learning and memory, provide additional mechanisms by which regulation of the nervous system can be altered by environmental exposure or by which events occurring during early life stages can influence responses later in life. This topical collection will focus on the integration of established biological processes and molecular events as they relate to the regulation of cellular and functional changes within the nervous system and how this may contribute to neurotoxicity. The collection will include aspects of neurological and neurodegenerative disease, neurodevelopmental disorders, and specific neurotoxicity from environmental or pharmaceutical agents. We are seeking novel research and/or review articles highlighting 1) the variety of molecular signals and integrated networks that underlie adverse responses in the nervous system, 2) how these alterations in molecular signaling translate to alterations in the structure or function of the nervous system (biochemical, physiology, behavior), 3) molecular events occurring during early life that can shift susceptibility in the adult, 4) epigenetic regulatory events as they contribute to neurotoxicity and 5) contributions to life stage events influencing human health.

Dr. G. Jean Harry
Collection Editor

Manuscript Submission Information

Manuscripts for the topical collection can be submitted online at www.mdpi.com by registering and logging in to this website. Once you are registered, click here to go to the submission form. All papers will be peer-reviewed. Accepted papers will be published continuously in the journal (as soon as accepted) and will be listed together on this website. The topical collection considers regular research articles, short communications and review articles. A guide for authors and other relevant information for submission of manuscripts is available on the Instructions for Authors page.

Please visit the Instructions for Authors page before submitting a manuscript. The Article Processing Charge (APC) for publication in this open access journal is 1600 CHF (Swiss Francs).


Keywords

  • oxidative stress
  • organophosphorus pesticides
  • neuropathy target esterase (nte)
  • animal models
  • transcription factor signaling
  • cell death
  • receptor mediated events
  • neural cell differentiation
  • glia
  • kynurenines
  • quinolinic acid
  • inflammation
  • cytokines
  • heat shock protein 70
  • neurobehavior
  • neuroprotection
  • seizures
  • neurotrophic factors
  • ischemia/hypoxia
  • microglia
  • cyanobacteria
  • heavy metals
  • pharmacological models
  • neurodegeneration
  • ischemia
  • perinatal brain injury
  • neurotoxicants
  • neurodegenerative diseases
  • zinc

Published Papers (26 papers)

2016

Jump to: 2015, 2014, 2013

Open AccessReview Toxin-Induced Experimental Models of Learning and Memory Impairment
Int. J. Mol. Sci. 2016, 17(9), 1447; doi:10.3390/ijms17091447
Received: 28 June 2016 / Revised: 24 August 2016 / Accepted: 25 August 2016 / Published: 1 September 2016
Cited by 1 | PDF Full-text (357 KB) | HTML Full-text | XML Full-text
Abstract
Animal models for learning and memory have significantly contributed to novel strategies for drug development and hence are an imperative part in the assessment of therapeutics. Learning and memory involve different stages including acquisition, consolidation, and retrieval and each stage can be characterized
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Animal models for learning and memory have significantly contributed to novel strategies for drug development and hence are an imperative part in the assessment of therapeutics. Learning and memory involve different stages including acquisition, consolidation, and retrieval and each stage can be characterized using specific toxin. Recent studies have postulated the molecular basis of these processes and have also demonstrated many signaling molecules that are involved in several stages of memory. Most insights into learning and memory impairment and to develop a novel compound stems from the investigations performed in experimental models, especially those produced by neurotoxins models. Several toxins have been utilized based on their mechanism of action for learning and memory impairment such as scopolamine, streptozotocin, quinolinic acid, and domoic acid. Further, some toxins like 6-hydroxy dopamine (6-OHDA), 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) and amyloid-β are known to cause specific learning and memory impairment which imitate the disease pathology of Parkinson’s disease dementia and Alzheimer’s disease dementia. Apart from these toxins, several other toxins come under a miscellaneous category like an environmental pollutant, snake venoms, botulinum, and lipopolysaccharide. This review will focus on the various classes of neurotoxin models for learning and memory impairment with their specific mechanism of action that could assist the process of drug discovery and development for dementia and cognitive disorders. Full article
Open AccessReview Local Anesthetic-Induced Neurotoxicity
Int. J. Mol. Sci. 2016, 17(3), 339; doi:10.3390/ijms17030339
Received: 22 December 2015 / Revised: 8 February 2016 / Accepted: 23 February 2016 / Published: 4 March 2016
PDF Full-text (746 KB) | HTML Full-text | XML Full-text
Abstract
This review summarizes current knowledge concerning incidence, risk factors, and mechanisms of perioperative nerve injury, with focus on local anesthetic-induced neurotoxicity. Perioperative nerve injury is a complex phenomenon and can be caused by a number of clinical factors. Anesthetic risk factors for perioperative
[...] Read more.
This review summarizes current knowledge concerning incidence, risk factors, and mechanisms of perioperative nerve injury, with focus on local anesthetic-induced neurotoxicity. Perioperative nerve injury is a complex phenomenon and can be caused by a number of clinical factors. Anesthetic risk factors for perioperative nerve injury include regional block technique, patient risk factors, and local anesthetic-induced neurotoxicity. Surgery can lead to nerve damage by use of tourniquets or by direct mechanical stress on nerves, such as traction, transection, compression, contusion, ischemia, and stretching. Current literature suggests that the majority of perioperative nerve injuries are unrelated to regional anesthesia. Besides the blockade of sodium channels which is responsible for the anesthetic effect, systemic local anesthetics can have a positive influence on the inflammatory response and the hemostatic system in the perioperative period. However, next to these beneficial effects, local anesthetics exhibit time and dose-dependent toxicity to a variety of tissues, including nerves. There is equivocal experimental evidence that the toxicity varies among local anesthetics. Even though the precise order of events during local anesthetic-induced neurotoxicity is not clear, possible cellular mechanisms have been identified. These include the intrinsic caspase-pathway, PI3K-pathway, and MAPK-pathways. Further research will need to determine whether these pathways are non-specifically activated by local anesthetics, or whether there is a single common precipitating factor. Full article

