Neurodegeneration In Central Nervous System Research Articles

Follow-up of pediatric patients treated by IVIG for Langerhans cell histiocytosis (LCH)-related neurodegenerative CNS disease.

The follow-up of eight Japanese children with Langerhans cell histiocytosis (LCH)-related neurodegenerative central nervous system (ND-CNS) disease who were treated with intravenous immunoglobulin (IVIG) for >3 years is described. The patients developed ND-CNS disease at a median age of 5.2 (range 3.5-10.0) years and received IVIG treatment for a median duration of 6.5 + (range 3.7 to 10+) years. After a median follow-up period of 11.6 + (8.3+ to 13.9+) years after ND-CNS disease diagnosis, the median Expanded Disability Status Scale (EDSS) score of the eight patients was 4.0 (range 2.0-9.5). At the last follow-up as of March 2014, three patients have low EDSS scores (<3.0) and can walk without any assistance. Another three patients have EDSS scores of 3.5-4.5 and can walk by themselves, albeit occasionally with supports. However, the remaining two patients are wheelchair bound or bed ridden. The school performance of seven of the eight patients was below average. IVIG appeared to be most beneficial when it was administered soon after ND-CNS disease diagnosis when the EDSS scores were low (1.0-2.5). The patients who began receiving IVIG when their high EDSS scores were higher (4.5-7.0) appeared to obtain less benefit. To prevent progression of ND-CNS disease in patients with LCH, it is recommended to introduce IVIG early and to continue this therapy for >3 years.

Optical coherence tomography for retinal imaging in multiple sclerosis.

Visual disturbances caused by inflammatory and demyelinating processes of the visual system, mainly in the optic nerve, are a common symptom in multiple sclerosis (MS). Optical coherence tomography (OCT) is a tool that is increasingly used for quantifying retinal damage in MS and other neurologic diseases. Based on spectral interferometry, it uses low-coherent infrared light to generate high-resolution spatial images of the retina. The retinal nerve fiber layer (RNFL) consists of unmyelinated axons that form the optic nerve, and thus represents a part of the central nervous system. OCT allows for noninvasive measurements of RNFL thickness in micrometer resolution. With the help of OCT, researchers have managed to demonstrate that eyes of MS patients show distinct RNFL thinning after an event of acute optic neuritis in MS, and even subclinical damage in eyes with no previous optic neuritis. OCT is also a useful tool in terms of providing a differential diagnosis of MS toward, for example, neuromyelitis optica, a disease that usually shows stronger retinal thinning, or Susac syndrome, which is characterized by distinct patchy thinning of the inner retinal layers. RNFL thinning is associated with magnetic resonance imaging-derived measurements of the brain, such as whole-brain atrophy, gray and white matter atrophy, and optic radiation damage. These features suggest that OCT-derived retinal measurements are a complement for measuring central nervous system neurodegeneration in the context of clinical trials – for example, with neuroprotective substances.

Role of SIRT1 in autoimmune demyelination and neurodegeneration.

Multiple sclerosis (MS) is a demyelinating disease characterized by chronic inflammation of the central nervous system, in which many factors can act together to influence disease susceptibility and progression. SIRT1 is a member of the histone deacetylase class III family of proteins and is an NAD(+)-dependent histone and protein deacetylase. SIRT1 can induce chromatin silencing through the deacetylation of histones and plays an important role as a key regulator of a wide variety of cellular and physiological processes including DNA damage, cell survival, metabolism, aging, and neurodegeneration. It has gained a lot of attention recently because many studies in animal models of demyelinating and neurodegenerative diseases have shown that SIRT1 induction can ameliorate the course of the disease. SIRT1 expression was found to be decreased in the peripheral blood mononuclear cells of MS patients during relapses. SIRT1 represents a possible biomarker of relapses and a potential new target for therapeutic intervention in MS. Modulation of SIRT1 may be a valuable strategy for treating or preventing MS and neurodegenerative central nervous system disorders.

Regulation of astrocyte activation by glycolipids drives chronic CNS inflammation.

