Mechanisms of inflammatory neurodegeneration: iNOS and NADPH oxidase

Brown, Guy C.

doi:10.1042/bst0351119

Cited by 272 publications

(182 citation statements)

References 42 publications

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“…The observations suggesting that the effects of hMSCs were mediated through microglia and/or macrophages are consistent with indications that both microglia and macrophages can be alternatively activated to play contrasting roles in response to injury (33)(34)(35). The increases in Gal-3 and Ym1 observed here provided a direct link between the effects of the hMSCs and activation of microglia or macrophages that may have been produced either by paracrines secreted by the hMSCs or by direct cell-to-cell contacts, as was observed during immunosuppression of T cells by MSCs (27).…”

Section: Discussionsupporting

confidence: 61%

Stem/progenitor cells from bone marrow decrease neuronal death in global ischemia by modulation of inflammatory/immune responses

Ohtaki

Ylöstalo

Foraker

et al. 2008

Proc. Natl. Acad. Sci. U.S.A.

368

297

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Human mesenchymal stromal cells (hMSCs) were injected into the hippocampus of adult mice 1 day after transient global ischemia. The hMSCs both improved neurologic function and markedly decreased neuronal cell death of the hippocampus. Microarray assays indicated that ischemia up-regulated 586 mouse genes. The hMSCs persisted for <7 days, but they down-regulated >10% of the ischemia-induced genes, most of which were involved in inflammatory and immune responses. The hMSCs also upregulated three mouse genes, including the neuroprotective gene Ym1 that is expressed by activated microglia/macrophages. In addition, the transcriptomes of the hMSC changed with upregulation of 170 human genes and down-regulation of 54 human genes. Protein assays of the hippocampus demonstrated increased expression in microglia/macrophages of Ym1, the cell survival factor insulin-like growth factor 1, galectin-3, cytokines reflective of a type 2 T cell immune bias, and the major histocompatibility complex II. The observed beneficial effects of hMSCs were largely explained by their modulation of inflammatory and immune responses, apparently by alternative activation of microglia and/or macrophages.inflammation ͉ mesenchymal stromal cells ͉ microglia ͉ mesenchymal stem cells O bservations in rodent and primate models suggest that a potential therapy for ischemia of the central nervous system is the administration of the adult stem/progenitor cells from bone marrow referred to as mesenchymal stem cells or multipotent mesenchymal stromal cells (MSCs) (1-3). Administration of MSCs also produced beneficial effects in animal models for neurodegenerative diseases, such as Parkinson's disease, experimental autoimmune encephalomyelitis, and amyotrophic lateral sclerosis (2-5). MSCs initially attracted interest for their ability to differentiate into multiple cellular phenotypes in culture and in vivo (1-7). However, recent observations indicate that only small numbers of the cells engraft into most injured tissues, and they disappear quickly (2-5, 8-10). When human MSCs (hMSCs) were injected into the dentate gyrus (DG) of the hippocampus in adult immunodeficient (ID) mice, most of the cells disappeared within 1 week, but they enhanced proliferation, migration, and neural differentiation of the endogenous neural stem cells (8). These and related observations have focused attention on the paracrine effects of MSCs (2, 3, 11). However, it has not been established whether the beneficial effects of MSCs in ischemic models of brain injury are explained by enhanced neurogenesis (8) or by neuroprotection.Experiments here were performed in a mouse model of global ischemia to assess the neuroprotective effects of hMSCs. Administration of hMSCs 1 day after transient common carotid artery occlusion (tCCAO) improved neurologic function and decreased the delayed neuronal cell death of the hippocampus. Surveys with microarrays indicated that the hMSCs decreased expression of many of the mouse genes that were induced by ischemia and that were involved in inflamma...

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Section: Discussionsupporting

confidence: 61%

Stem/progenitor cells from bone marrow decrease neuronal death in global ischemia by modulation of inflammatory/immune responses

Ohtaki

Ylöstalo

Foraker

et al. 2008

Proc. Natl. Acad. Sci. U.S.A.