2015

Jump to: 2016, 2014, 2013

Open AccessReview Overnutrition Determines LPS Regulation of Mycotoxin Induced Neurotoxicity in Neurodegenerative Diseases
Int. J. Mol. Sci. 2015, 16(12), 29554-29573; doi:10.3390/ijms161226190
Received: 7 October 2015 / Revised: 19 November 2015 / Accepted: 1 December 2015 / Published: 10 December 2015
Cited by 3 | PDF Full-text (1177 KB) | HTML Full-text | XML Full-text
Abstract
Chronic neurodegenerative diseases are now associated with obesity and diabetes and linked to the developing and developed world. Interests in healthy diets have escalated that may prevent neurodegenerative diseases such as Parkinson’s and Alzheimer’s disease. The global metabolic syndrome involves lipoprotein abnormalities and
[...] Read more.
Chronic neurodegenerative diseases are now associated with obesity and diabetes and linked to the developing and developed world. Interests in healthy diets have escalated that may prevent neurodegenerative diseases such as Parkinson’s and Alzheimer’s disease. The global metabolic syndrome involves lipoprotein abnormalities and insulin resistance and is the major disorder for induction of neurological disease. The effects of bacterial lipopolysaccharides (LPS) on dyslipidemia and NAFLD indicate that the clearance and metabolism of fungal mycotoxins are linked to hypercholesterolemia and amyloid beta oligomers. LPS and mycotoxins are associated with membrane lipid disturbances with effects on cholesterol interacting proteins, lipoprotein metabolism, and membrane apo E/amyloid beta interactions relevant to hypercholesterolemia with close connections to neurological diseases. The influence of diet on mycotoxin metabolism has accelerated with the close association between mycotoxin contamination from agricultural products such as apple juice, grains, alcohol, and coffee. Cholesterol efflux in lipoproteins and membrane cholesterol are determined by LPS with involvement of mycotoxin on amyloid beta metabolism. Nutritional interventions such as diets low in fat/carbohydrate/cholesterol have become of interest with relevance to low absorption of lipophilic LPS and mycotoxin into lipoproteins with rapid metabolism of mycotoxin to the liver with the prevention of neurodegeneration. Full article
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Open AccessArticle Major Alterations of Phosphatidylcholine and Lysophosphotidylcholine Lipids in the Substantia Nigra Using an Early Stage Model of Parkinson’s Disease
Int. J. Mol. Sci. 2015, 16(8), 18865-18877; doi:10.3390/ijms160818865
Received: 18 June 2015 / Revised: 6 August 2015 / Accepted: 6 August 2015 / Published: 12 August 2015
Cited by 2 | PDF Full-text (1024 KB) | HTML Full-text | XML Full-text
Abstract
Parkinson’s disease (PD) is a progressive neurodegenerative disease affecting the nigrostriatal pathway, where patients do not manifest motor symptoms until >50% of neurons are lost. Thus, it is of great importance to determine early neuronal changes that may contribute to disease progression. Recent
[...] Read more.
Parkinson’s disease (PD) is a progressive neurodegenerative disease affecting the nigrostriatal pathway, where patients do not manifest motor symptoms until >50% of neurons are lost. Thus, it is of great importance to determine early neuronal changes that may contribute to disease progression. Recent attention has focused on lipids and their role in pro- and anti-apoptotic processes. However, information regarding the lipid alterations in animal models of PD is lacking. In this study, we utilized high performance liquid chromatography electrospray ionization tandem mass spectrometry (HPLC-ESI-MS/MS) and novel HPLC solvent methodology to profile phosphatidylcholines and sphingolipids within the substantia nigra. The ipsilateral substantia nigra pars compacta was collected from rats 21 days after an infusion of 6-hydroxydopamine (6-OHDA), or vehicle into the anterior dorsal striatum. We identified 115 lipid species from their mass/charge ratio using the LMAPS Lipid MS Predict Database. Of these, 19 lipid species (from phosphatidylcholine and lysophosphotidylcholine lipid classes) were significantly altered by 6-OHDA, with most being down-regulated. The two lipid species that were up-regulated were LPC (16:0) and LPC (18:1), which are important for neuroinflammatory signalling. These findings provide a first step in the characterization of lipid changes in early stages of PD-like pathology and could provide novel targets for early interventions in PD. Full article
Open AccessArticle Combination of Aβ Secretion and Oxidative Stress in an Alzheimer-Like Cell Line Leads to the Over-Expression of the Nucleotide Excision Repair Proteins DDB2 and XPC
Int. J. Mol. Sci. 2015, 16(8), 17422-17444; doi:10.3390/ijms160817422
Received: 7 May 2015 / Revised: 19 June 2015 / Accepted: 29 June 2015 / Published: 30 July 2015
Cited by 1 | PDF Full-text (1245 KB) | HTML Full-text | XML Full-text
Abstract
Repair of oxidative DNA damage, particularly Base Excision Repair (BER), impairment is often associated with Alzheimer’s disease pathology. Here, we aimed at investigating the complete Nucleotide Excision Repair (NER), a DNA repair pathway involved in the removal of bulky DNA adducts, status in
[...] Read more.
Repair of oxidative DNA damage, particularly Base Excision Repair (BER), impairment is often associated with Alzheimer’s disease pathology. Here, we aimed at investigating the complete Nucleotide Excision Repair (NER), a DNA repair pathway involved in the removal of bulky DNA adducts, status in an Alzheimer-like cell line. The level of DNA damage was quantified using mass spectrometry, NER gene expression was assessed by qPCR, and the NER protein activity was analysed through a modified version of the COMET assay. Interestingly, we found that in the presence of the Amyloid β peptide (Aβ), NER factors were upregulated at the mRNA level and that NER capacities were also specifically increased following oxidative stress. Surprisingly, NER capacities were not differentially improved following a typical NER-triggering of ultraviolet C (UVC) stress. Oxidative stress generates a differential and specific DNA damage response in the presence of Aβ. We hypothesized that the release of NER components such as DNA damage binding protein 2 (DDB2) and Xeroderma Pigmentosum complementation group C protein (XPC) following oxidative stress might putatively involve their apoptotic role rather than DNA repair function. Full article
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Open AccessArticle Humic Acid Increases Amyloid β-Induced Cytotoxicity by Induction of ER Stress in Human SK-N-MC Neuronal Cells
Int. J. Mol. Sci. 2015, 16(5), 10426-10442; doi:10.3390/ijms160510426
Received: 25 January 2015 / Revised: 23 April 2015 / Accepted: 4 May 2015 / Published: 7 May 2015
Cited by 4 | PDF Full-text (3753 KB) | HTML Full-text | XML Full-text
Abstract
Humic acid (HA) is a possible etiological factor associated with for several vascular diseases. It is known that vascular risk factors can directly increase the susceptibility to Alzheimer’s disease (AD), which is a neurodegenerative disorder due to accumulation of amyloid β (Aβ) peptide
[...] Read more.
Humic acid (HA) is a possible etiological factor associated with for several vascular diseases. It is known that vascular risk factors can directly increase the susceptibility to Alzheimer’s disease (AD), which is a neurodegenerative disorder due to accumulation of amyloid β (Aβ) peptide in the brain. However, the role that HA contributes to Aβ-induced cytotoxicity has not been demonstrated. In the present study, we demonstrate that HA exhibits a synergistic effect enhancing Aβ-induced cytotoxicity in cultured human SK-N-MC neuronal cells. Furthermore, this deterioration was mediated through the activation of endoplasmic reticulum (ER) stress by stimulating PERK and eIF2α phosphorylation. We also observed HA and Aβ-induced cytotoxicity is associated with mitochondrial dysfunction caused by down-regulation of the Sirt1/PGC1α pathway, while in contrast, treating the cells with the ER stress inhibitor Salubrinal, or over-expression of Sirt1 significantly reduced loss of cell viability by HA and Aβ. Our findings suggest a new mechanism by which HA can deteriorate Aβ-induced cytotoxicity through modulation of ER stress, which may provide significant insights into the pathogenesis of AD co-occurring with vascular injury. Full article