Astrocytes have complex roles in health and disease, thus it is important to study the pathways that regulate their function. Here we report that lactosylceramide (LacCer) synthesized by β-1,4-galactosyltransferase 6 (B4GALT6) is upregulated in the central nervous system (CNS) of mice during chronic experimental autoimmune encephalomyelitis (EAE), a model of multiple sclerosis (MS). LacCer acts in an autocrine manner to control astrocyte transcriptional programs that promote neurodegeneration. In addition, LacCer in astrocytes controls the recruitment and activation of microglia and CNS-infiltrating monocytes in a non-cell autonomous manner by regulating production of the chemokine CCL2 and granulocyte-macrophage colony-stimulating factor (GM-CSF), respectively. We also detected high B4GALT6 gene expression and LacCer concentrations in CNS MS lesions. Inhibition of LacCer synthesis in mice suppressed local CNS innate immunity and neurodegeneration in EAE and interfered with the activation of human astrocytes in vitro. Thus, B4GALT6 regulates astrocyte activation and is a potential therapeutic target for MS and other neuroinflammatory disorders.

MicroRNA-145 as one negative regulator of astrogliosis.

Astrogliosis occurs at the lesion site within days to weeks after spinal cord injury (SCI) and involves the proliferation and hypertrophy of astrocytes, leading to glia scar formation. Changes in gene expression by deregulated microRNAs (miRNAs) are involved in the process of central nervous system neurodegeneration. Here, we report that mir-145, a miRNA enriched in rat spinal neurons and astrocytes, was downregulated at 1 week and 1 month after SCI. Our in vitro studies using astrocytes prepared from neonatal spinal cord tissues indicated that potent inflammagen lipopolysaccharide downregulated mir-145 expression in astrocytes, suggesting that SCI-triggered inflammatory signaling pathways could play the inhibitory role in astrocytic mir-145 expression. To induce overexpression of mir-145 in astrocytes at the spinal cord lesion site, we developed a lentivirus-mediated pre-miRNA delivery system using the promoter of glial fibrillary acidic protein (GFAP), an astrocyte-specific intermediate filament. The results indicated that astrocyte-specific overexpression of mir-145 reduced astrocytic cell density at the lesion border of the injured spinal cord. In parallel, overexpression of mir-145 reduced the size of astrocytes and the number of related cell processes, as well as cell proliferation and migration. Through a luciferase reporter system, we found that GFAP and c-myc were the two potential targets of mir-145 in astrocytes. Together, the findings demonstrate the novel role of mir-145 in the regulation of astrocytic dynamics, and reveal that the downregulation of mir-145 in astrocytes is a critical factor inducing astrogliosis after SCI. GLIA 2015;63:194-205.

Neuroprotective effects of metallothionein against rotenone-induced myenteric neurodegeneration in parkinsonian mice.

Parkinson's disease (PD) is a neurodegenerative disease with motor symptoms as well as non-motor symptoms that precede the onset of motor symptoms. Mitochondrial complex I inhibitor, rotenone, has been widely used to reproduce PD pathology in the central nervous system (CNS) and enteric nervous system (ENS). We reported previously that metallothioneins (MTs) released from astrocytes can protect dopaminergic neurons against oxidative stress. The present study examined the changes in MT expression by chronic systemic rotenone administration in the striatum and colonic myenteric plexus of C57BL mice. In addition, we investigated the effects of MT depletion on rotenone-induced neurodegeneration in CNS and ENS using MT-1 and MT-2 knockout (MT KO) mice, or using primary cultured neurons from MT KO mice. In normal C57BL mice, subcutaneous administration of rotenone for 6 weeks caused neurodegeneration, increased MT expression with astrocytes activation in the striatum and myenteric plexus. MT KO mice showed more severe myenteric neuronal damage by rotenone administration after 4 weeks than wild-type mice, accompanied by reduced astroglial activation. In primary cultured mesencephalic neurons from MT KO mice, rotenone exposure induced neurotoxicity in dopaminergic neurons, which was complemented by addition of recombinant protein. The present results suggest that MT seems to provide protection against neurodegeneration in ENS of rotenone-induced PD model mice.

Optic nerve crush induces spatial and temporal gene expression patterns in retina and optic nerve of BALB/cJ mice.