368

297

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“…Microglia are brain macrophages that produce oxidants and induce expression of iNOS if they detect pathogens or damage (Brown, 2007). This study showed non significant alteration in brain lipid peroxidation, consequently no brain damage.…”

Section: Discussionmentioning

confidence: 79%

Impact of L-Carnitine and Cinnamon on Insulin-Like Growth Factor-1 and Inducible Nitric Oxide Synthase Gene Expression in Heart and Brain of Insulin Resistant Rats

Mohamed¹

2010

American Journal of Biochemistry and Biotechnology

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Problem statement: Evaluate the effects of daily administration of L-carnitine and cinnamon extract for two weeks on the expression of Insulin-like Growth Factor-1 (IGF-1) and inducible Nitric Oxide Synthase (iNOS) genes in cardiac and brain tissues of rats with Insulin Resistance (IR). Approach: Rats were divided into 4 groups (8 animals each): Group (1) rats fed control diet (60% starch) as control while groups (2, 3 and 4) fed high fructose diet (60% fructose). At the beginning of the 3rd week of feeding, rats of group (3) were treated with L-carnitine (300 mg kg −1 body weight/day, i.p.) and animals of group (4) received a daily oral dose of cinnamon aqueous extract (0.5 mL rat −1 ). The animals were maintained in their respective groups for 4 weeks. Results:Feeding high fructose diet causes significant reduction in Insulin Receptor Substrate-1 (IRS-1) (amounted 30.65%) and elevation in iNOS expression (reached 51%) in the cardiac tissues as compared to control. In brain tissues, the IGF-1 mRNA was reduced in fructose loaded groups (28.81%). Administration of either L-carnitine or cinnamon extract significantly improves the expression of the cardiac studied genes but with no effects on the brain tissues. Conclusion: The present study illustrated that CE was more potent than L-carnitine in improving the IR.Key word: Insulin resistance, insulin-like growth factor-1, inducible nitric oxide synthase, insulin receptor substrate-1

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“…Activated microglia, via production of peroxynitrite and various pro-inflammatory cytokines and prostanoids, are suspected to contribute to the pathogenesis of many neurodegenerative disorders (Brown 2007). In light of the anti-inflammatory potential of AMPK as noted above, it is reasonable to suspect that AMPK activation might be protective in this regard, and indeed, several studies demonstrate that AMPK activators can exert antiinflammatory effects on cultured microglia.…”

Section: Preventing Neurodegenerative Disordersmentioning

confidence: 99%

AMPK activation—protean potential for boosting healthspan

McCarty

2013

AGE

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AMP-activated kinase (AMPK) is activated when the cellular (AMP+ADP)/ATP ratio rises; it therefore serves as a detector of cellular "fuel deficiency." AMPK activation is suspected to mediate some of the health-protective effects of long-term calorie restriction. Several drugs and nutraceuticals which slightly and safely impede the efficiency of mitochondrial ATP g e n e r a t i o n -m o s t n o t a b l y m e t f o r m i n a n d berberine-can be employed as clinical AMPK activators and, hence, may have potential as calorie restriction mimetics for extending healthspan. Indeed, current evidence indicates that AMPK activators may reduce risk for atherosclerosis, heart attack, and stroke; help to prevent ventricular hypertrophy and manage congestive failure; ameliorate metabolic syndrome, reduce risk for type 2 diabetes, and aid glycemic control in diabetics; reduce risk for weight gain; decrease risk for a number of common cancers while improving prognosis in cancer therapy; decrease risk for dementia and possibly other neurodegenerative disorders; help to preserve the proper structure of bone and cartilage; and possibly aid in the prevention and control of autoimmunity. While metformin and berberine appear to have the greatest utility as clinical AMPK activators-as reflected by their efficacy in diabetes management-regular ingestion of vinegar, as well as moderate alcohol consumption, may also achieve a modest degree of healthprotective AMPK activation. The activation of AMPK achievable with any of these measures may be potentiated by clinical doses of the drug salicylate, which can bind to AMPK and activate it allosterically.

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Mechanisms of inflammatory neurodegeneration: iNOS and NADPH oxidase

Cited by 272 publications

References 42 publications

Stem/progenitor cells from bone marrow decrease neuronal death in global ischemia by modulation of inflammatory/immune responses

Stem/progenitor cells from bone marrow decrease neuronal death in global ischemia by modulation of inflammatory/immune responses

Impact of L-Carnitine and Cinnamon on Insulin-Like Growth Factor-1 and Inducible Nitric Oxide Synthase Gene Expression in Heart and Brain of Insulin Resistant Rats

AMPK activation—protean potential for boosting healthspan

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