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Open AccessArticle Interleukin-1 Receptor Antagonist Reduces Neonatal Lipopolysaccharide-Induced Long-Lasting Neurobehavioral Deficits and Dopaminergic Neuronal Injury in Adult Rats
Int. J. Mol. Sci. 2015, 16(4), 8635-8654; doi:10.3390/ijms16048635
Received: 26 January 2015 / Revised: 31 March 2015 / Accepted: 10 April 2015 / Published: 17 April 2015
Cited by 7 | PDF Full-text (3747 KB) | HTML Full-text | XML Full-text
Abstract
Our previous study showed that a single lipopolysaccharide (LPS) treatment to neonatal rats could induce a long-lasting neuroinflammatory response and dopaminergic system injury late in life. This is evidenced by a sustained activation of microglia and elevated interleukin-1β (IL-1β) levels, as well as
[...] Read more.
Our previous study showed that a single lipopolysaccharide (LPS) treatment to neonatal rats could induce a long-lasting neuroinflammatory response and dopaminergic system injury late in life. This is evidenced by a sustained activation of microglia and elevated interleukin-1β (IL-1β) levels, as well as reduced tyrosine hydroxylase (TH) expression in the substantia nigra (SN) of P70 rat brain. The object of the current study was to test whether co-administration of IL-1 receptor antagonist (IL-1ra) protects against LPS-induced neurological dysfunction later in life. LPS (1 mg/kg) with or without IL-1ra (0.1 mg/kg), or sterile saline was injected intracerebrally into postnatal day 5 (P5) Sprague-Dawley male rat pups. Motor behavioral tests were carried out from P7 to P70 with subsequent examination of brain injury. Our results showed that neonatal administration of IL-1ra significantly attenuated LPS-induced motor behavioral deficits, loss of TH immunoreactive neurons, as well as microglia activation in the SN of P70 rats. These data suggest that IL-1β may play a pivotal role in mediating a chronic neuroinflammation status by a single LPS exposure in early postnatal life, and blockading IL-1β might be a novel approach to protect the dopaminergic system against perinatal infection/inflammation exposure. Full article
Open AccessReview A Heme Oxygenase-1 Transducer Model of Degenerative and Developmental Brain Disorders
Int. J. Mol. Sci. 2015, 16(3), 5400-5419; doi:10.3390/ijms16035400
Received: 11 December 2014 / Revised: 28 January 2015 / Accepted: 22 February 2015 / Published: 9 March 2015
Cited by 5 | PDF Full-text (4591 KB) | HTML Full-text | XML Full-text
Abstract
Heme oxygenase-1 (HO-1) is a 32 kDa protein which catalyzes the breakdown of heme to free iron, carbon monoxide and biliverdin. The Hmox1 promoter contains numerous consensus sequences that render the gene exquisitely sensitive to induction by diverse pro-oxidant and inflammatory stimuli. In
[...] Read more.
Heme oxygenase-1 (HO-1) is a 32 kDa protein which catalyzes the breakdown of heme to free iron, carbon monoxide and biliverdin. The Hmox1 promoter contains numerous consensus sequences that render the gene exquisitely sensitive to induction by diverse pro-oxidant and inflammatory stimuli. In “stressed” astroglia, HO-1 hyperactivity promotes mitochondrial iron sequestration and macroautophagy and may thereby contribute to the pathological iron deposition and bioenergetic failure documented in Alzheimer disease, Parkinson disease and certain neurodevelopmental conditions. Glial HO-1 expression may also impact neuroplasticity and cell survival by modulating brain sterol metabolism and the proteasomal degradation of neurotoxic proteins. The glial HO-1 response may represent a pivotal transducer of noxious environmental and endogenous stressors into patterns of neural damage and repair characteristic of many human degenerative and developmental CNS disorders. Full article
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Open AccessReview Extracellular Vesicles in Alzheimer’s Disease: Friends or Foes? Focus on Aβ-Vesicle Interaction
Int. J. Mol. Sci. 2015, 16(3), 4800-4813; doi:10.3390/ijms16034800
Received: 23 December 2014 / Revised: 16 February 2015 / Accepted: 17 February 2015 / Published: 3 March 2015
Cited by 16 | PDF Full-text (1133 KB) | HTML Full-text | XML Full-text
Abstract
The intercellular transfer of amyloid-β (Aβ) and tau proteins has received increasing attention in Alzheimer’s disease (AD). Among other transfer modes, Aβ and tau dissemination has been suggested to occur through release of Extracellular Vesicles (EVs), which may facilitate delivery of pathogenic proteins
[...] Read more.
The intercellular transfer of amyloid-β (Aβ) and tau proteins has received increasing attention in Alzheimer’s disease (AD). Among other transfer modes, Aβ and tau dissemination has been suggested to occur through release of Extracellular Vesicles (EVs), which may facilitate delivery of pathogenic proteins over large distances. Recent evidence indicates that EVs carry on their surface, specific molecules which bind to extracellular Aβ, opening the possibility that EVs may also influence Aβ assembly and synaptotoxicity. In this review we focus on studies which investigated the impact of EVs in Aβ-mediated neurodegeneration and showed either detrimental or protective role for EVs in the pathology. Full article
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Open AccessArticle Human Adipose Tissue Conditioned Media from Lean Subjects Is Protective against H2O2 Induced Neurotoxicity in Human SH-SY5Y Neuronal Cells
Int. J. Mol. Sci. 2015, 16(1), 1221-1231; doi:10.3390/ijms16011221
Received: 22 September 2014 / Accepted: 24 December 2014 / Published: 6 January 2015
Cited by 3 | PDF Full-text (1094 KB) | HTML Full-text | XML Full-text
Abstract
Adipose tissue secretes numerous hormone-like factors, which are known as adipokines. Adipokine receptors have been identified in the central nervous system but the potential role of adipokine signaling in neuroprotection is unclear. The aim of this study is to determine (1) Whether adipokines
[...] Read more.
Adipose tissue secretes numerous hormone-like factors, which are known as adipokines. Adipokine receptors have been identified in the central nervous system but the potential role of adipokine signaling in neuroprotection is unclear. The aim of this study is to determine (1) Whether adipokines secreted from cultured adipose tissue of lean humans is protective against oxidative stress-induced neurotoxicity in human SH-SY5Y neuronal cells; and (2) To explore potential signaling pathways involved in these processes. Adipose tissue conditioned media (ATCM) from healthy lean subjects completely prevented H2O2 induced neurotoxicity, while this effect is lost after heating ATCM. ATCM activated the phosphorylation of ERK1/2, JNK and Akt at serine 308 in SH-SY5Y cells. PD98059 (25 µM), SP600125 (5 µM) and LY29400 (20 µM) partially blocked the protective effects of ATCM against H2O2 induced neurotoxicity. Findings demonstrate that heat-sensitive factors secreted from human adipose tissue of lean subjects are protective against H2O2 induced neurotoxicity and ERK1/2, JNK, and PI3K signaling pathways are involved in these processes. In conclusion, this study demonstrates preliminary but encouraging data to further support that adipose tissue secreted factors from lean human subjects might possess neuroprotective properties and unravel the specific roles of ERK1/2, JNK and PI3K in these processes. Full article