BackgroundCentral nervous system (CNS) trauma and neurodegenerative disorders trigger a cascade of cellular and molecular events resulting in neuronal apoptosis and regenerative failure. The pathogenic mechanisms and gene expression changes associated with these detrimental events can be effectively studied using a rodent optic nerve crush (ONC) model. The purpose of this study was to use a mouse ONC model to: (a) evaluate changes in retina and optic nerve (ON) gene expression, (b) identify neurodegenerative pathogenic pathways and (c) discover potential new therapeutic targets.ResultsOnly 54% of total neurons survived in the ganglion cell layer (GCL) 28 days post crush. Using Bayesian Estimation of Temporal Regulation (BETR) gene expression analysis, we identified significantly altered expression of 1,723 and 2,110 genes in the retina and ON, respectively. Meta-analysis of altered gene expression (≥1.5, ≤-1.5, p < 0.05) using Partek and DAVID demonstrated 28 up and 20 down-regulated retinal gene clusters and 57 up and 41 down-regulated optic nerve clusters. Regulated gene clusters included regenerative change, synaptic plasticity, axonogenesis, neuron projection, and neuron differentiation. Expression of selected genes (Vsnl1, Syt1, Synpr and Nrn1) from retinal and ON neuronal clusters were quantitatively and qualitatively examined for their relation to axonal neurodegeneration by immunohistochemistry and qRT-PCR.ConclusionA number of detrimental gene expression changes occur that contribute to trauma-induced neurodegeneration after injury to ON axons. Nrn1 (synaptic plasticity gene), Synpr and Syt1 (synaptic vesicle fusion genes), and Vsnl1 (neuron differentiation associated gene) were a few of the potentially unique genes identified that were down-regulated spatially and temporally in our rodent ONC model. Bioinformatic meta-analysis identified significant tissue-specific and time-dependent gene clusters associated with regenerative changes, synaptic plasticity, axonogenesis, neuron projection, and neuron differentiation. These ONC induced neuronal loss and regenerative failure associated clusters can be extrapolated to changes occurring in other forms of CNS trauma or in clinical neurodegenerative pathological settings. In conclusion, this study identified potential therapeutic targets to address two key mechanisms of CNS trauma and neurodegeneration: neuronal loss and regenerative failure.

Neural and oligodendrocyte progenitor cells: transferrin effects on cell proliferation.

NSC (neural stem cells)/NPC (neural progenitor cells) are multipotent and self-renew throughout adulthood in the SVZ (subventricular zone) of the mammalian CNS (central nervous system). These cells are considered interesting targets for CNS neurodegenerative disorder cell therapies, and understanding their behaviour in vitro is crucial if they are to be cultured prior to transplantation. We cultured the SVZ tissue belonging to newborn rats under the form of NS (neurospheres) to evaluate the effects of Tf (transferrin) on cell proliferation. The NS were heterogeneous in terms of the NSC/NPC markers GFAP (glial fibrillary acidic protein), Nestin and Sox2 and the OL (oligodendrocyte) progenitor markers NG2 (nerve/glia antigen 2) and PDGFRα (platelet-derived growth factor receptor α). The results of this study indicate that aTf (apoTransferrin) is able to increase cell proliferation of SVZ-derived cells in vitro, and that these effects were mediated at least in part by the TfRc1 (Tf receptor 1). Since OPCs (oligodendrocyte progenitor cells) represent a significant proportion of the proliferating cells in the SVZ-derived primary cultures, we used the immature OL cell line N20.1 to show that Tf was able to augment the proliferation rate of OPC, either by adding aTf to the culture medium or by overexpressing rat Tf in situ. The culture medium supplemented with ferric iron, together with aTf, increased the DNA content, while ferrous iron did not. The present work provides data that could have a potential application in human cell replacement therapies for neurodegenerative disease and/or CNS injury that require the use of in vitro amplified NPCs.

Insights into the Mechanisms of the Therapeutic Efficacy of Alemtuzumab in Multiple Sclerosis

The pathogenesis of multiple sclerosis (MS) is thought to involve peripheral activation of immune cells against central nervous system (CNS) antigens and their migration across the blood-brain barrier, leading to CNS inflammation and neurodegeneration. Alemtuzumab, a humanized anti-CD52 monoclonal antibody that rapidly depletes CD52-expressing cells from the circulation, is being investigated as a new treatment option in relapsing-remitting MS (RRMS). Clinical and radiologic results indicate robust suppression of inflammation related to the depletion of T and B lymphocytes during each treatment course of alemtuzumab. Furthermore, several lines of evidence suggest that the long-term clinical effects of alemtuzumab are attributable to qualitative changes in repopulating lymphocyte subsets potentially leading to a rebalancing of the immune system. Here, we review the contribution of data from animal models, ex vivo human studies, and clinical trials to the understanding of the mechanisms underlying the therapeutic effect of alemtuzumab in patients with RRMS.