2014

Jump to: 2016, 2015, 2013

Open AccessReview P2X and P2Y Receptors—Role in the Pathophysiology of the Nervous System
Int. J. Mol. Sci. 2014, 15(12), 23672-23704; doi:10.3390/ijms151223672
Received: 4 November 2014 / Revised: 3 December 2014 / Accepted: 6 December 2014 / Published: 18 December 2014
Cited by 10 | PDF Full-text (828 KB) | HTML Full-text | XML Full-text
Abstract
Purinergic signalling plays a crucial role in proper functioning of the nervous system. Mechanisms depending on extracellular nucleotides and their P2 receptors also underlie a number of nervous system dysfunctions. This review aims to present the role of purinergic signalling, with particular focus
[...] Read more.
Purinergic signalling plays a crucial role in proper functioning of the nervous system. Mechanisms depending on extracellular nucleotides and their P2 receptors also underlie a number of nervous system dysfunctions. This review aims to present the role of purinergic signalling, with particular focus devoted to role of P2 family receptors, in epilepsy, depression, neuropathic pain, nervous system neoplasms, such as glioma and neuroblastoma, neurodegenerative diseases like Parkinson’s disease, Alzheimer’s disease and multiple sclerosis. The above-mentioned conditions are associated with changes in expression of extracellular ectonucleotidases, P2X and P2Y receptors in neurons and glial cells, as well as releasing considerable amounts of nucleotides from activated or damaged nervous tissue cells into the extracellular space, which contributes to disturbance in purinergic signalling. The numerous studies indicate a potential possibility of using synthetic agonists/antagonists of P2 receptors in treatment of selected nervous system diseases. This is of particular significance, since numerous available agents reveal a low effectiveness and often produce side effects. Full article
Open AccessReview Molecular Mechanisms Underlying the Effects of Statins in the Central Nervous System
Int. J. Mol. Sci. 2014, 15(11), 20607-20637; doi:10.3390/ijms151120607
Received: 16 September 2014 / Revised: 23 October 2014 / Accepted: 30 October 2014 / Published: 10 November 2014
Cited by 12 | PDF Full-text (878 KB) | HTML Full-text | XML Full-text
Abstract
3-Hydroxy-3-methylglutaryl coenzyme A reductase inhibitors, commonly referred to as statins, are widely used in the treatment of dyslipidaemia, in addition to providing primary and secondary prevention against cardiovascular disease and stroke. Statins’ effects on the central nervous system (CNS), particularly on cognition and
[...] Read more.
3-Hydroxy-3-methylglutaryl coenzyme A reductase inhibitors, commonly referred to as statins, are widely used in the treatment of dyslipidaemia, in addition to providing primary and secondary prevention against cardiovascular disease and stroke. Statins’ effects on the central nervous system (CNS), particularly on cognition and neurological disorders such as stroke and multiple sclerosis, have received increasing attention in recent years, both within the scientific community and in the media. Current understanding of statins’ effects is limited by a lack of mechanism-based studies, as well as the assumption that all statins have the same pharmacological effect in the central nervous system. This review aims to provide an updated discussion on the molecular mechanisms contributing to statins’ possible effects on cognitive function, neurodegenerative disease, and various neurological disorders such as stroke, epilepsy, depression and CNS cancers. Additionally, the pharmacokinetic differences between statins and how these may result in statin-specific neurological effects are also discussed. Full article
Open AccessArticle Genomic and Phenotypic Alterations of the Neuronal-Like Cells Derived from Human Embryonal Carcinoma Stem Cells (NT2) Caused by Exposure to Organophosphorus Compounds Paraoxon and Mipafox
Int. J. Mol. Sci. 2014, 15(1), 905-926; doi:10.3390/ijms15010905
Received: 14 October 2013 / Revised: 8 December 2013 / Accepted: 17 December 2013 / Published: 9 January 2014
Cited by 8 | PDF Full-text (780 KB) | HTML Full-text | XML Full-text | Supplementary Files
Abstract
Historically, only few chemicals have been identified as neurodevelopmental toxicants, however, concern remains, and has recently increased, based upon the association between chemical exposures and increased developmental disorders. Diminution in motor speed and latency has been reported in preschool children from agricultural communities.
[...] Read more.
Historically, only few chemicals have been identified as neurodevelopmental toxicants, however, concern remains, and has recently increased, based upon the association between chemical exposures and increased developmental disorders. Diminution in motor speed and latency has been reported in preschool children from agricultural communities. Organophosphorus compounds (OPs) are pesticides due to their acute insecticidal effects mediated by the inhibition of acetylcholinesterase, although other esterases as neuropathy target esterase (NTE) can also be inhibited. Other neurological and neurodevelopmental toxic effects with unknown targets have been reported after chronic exposure to OPs in vivo. We studied the initial stages of retinoic acid acid-triggered differentiation of pluripotent cells towards neural progenitors derived from human embryonal carcinoma stem cells to determine if neuropathic OP, mipafox, and non-neuropathic OP, paraoxon, are able to alter differentiation of neural precursor cells in vitro. Exposure to 1 µM paraoxon (non-cytotoxic concentrations) altered the expression of different genes involved in signaling pathways related to chromatin assembly and nucleosome integrity. Conversely, exposure to 5 µM mipafox, a known inhibitor of NTE activity, showed no significant changes on gene expression. We conclude that 1 µM paraoxon could affect the initial stage of in vitro neurodifferentiation possibly due to a teratogenic effect, while the absence of transcriptional alterations by mipafox exposure did not allow us to conclude a possible effect on neurodifferentiation pathways at the tested concentration. Full article

2013

Jump to: 2016, 2015, 2014

Open AccessReview Oxidative Stress and Neurodegenerative Disorders
Int. J. Mol. Sci. 2013, 14(12), 24438-24475; doi:10.3390/ijms141224438
Received: 14 October 2013 / Revised: 27 November 2013 / Accepted: 6 December 2013 / Published: 16 December 2013
Cited by 59 | PDF Full-text (523 KB) | HTML Full-text | XML Full-text
Abstract
Living cells continually generate reactive oxygen species (ROS) through the respiratory chain during energetic metabolism. ROS at low or moderate concentration can play important physiological roles. However, an excessive amount of ROS under oxidative stress would be extremely deleterious. The central nervous system
[...] Read more.
Living cells continually generate reactive oxygen species (ROS) through the respiratory chain during energetic metabolism. ROS at low or moderate concentration can play important physiological roles. However, an excessive amount of ROS under oxidative stress would be extremely deleterious. The central nervous system (CNS) is particularly vulnerable to oxidative stress due to its high oxygen consumption, weakly antioxidative systems and the terminal-differentiation characteristic of neurons. Thus, oxidative stress elicits various neurodegenerative diseases. In addition, chemotherapy could result in severe side effects on the CNS and peripheral nervous system (PNS) of cancer patients, and a growing body of evidence demonstrates the involvement of ROS in drug-induced neurotoxicities as well. Therefore, development of antioxidants as neuroprotective drugs is a potentially beneficial strategy for clinical therapy. In this review, we summarize the source, balance maintenance and physiologic functions of ROS, oxidative stress and its toxic mechanisms underlying a number of neurodegenerative diseases, and the possible involvement of ROS in chemotherapy-induced toxicity to the CNS and PNS. We ultimately assess the value for antioxidants as neuroprotective drugs and provide our comments on the unmet needs. Full article
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Open AccessReview Oxidative Stress Mechanisms Underlying Parkinson’s Disease-Associated Neurodegeneration in C. elegans
Int. J. Mol. Sci. 2013, 14(11), 23103-23128; doi:10.3390/ijms141123103
Received: 14 August 2013 / Revised: 8 October 2013 / Accepted: 16 October 2013 / Published: 21 November 2013
Cited by 15 | PDF Full-text (311 KB) | HTML Full-text | XML Full-text
Abstract
Oxidative stress is thought to play a significant role in the development and progression of neurodegenerative diseases. Although it is currently considered a hallmark of such processes, the interweaving of a multitude of signaling cascades hinders complete understanding of the direct role of
[...] Read more.
Oxidative stress is thought to play a significant role in the development and progression of neurodegenerative diseases. Although it is currently considered a hallmark of such processes, the interweaving of a multitude of signaling cascades hinders complete understanding of the direct role of oxidative stress in neurodegeneration. In addition to its extensive use as an aging model, some researchers have turned to the invertebrate model Caenorhabditis elegans (C. elegans) in order to further investigate molecular mediators that either exacerbate or protect against reactive oxygen species (ROS)-mediated neurodegeneration. Due to their fully characterized genome and short life cycle, rapid generation of C. elegans genetic models can be useful to study upstream markers of oxidative stress within interconnected signaling pathways. This report will focus on the roles of C. elegans homologs for the oxidative stress-associated transcription factor Nrf2, as well as the autosomal recessive, early-onset Parkinson’s disease (PD)-associated proteins Parkin, DJ-1, and PINK1, in neurodegenerative processes. Full article
Open AccessReview How Parkinsonian Toxins Dysregulate the Autophagy Machinery
Int. J. Mol. Sci. 2013, 14(11), 22163-22189; doi:10.3390/ijms141122163
Received: 30 September 2013 / Revised: 28 October 2013 / Accepted: 28 October 2013 / Published: 8 November 2013
Cited by 16 | PDF Full-text (782 KB) | HTML Full-text | XML Full-text
Abstract
Since their discovery, Parkinsonian toxins (6-hydroxydopamine, MPP+, paraquat, and rotenone) have been widely employed as in vivo and in vitro chemical models of Parkinson’s disease (PD). Alterations in mitochondrial homeostasis, protein quality control pathways, and more recently, autophagy/mitophagy have been implicated in neurotoxin
[...] Read more.
Since their discovery, Parkinsonian toxins (6-hydroxydopamine, MPP+, paraquat, and rotenone) have been widely employed as in vivo and in vitro chemical models of Parkinson’s disease (PD). Alterations in mitochondrial homeostasis, protein quality control pathways, and more recently, autophagy/mitophagy have been implicated in neurotoxin models of PD. Here, we highlight the molecular mechanisms by which different PD toxins dysregulate autophagy/mitophagy and how alterations of these pathways play beneficial or detrimental roles in dopamine neurons. The convergent and divergent effects of PD toxins on mitochondrial function and autophagy/mitophagy are also discussed in this review. Furthermore, we propose new diagnostic tools and discuss how pharmacological modulators of autophagy/mitophagy can be developed as disease-modifying treatments for PD. Finally, we discuss the critical need to identify endogenous and synthetic forms of PD toxins and develop efficient health preventive programs to mitigate the risk of developing PD. Full article
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Open AccessReview The Molecular Mechanisms of Zinc Neurotoxicity and the Pathogenesis of Vascular Type Senile Dementia
Int. J. Mol. Sci. 2013, 14(11), 22067-22081; doi:10.3390/ijms141122067
Received: 18 September 2013 / Revised: 18 October 2013 / Accepted: 22 October 2013 / Published: 7 November 2013
Cited by 13 | PDF Full-text (568 KB) | HTML Full-text | XML Full-text
Abstract
Zinc (Zn) is an essential trace element that is abundantly present in the brain. Despite its importance in normal brain functions, excess Zn is neurotoxic and causes neurodegeneration following transient global ischemia and plays a crucial role in the pathogenesis of vascular-type dementia