STEM CELLS IN TRAUMATIC BRAIN INJURY

Traumatic Brain Injury (TBI) is a devastating clini cal condition that often causes permanent incapacit y, especially in the younger population. The clinical relevant of TBI justifies the scientific interest i n the pathophysiology of TBI, as well as in protective ef fects and development of treatment options. Stem ce lls have the ability to induce neuroprotection and neur al repair inflammatory suppression, causing tissue reconstruction completely or partially damaged cell s to preventing cell death to evolve. However the neurological improvement observed in preclinical st udies and clinical tests based on neurological and behavioral disorders and the mechanism of action of stem cells remains unknown. In this study the authors discuss the current status of using stem ce lls to treat TBI, including the basic cell types an d potential mechanisms of action, preclinical data an d points out lack of studies and hurdles for clinic al application. The authors also focusing on the recen t demonstration that neurogenesis occurs in all mammals throughout adult life, although at a low ra te, is possible to induce neurogenesis de novo in t he adult mammalian brain, particularly in the neocorte x where it does not normally occur and that it may become possible to manipulate endogenous multipotent precursors in situ to replace lost or damaged neurons. Elucidation of the relevant molecular cont rols may both allow control over transplanted precursor cells and potentially allow the developme nt of neuronal replacement therapies for neurodegenerative disease and other central nervous system injuries that do not require transplantatio n of exogenous cells. Discuss strategies of enhance the neurogenesis (for example by exogenous tropics fact or administration) and the transplantation of differen t types of neural progenitor cells after TBI. Each strategy is discussed with an emphasis on highlight ing the progress and limiting factors relevant to t he development of clinical trials of cellular replacem ent therapy for severe TBI in humans.

Dimethyl Fumarate Modulation of Immune and Antioxidant Responses: Application to HIV Therapy

The persistence of chronic immune activation and oxidative stress in human immunodeficiency virus (HIV)-infected, antiretroviral drug-treated individuals are major obstacles to fully preventing HIV disease progression. The immune modulator and antioxidant dimethyl fumarate (DMF) is effective in treating immune-mediated diseases and it also has potential applications to limiting HIV disease progression. Among the relevant effects of DMF and its active metabolite monomethyl fumarate (MMF) are induction of a Th1 to Th2 lymphocyte shift, inhibition of pro-inflammatory cytokine signaling, inhibition of NF-κB nuclear translocation, inhibition of dendritic cell maturation, suppression of lymphocyte and endothelial cell adhesion molecule expression, and induction of the Nrf2-dependent antioxidant response element (ARE) and effector genes. Associated with these effects are reduced lymphocyte and monocyte infiltration into psoriatic skin lesions in humans and immune-mediated demyelinating brain lesions in rodents, which confirms potent systemic and central nervous system (CNS) effects. In addition, DMF and MMF limit HIV infection in macrophages in vitro, albeit by unknown mechanisms. Finally, DMF and MMF also suppress neurotoxin production from HIV-infected macrophages, which drives CNS neurodegeneration. Thus, DMF might protect against systemic and CNS complications in HIV infection through its effective suppression of immune activation, oxidative stress, HIV replication, and macrophage-associated neuronal injury.

Characterization of conformation-dependent prion protein epitopes.

Whereas prion replication involves structural rearrangement of cellular prion protein (PrP(C)), the existence of conformational epitopes remains speculative and controversial, and PrP transformation is monitored by immunoblot detection of PrP(27-30), a protease-resistant counterpart of the pathogenic scrapie form (PrP(Sc)) of PrP. We now describe the involvement of specific amino acids in conformational determinants of novel monoclonal antibodies (mAbs) raised against randomly chimeric PrP. Epitope recognition of two mAbs depended on polymorphisms controlling disease susceptibility. Detection by one, referred to as PRC5, required alanine and asparagine at discontinuous mouse PrP residues 132 and 158, which acquire proximity when residues 126-218 form a structured globular domain. The discontinuous epitope of glycosylation-dependent mAb PRC7 also mapped within this domain at residues 154 and 185. In accordance with their conformational dependence, tertiary structure perturbations compromised recognition by PRC5, PRC7, as well as previously characterized mAbs whose epitopes also reside in the globular domain, whereas conformation-independent epitopes proximal or distal to this region were refractory to such destabilizing treatments. Our studies also address the paradox of how conformational epitopes remain functional following denaturing treatments and indicate that cellular PrP and PrP(27-30) both renature to a common structure that reconstitutes the globular domain.