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Zinc (Zn) is an essential trace element that is abundantly present in the brain. Despite its importance in normal brain functions, excess Zn is neurotoxic and causes neurodegeneration following transient global ischemia and plays a crucial role in the pathogenesis of vascular-type dementia (VD). We have investigated the molecular mechanisms of Zn-induced neurotoxicity using immortalized hypothalamic neurons (GT1-7 cells) and found that carnosine (β-alanyl histidine) and histidine (His) inhibited Zn2+-induced neuronal death. A DNA microarray analysis revealed that the expression of several genes, including metal-related genes (metallothionein and Zn transporter 1), endoplasmic reticulum (ER)-stress related genes (GADD34, GADD45, and p8), and the calcium (Ca)-related gene Arc (activity-related cytoskeleton protein), were affected after Zn exposure. The co-existence of carnosine or His inhibited the expression of GADD34, p8, and Arc, although they did not influence the expression of the metal-related genes. Therefore, ER-stress and the disruption of Ca homeostasis may underlie the mechanisms of Zn-induced neurotoxicity, and carnosine might be a possible drug candidate for the treatment of VD. Full article
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Open AccessArticle Quinolinic Acid: Neurotoxin or Oxidative Stress Modulator?
Int. J. Mol. Sci. 2013, 14(11), 21328-21338; doi:10.3390/ijms141121328
Received: 2 September 2013 / Revised: 2 October 2013 / Accepted: 22 October 2013 / Published: 25 October 2013
Cited by 6 | PDF Full-text (482 KB) | HTML Full-text | XML Full-text
Abstract
Quinolinic acid (2,3-pyridinedicarboxylic acid, QUIN) is a well-known neurotoxin. Consequently, QUIN could produce reactive oxygen species (ROS). ROS are generated in reactions catalyzed by transition metals, especially iron (Fe). QUIN can form coordination complexes with iron. A combination of differential pulse voltammetry, deoxyribose
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Quinolinic acid (2,3-pyridinedicarboxylic acid, QUIN) is a well-known neurotoxin. Consequently, QUIN could produce reactive oxygen species (ROS). ROS are generated in reactions catalyzed by transition metals, especially iron (Fe). QUIN can form coordination complexes with iron. A combination of differential pulse voltammetry, deoxyribose degradation and Fe(II) autoxidation assays was used for explorating ROS formation in redox reactions that are catalyzed by iron in QUIN-Fe complexes. Differential pulse voltammetry showed an anodic shift of the iron redox potential if iron was liganded by QUIN. In the H2O2/FeCl3/ascorbic acid variant of the deoxyribose degradation assay, the dose-response curve was U-shaped. In the FeCl3/ascorbic acid variant, QUIN unambiguously showed antioxidant effects. In the Fe(II) autoxidation assay, QUIN decreased the rate of ROS production caused by Fe(II) oxidation. Our study confirms that QUIN toxicity may be caused by ROS generation via the Fenton reaction. This, however, applies only for unnaturally high concentrations that were used in attempts to provide support for the neurotoxic effect. In lower concentrations, we show that by liganding iron, QUIN affects the Fe(II)/Fe(III) ratios that are beneficial to homeostasis. Our results support the notion that redox chemistry can contribute to explaining the hormetic dose-response effects. Full article
Open AccessReview Impaired Glutathione Synthesis in Neurodegeneration
Int. J. Mol. Sci. 2013, 14(10), 21021-21044; doi:10.3390/ijms141021021
Received: 23 August 2013 / Revised: 30 September 2013 / Accepted: 1 October 2013 / Published: 18 October 2013
Cited by 34 | PDF Full-text (665 KB) | HTML Full-text | XML Full-text
Abstract
Glutathione (GSH) was discovered in yeast cells in 1888. Studies of GSH in mammalian cells before the 1980s focused exclusively on its function for the detoxication of xenobiotics or for drug metabolism in the liver, in which GSH is present at its highest
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Glutathione (GSH) was discovered in yeast cells in 1888. Studies of GSH in mammalian cells before the 1980s focused exclusively on its function for the detoxication of xenobiotics or for drug metabolism in the liver, in which GSH is present at its highest concentration in the body. Increasing evidence has demonstrated other important roles of GSH in the brain, not only for the detoxication of xenobiotics but also for antioxidant defense and the regulation of intracellular redox homeostasis. GSH also regulates cell signaling, protein function, gene expression, and cell differentiation/proliferation in the brain. Clinically, inborn errors in GSH-related enzymes are very rare, but disorders of GSH metabolism are common in major neurodegenerative diseases showing GSH depletion and increased levels of oxidative stress in the brain. GSH depletion would precipitate oxidative damage in the brain, leading to neurodegenerative diseases. This review focuses on the significance of GSH function, the synthesis of GSH and its metabolism, and clinical disorders of GSH metabolism. A potential approach to increase brain GSH levels against neurodegeneration is also discussed. Full article
Open AccessArticle Cytokines, Chaperones and Neuroinflammatory Responses in Heroin-Related Death: What Can We Learn from Different Patterns of Cellular Expression?
Int. J. Mol. Sci. 2013, 14(10), 19831-19845; doi:10.3390/ijms141019831
Received: 26 August 2013 / Revised: 22 September 2013 / Accepted: 26 September 2013 / Published: 30 September 2013
Cited by 3 | PDF Full-text (4702 KB) | HTML Full-text | XML Full-text
Abstract
Heroin (3,6-diacetylmorphine) has various effects on the central nervous system with several neuropathological alterations including hypoxic-ischemic brain damage from respiratory depressing effects and neuroinflammatory response. Both of these mechanisms induce the release of cytokines, chemokines and other inflammatory mediators by the activation of
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Heroin (3,6-diacetylmorphine) has various effects on the central nervous system with several neuropathological alterations including hypoxic-ischemic brain damage from respiratory depressing effects and neuroinflammatory response. Both of these mechanisms induce the release of cytokines, chemokines and other inflammatory mediators by the activation of many cell types such as leucocytes and endothelial and glial cells, especially microglia, the predominant immunocompetent cell type within the central nervous system. The aim of this study is to clarify the correlation between intravenous heroin administration in heroin related death and the neuroinflammatory response. We selected 45 cases among autopsies executed for heroin-related death (358 total cases); immunohistochemical studies and Western blotting analyses were used to investigate the expression of brain markers such as tumor necrosis factor-α, oxygen-regulated protein 150, (interleukins) IL-1β, IL-6, IL-8, IL-10, IL-15, cyclooxygenase-2, heat shock protein 70, and CD68 (MAC387). Findings demonstrated that morphine induces inflammatory response and cytokine release. In particular, oxygen-regulated protein 150, cyclooxygenase-2, heat shock protein 70, IL-6 and IL-15 cytokines were over-expressed with different patterns of cellular expression. Full article
Open AccessArticle Exposure to Enriched Environment Decreases Neurobehavioral Deficits Induced by Neonatal Glutamate Toxicity
Int. J. Mol. Sci. 2013, 14(9), 19054-19066; doi:10.3390/ijms140919054
Received: 19 July 2013 / Revised: 8 August 2013 / Accepted: 14 August 2013 / Published: 16 September 2013
Cited by 5 | PDF Full-text (351 KB) | HTML Full-text | XML Full-text
Abstract
Environmental enrichment is a popular strategy to enhance motor and cognitive performance and to counteract the effects of various harmful stimuli. The protective effects of enriched environment have been shown in traumatic, ischemic and toxic nervous system lesions. Monosodium glutamate (MSG) is a
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Environmental enrichment is a popular strategy to enhance motor and cognitive performance and to counteract the effects of various harmful stimuli. The protective effects of enriched environment have been shown in traumatic, ischemic and toxic nervous system lesions. Monosodium glutamate (MSG) is a commonly used taste enhancer causing excitotoxic effects when given in newborn animals. We have previously demonstrated that MSG leads to a delay in neurobehavioral development, as shown by the delayed appearance of neurological reflexes and maturation of motor coordination. In the present study we aimed at investigating whether environmental enrichment is able to decrease the neurobehavioral delay caused by neonatal MSG treatment. Newborn pups were treated with MSG subcutaneously on postnatal days 1, 5 and 9. For environmental enrichment, we placed rats in larger cages, supplemented with different toys that were altered daily. Normal control and enriched control rats received saline treatment only. Physical parameters such as weight, day of eye opening, incisor eruption and ear unfolding were recorded. Animals were observed for appearance of reflexes such as negative geotaxis, righting reflexes, fore- and hindlimb grasp, fore- and hindlimb placing, sensory reflexes and gait. In cases of negative geotaxis, surface righting and gait, the time to perform the reflex was also recorded daily. For examining motor coordination, we performed grid walking, footfault, rope suspension, rota-rod, inclined board and walk initiation tests. We found that enriched environment alone did not lead to marked alterations in the course of development. On the other hand, MSG treatment caused a slight delay in reflex development and a pronounced delay in weight gain and motor coordination maturation. This delay in most signs and tests could be reversed by enriched environment: MSG-treated pups kept under enriched conditions showed no weight retardation, no reflex delay in some signs and performed better in most coordination tests. These results show that environmental enrichment is able to decrease the neurobehavioral delay caused by neonatal excitotoxicity. Full article
Open AccessReview Experimental Models of Status Epilepticus and Neuronal Injury for Evaluation of Therapeutic Interventions
Int. J. Mol. Sci. 2013, 14(9), 18284-18318; doi:10.3390/ijms140918284
Received: 3 July 2013 / Revised: 31 July 2013 / Accepted: 9 August 2013 / Published: 5 September 2013
Cited by 38 | PDF Full-text (441 KB) | HTML Full-text | XML Full-text
Abstract
This article describes current experimental models of status epilepticus (SE) and neuronal injury for use in the screening of new therapeutic agents. Epilepsy is a common neurological disorder characterized by recurrent unprovoked seizures. SE is an emergency condition associated with continuous seizures lasting
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This article describes current experimental models of status epilepticus (SE) and neuronal injury for use in the screening of new therapeutic agents. Epilepsy is a common neurological disorder characterized by recurrent unprovoked seizures. SE is an emergency condition associated with continuous seizures lasting more than 30 min. It causes significant mortality and morbidity. SE can cause devastating damage to the brain leading to cognitive impairment and increased risk of epilepsy. Benzodiazepines are the first-line drugs for the treatment of SE, however, many people exhibit partial or complete resistance due to a breakdown of GABA inhibition. Therefore, new drugs with neuroprotective effects against the SE-induced neuronal injury and degeneration are desirable. Animal models are used to study the pathophysiology of SE and for the discovery of newer anticonvulsants. In SE paradigms, seizures are induced in rodents by chemical agents or by electrical stimulation of brain structures. Electrical stimulation includes perforant path and self-sustaining stimulation models. Pharmacological models include kainic acid, pilocarpine, flurothyl, organophosphates and other convulsants that induce SE in rodents. Neuronal injury occurs within the initial SE episode, and animals exhibit cognitive dysfunction and spontaneous seizures several weeks after this precipitating event. Current SE models have potential applications but have some limitations. In general, the experimental SE model should be analogous to the human seizure state and it should share very similar neuropathological mechanisms. The pilocarpine and diisopropylfluorophosphate models are associated with prolonged, diazepam-insensitive seizures and neurodegeneration and therefore represent paradigms of refractory SE. Novel mechanism-based or clinically relevant models are essential to identify new therapies for SE and neuroprotective interventions. Full article
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Open AccessReview Gene Expression Profiling as a Tool to Investigate the Molecular Machinery Activated during Hippocampal Neurodegeneration Induced by Trimethyltin (TMT) Administration
Int. J. Mol. Sci. 2013, 14(8), 16817-16835; doi:10.3390/ijms140816817
Received: 23 July 2013 / Revised: 6 August 2013 / Accepted: 8 August 2013 / Published: 15 August 2013
Cited by 11 | PDF Full-text (1203 KB) | HTML Full-text | XML Full-text
Abstract
Trimethyltin (TMT) is an organotin compound exhibiting neurotoxicant effects selectively localized in the limbic system and especially marked in the hippocampus, in both experimental animal models and accidentally exposed humans. TMT administration causes selective neuronal death involving either the granular neurons of the