ATM kinase inhibition in glial cells activates the innate immune response and causes neurodegeneration inDrosophila

To investigate the mechanistic basis for central nervous system (CNS) neurodegeneration in the disease ataxia-telangiectasia (A-T), we analyzed flies mutant for the causative gene A-T mutated (ATM). ATM encodes a protein kinase that functions to monitor the genomic integrity of cells and control cell cycle, DNA repair, and apoptosis programs. Mutation of the C-terminal amino acid in Drosophila ATM inhibited the kinase activity and caused neuron and glial cell death in the adult brain and a reduction in mobility and longevity. These data indicate that reduced ATM kinase activity is sufficient to cause neurodegeneration in A-T. ATM kinase mutant flies also had elevated expression of innate immune response genes in glial cells. ATM knockdown in glial cells, but not neurons, was sufficient to cause neuron and glial cell death, a reduction in mobility and longevity, and elevated expression of innate immune response genes in glial cells, indicating that a non-cell-autonomous mechanism contributes to neurodegeneration in A-T. Taken together, these data suggest that early-onset CNS neurodegeneration in A-T is similar to late-onset CNS neurodegeneration in diseases such as Alzheimer's in which uncontrolled inflammatory response mediated by glial cells drives neurodegeneration.

Langerhans cell histiocytosis with disequilibrium

Langerhans cell histiocytosis (LCH) is a very rare disease in which granulation tissue forms in various organs and the central nervous system (CNS) due to monoclonal proliferation of Langerhans cells. Some patients develop ataxia, tremor, or neurodegenerative abnormalities (such as personality changes and mental deterioration) several years after the onset as the late effects of LCH. We report a case of a 4-year-old boy with LCH, showing speech disorder, truncal ataxia and a wide-based gait with abnormal findings of central nervous system in CT and MRI image. The results of auditory brain stem response revealed a conduction block in the auditory conduction pathway, suggesting an axonopathy of the brain stem. Disequilibrium may be due to brainstem dysfunction associated with paraneoplastic syndrome because an anti-GluRε2 antibody was seen. Paraneoplastic syndrome is a neuropathy induced through an autoimmune mechanism caused by an antibody directed against the nervous system. Neuro-otological examination is helpful for the assessment of CNS neurodegeneration associated with LCH.

Anti-Inflammatory Efficacy of Dexamethasone and Nrf2 Activators in the CNS Using Brain Slices as a Model of Acute Injury

Limiting excessive production of inflammatory mediators is an effective therapeutic strategy for many diseases. It's also a promising remedy for neurodegenerative diseases and central nervous system (CNS) injuries. Glucocorticoids are valuable anti-inflammatory agents, but their use is constrained by adverse side-effects. Activators of NF-E2-related factor-2 (Nrf2) signaling represent an attractive anti-inflammatory alternative. In this study, dexamethasone, a synthetic glucocorticoid, and several molecular activators of Nrf2 were evaluated for efficacy in slices of cerebral cortex derived from adult SJL/J mice. Cortical explants increased expression of IL-1β and TNF-α mRNAs in culture within 5h of sectioning. This expression was inhibited with dexamethasone in the explant medium or injected systemically in mice before sectioning. Semi-synthetic triterpenoid (SST) derivatives, potent activators of the Nrf2 pathway, demonstrated fast-acting anti-inflammatory activity in microglia cultures, but not in the cortical slice system. Quercetin, luteolin, and dimethyl fumarate were also evaluated as molecular activators of Nrf2. While expression of inflammatory mediators in microglia cultures was inhibited, these compounds did not demonstrate anti-inflammatory efficacy in cortical slices. In conclusion, brain slices were amenable to pharmacological modification as demonstrated by anti-inflammatory activity with dexamethasone. The utilization of Nrf2 activators to limit inflammatory mediators within the CNS requires further investigation. Inactivity in CNS tissue, however, suggests their safe use without neurological side-effects in treating non-CNS disorders. Short-term CNS explants may provide a more accurate model of in vivo conditions than microglia cultures since the complex tissue microenvironment is maintained.

Quantitative Proteomics and Metabolomics Analysis of Normal Human Cerebrospinal Fluid Samples

The analysis of cerebrospinal fluid (CSF) is used in biomarker discovery studies for various neurodegenerative central nervous system (CNS) disorders. However, little is known about variation of CSF proteins and metabolites between patients without neurological disorders. A baseline for a large number of CSF compounds appears to be lacking. To analyze the variation in CSF protein and metabolite abundances in a number of well-defined individual samples of patients undergoing routine, non-neurological surgical procedures, we determined the variation of various proteins and metabolites by multiple analytical platforms. A total of 126 common proteins were assessed for biological variations between individuals by ESI-Orbitrap. A large spread in inter-individual variation was observed (relative standard deviations [RSDs] ranged from 18 to 148%) for proteins with both high abundance and low abundance. Technical variation was between 15 and 30% for all 126 proteins. Metabolomics analysis was performed by means of GC-MS and nuclear magnetic resonance (NMR) imaging and amino acids were specifically analyzed by LC-MS/MS, resulting in the detection of more than 100 metabolites. The variation in the metabolome appears to be much more limited compared with the proteome: the observed RSDs ranged from 12 to 70%. Technical variation was less than 20% for almost all metabolites. Consequently, an understanding of the biological variation of proteins and metabolites in CSF of neurologically normal individuals appears to be essential for reliable interpretation of biomarker discovery studies for CNS disorders because such results may be influenced by natural inter-individual variations. Therefore, proteins and metabolites with high variation between individuals ought to be assessed with caution as candidate biomarkers because at least part of the difference observed between the diseased individuals and the controls will not be caused by the disease, but rather by the natural biological variation between individuals.

Quantitative Proteomics and Metabolomics Analysis of Normal Human Cerebrospinal Fluid Samples*

The analysis of cerebrospinal fluid (CSF) is used in biomarker discovery studies for various neurodegenerative central nervous system (CNS) disorders. However, little is known about variation of CSF proteins and metabolites between patients without neurological disorders. A baseline for a large number of CSF compounds appears to be lacking. To analyze the variation in CSF protein and metabolite abundances in a number of well-defined individual samples of patients undergoing routine, non-neurological surgical procedures, we determined the variation of various proteins and metabolites by multiple analytical platforms. A total of 126 common proteins were assessed for biological variations between individuals by ESI-Orbitrap. A large spread in inter-individual variation was observed (relative standard deviations [RSDs] ranged from 18 to 148%) for proteins with both high abundance and low abundance. Technical variation was between 15 and 30% for all 126 proteins. Metabolomics analysis was performed by means of GC-MS and nuclear magnetic resonance (NMR) imaging and amino acids were specifically analyzed by LC-MS/MS, resulting in the detection of more than 100 metabolites. The variation in the metabolome appears to be much more limited compared with the proteome: the observed RSDs ranged from 12 to 70%. Technical variation was less than 20% for almost all metabolites. Consequently, an understanding of the biological variation of proteins and metabolites in CSF of neurologically normal individuals appears to be essential for reliable interpretation of biomarker discovery studies for CNS disorders because such results may be influenced by natural inter-individual variations. Therefore, proteins and metabolites with high variation between individuals ought to be assessed with caution as candidate biomarkers because at least part of the difference observed between the diseased individuals and the controls will not be caused by the disease, but rather by the natural biological variation between individuals.

Anti-inflammatory effects of pioglitazone on iron-induced oxidative injury in the nigrostriatal dopaminergic system