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Trimethyltin (TMT) is an organotin compound exhibiting neurotoxicant effects selectively localized in the limbic system and especially marked in the hippocampus, in both experimental animal models and accidentally exposed humans. TMT administration causes selective neuronal death involving either the granular neurons of the dentate gyrus or the pyramidal cells of the Cornu Ammonis, with a different pattern of localization depending on the different species studied or the dosage schedule. TMT is broadly used to realize experimental models of hippocampal neurodegeneration associated with cognitive impairment and temporal lobe epilepsy, though the molecular mechanisms underlying the associated selective neuronal death are still not conclusively clarified. Experimental evidence indicates that TMT-induced neurodegeneration is a complex event involving different pathogenetic mechanisms, probably acting differently in animal and cell models, which include neuroinflammation, intracellular calcium overload, and oxidative stress. Microarray-based, genome-wide expression analysis has been used to investigate the molecular scenario occurring in the TMT-injured brain in different in vivo and in vitro models, producing an overwhelming amount of data. The aim of this review is to discuss and rationalize the state-of-the-art on TMT-associated genome wide expression profiles in order to identify comparable and reproducible data that may allow focusing on significantly involved pathways. Full article
Open AccessArticle Effect of δ-Opioid Receptor Activation on BDNF-TrkB vs. TNF-α in the Mouse Cortex Exposed to Prolonged Hypoxia
Int. J. Mol. Sci. 2013, 14(8), 15959-15976; doi:10.3390/ijms140815959
Received: 19 June 2013 / Revised: 25 July 2013 / Accepted: 25 July 2013 / Published: 31 July 2013
Cited by 15 | PDF Full-text (3262 KB) | HTML Full-text | XML Full-text
Abstract
We investigated whether δ-opioid receptor (DOR)-induced neuroprotection involves the brain-derived neurotrophic factor (BDNF) pathway. We studied the effect of DOR activation on the expression of BDNF and other proteins in the cortex of C57BL/6 mice exposed to hypoxia (10% of oxygen) for 1–10
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We investigated whether δ-opioid receptor (DOR)-induced neuroprotection involves the brain-derived neurotrophic factor (BDNF) pathway. We studied the effect of DOR activation on the expression of BDNF and other proteins in the cortex of C57BL/6 mice exposed to hypoxia (10% of oxygen) for 1–10 days. The results showed that: (1) 1-day hypoxia had no appreciable effect on BDNF expression, while 3- and 10-day hypoxia progressively decreased BDNF expression, resulting in 37.3% reduction (p < 0.05) after 10-day exposure; (2) DOR activation with UFP-512 (1 mg/kg, i.p., daily) partially reversed the hypoxia-induced reduction of BDNF expression in the 3- or 10-day exposed cortex; (3) DOR activation partially reversed the hypoxia-induced reduction in functional TrkB (140-kDa) and attenuated hypoxia-induced increase in truncated TrkB (90-kDa) in the 3- or 10-day hypoxic cortex; and (4) prolonged hypoxia (10 days) significantly increased TNF-α level and decreased CD11b expression in the cortex, which was completely reversed following DOR activation; and (5) there was no significant change in pCREB and pATF-1 levels in the hypoxic cortex. We conclude that prolonged hypoxia down-regulates BDNF-TrkB signaling leading to an increase in TNF-α in the cortex, while DOR activation up-regulates BDNF-TrkB signaling thereby decreasing TNF-α levels in the hypoxic cortex. Full article
Open AccessReview Exposure to Environmental Toxicants and Pathogenesis of Amyotrophic Lateral Sclerosis: State of the Art and Research Perspectives
Int. J. Mol. Sci. 2013, 14(8), 15286-15311; doi:10.3390/ijms140815286
Received: 11 April 2013 / Revised: 5 July 2013 / Accepted: 8 July 2013 / Published: 24 July 2013
Cited by 20 | PDF Full-text (652 KB) | HTML Full-text | XML Full-text
Abstract
There is a broad scientific consensus that amyotrophic lateral sclerosis (ALS), a fatal neuromuscular disease, is caused by gene-environment interactions. In fact, given that only about 10% of all ALS diagnosis has a genetic basis, gene-environmental interaction may give account for the remaining
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There is a broad scientific consensus that amyotrophic lateral sclerosis (ALS), a fatal neuromuscular disease, is caused by gene-environment interactions. In fact, given that only about 10% of all ALS diagnosis has a genetic basis, gene-environmental interaction may give account for the remaining percentage of cases. However, relatively little attention has been paid to environmental and lifestyle factors that may trigger the cascade of motor neuron degeneration leading to ALS, although exposure to chemicals—including lead and pesticides—agricultural environments, smoking, intense physical activity, trauma and electromagnetic fields have been associated with an increased risk of ALS. This review provides an overview of our current knowledge of potential toxic etiologies of ALS with emphasis on the role of cyanobacteria, heavy metals and pesticides as potential risk factors for developing ALS. We will summarize the most recent evidence from epidemiological studies and experimental findings from animal and cellular models, revealing that potential causal links between environmental toxicants and ALS pathogenesis have not been fully ascertained, thus justifying the need for further research. Full article
Open AccessReview Death Associated Protein Kinases: Molecular Structure and Brain Injury
Int. J. Mol. Sci. 2013, 14(7), 13858-13872; doi:10.3390/ijms140713858
Received: 24 May 2013 / Revised: 14 June 2013 / Accepted: 27 June 2013 / Published: 4 July 2013
Cited by 9 | PDF Full-text (2204 KB) | HTML Full-text | XML Full-text
Abstract
Perinatal brain damage underlies an important share of motor and neurodevelopmental disabilities, such as cerebral palsy, cognitive impairment, visual dysfunction and epilepsy. Clinical, epidemiological, and experimental studies have revealed that factors such as inflammation, excitotoxicity and oxidative stress contribute considerably to both white
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Perinatal brain damage underlies an important share of motor and neurodevelopmental disabilities, such as cerebral palsy, cognitive impairment, visual dysfunction and epilepsy. Clinical, epidemiological, and experimental studies have revealed that factors such as inflammation, excitotoxicity and oxidative stress contribute considerably to both white and grey matter injury in the immature brain. A member of the death associated protein kinase (DAPk) family, DAPk1, has been implicated in cerebral ischemic damage, whereby DAPk1 potentiates NMDA receptor-mediated excitotoxicity through interaction with the NR2BR subunit. DAPk1 also mediate a range of activities from autophagy, membrane blebbing and DNA fragmentation ultimately leading to cell death. DAPk mRNA levels are particularly highly expressed in the developing brain and thus, we hypothesize that DAPk1 may play a role in perinatal brain injury. In addition to reviewing current knowledge, we present new aspects of the molecular structure of DAPk domains, and relate these findings to interacting partners of DAPk1, DAPk-regulation in NMDA-induced cerebral injury and novel approaches to blocking the injurious effects of DAPk1. Full article
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