Transition metals, oxidative stress and neuroinflammation have been proposed as part of a vicious cycle in central nervous system neurodegeneration. Our aim was to study the anti-inflammatory effect of pioglitazone, a peroxisome proliferative activated receptor-γ agonist, on iron-induced oxidative injury in rat brain. Intranigral infusion of ferrous citrate (iron) was performed on anaesthetized rats. Pioglitazone (20 mg/kg) was orally administered. Oxidative injury was investigated by measuring lipid peroxidation in the substantia nigra (SN) and dopamine content in the striatum. Western blot assay and DNA fragmentation were employed to study the involvement of α-synuclein aggregation, neuroinflammation as well as activation of endoplasmic reticulum (ER) and mitochondrial pathways in iron-induced apoptosis. Intranigral infusion of iron time-dependently increased α-synuclein aggregation and haem oxygenase-1 levels. Furthermore, apoptosis was demonstrated by TUNEL-positive cells and DNA fragmentation in the iron-infused SN. Systemic pioglitazone was found to potentiate iron-induced elevation in nuclear peroxisome proliferative activated receptor-γ levels. However, pioglitazone inhibited iron-induced α-synuclein aggregation, elevations in interleukin-1β and interleukin-6 mRNA levels as well as increases in oxygenase-1, cyclo-oxygenase II, nitric oxide synthase and ED-1 protein levels, an indicator of activated microglia. Moreover, iron-induced DNA laddering as well as activation of ER and mitochondrial pathways were attenuated by pioglitazone. In addition, pioglitazone decreased iron-induced elevation in lipid peroxidation in the infused SN and depletion in striatal dopamine level. Our results suggest that pioglitazone prevents iron-induced apoptosis via both ER and mitochondrial pathways. Furthermore, inhibition of α-synuclein aggregation and neuroinflammation may contribute to the pioglitazone-induced neuroprotection in central nervous system.

Mitochondria and the Link Between Neuroinflammation and Neurodegeneration

The innate immune response is thought to exert a dichotomous role in the brain. Indeed, although molecules of the innate immune response can promote repair mechanisms, during neuroinflammatory processes many harmful mediators are also released. Signs of neuroinflammation and neurodegeneration represent a ubiquitous pathological finding during the course of several different neurological diseases. Interestingly, it has been proposed that mitochondria may exert a crucial role in the pathogenesis of both inflammatory and neurodegenerative central nervous system disorders. In this review, we describe the mechanisms by which neuroinflammation and mitochondrial impairment may synergistically trigger a vicious cycle ultimately leading to neuronal death. In particular, we describe the close relationship existing among neuroinflammation, neurodegeneration, and mitochondrial impairment in three different widely-diffused neurological diseases in which these pathogenetic events coexist, namely multiple sclerosis, Parkinson's disease, and Alzheimer's disease.

Arsenite induces oxidative injury in rat brain

Sodium arsenite (arsenite)-induced neurotoxicity and its interaction with ferrous citrate (iron) was investigated in rat brain. In vitro data showed that arsenite (1-10 micromol/L) concentration dependently increased lipid peroxidation and the potency of arsenite was less than that of iron. The oxidative activity of arsenite, sodium arsenate (arsenate), monomethylarsonic acid (MMA), and dimethylarsinic acid (DMA) were evaluated by inducing lipid peroxidation in cortical homogenates, and the potency for this effect was as follows: arsenite > arsenate > MMA and DMA. Several well-known antioxidants, including glutathione, melatonin, and beta-estradiol inhibited arsenite-induced lipid peroxidation in a concentration-dependent manner. Our in vivo study employed intranigral infusion of arsenite (5 nmol) in the substantia nigra (SN) of anesthetized rats. Four hours to 7 days after infusion, lipid peroxidation was elevated while glutathione was depleted in the infused SN. The dopamine content in the striatum ipsilateral to arsenite-infused SN was first elevated 24 h and then decreased 7 days after intranigral infusion of arsenite. Using pretreatment of l-buthionine-[S,R]-sulfoximine (l-BSO, i.c.v.) to reduce glutathione content in rat brain, arsenite-induced oxidative injury was augmented. Low doses of arsenite (1.5 nmol) and iron (3 nmol) alone induced minimal oxidative injury; however, co-infusion of arsenite and iron augmented neurotoxicity, including elevated lipid peroxidation and reduced striatal dopamine content. Moreover, expression of heme oxygenase-1, alpha-synuclein aggregation, and DNA fragmentation were significantly enhanced in SN co-infused with low doses of arsenite and iron. Taken together, our study demonstrates that arsenite was less potent than iron in inducing oxidative stress. Furthermore, concomitant arsenite and iron potentiated oxidative injury in the nigrostriatal dopaminergic system, indicating that interaction of metals plays a more clinically-relevant role in pathophysiology of central nervous system neurodegeneration.