Marchetti B, Abbracchio MPTo be or not to be (inflamed)- is that the question in anti-inflammatory drug therapy of neurodegenerative disorders? Trends Pharmacol Sci 26:517-525

Department of Pharmacology, University of Sassari Medical School, Sassari, Sardinia, Italy.
Trends in Pharmacological Sciences (Impact Factor: 11.54). 11/2005; 26(10):517-25. DOI: 10.1016/
Source: PubMed


A sustained inflammatory reaction is present in acute (e.g. stroke) and chronic (e.g. Alzheimer's disease, Parkinson's disease and multiple sclerosis) neurodegenerative disorders. Inflammation, which is fostered by both residential glial cells and blood-circulating cells that infiltrate the diseased brain, probably starts as a time- and site-specific defense mechanism that could later evolve into a destructive and uncontrolled reaction. In this article, we review the crucial dichotomy of brain inflammation, where failure to resolve an acute beneficial response could lead to a vicious and anarchic state of chronic activation. The possible use of non-steroidal anti-inflammatory drugs for the management of neurodegenerative diseases is discussed in light of recent data demonstrating a neuroprotective role of local innate and adaptive immune responses. Novel therapeutic approaches must rely on potentiation of endogenous anti-inflammatory pathways, identification of early markers of neuronal deterioration and a combination treatment involving immune modulation and anti-inflammatory therapies.

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    • "Inflammation is also associated with neurocognitive dysfunction (Krabbe, Pedersen, & Bruunsgaard, 2004; Marsland et al., 2006; Teunissen et al., 2003). Novel antiinflammatory therapies are currently being tested and used in individuals with chronic inflammatory conditions (Canvin & el-Gabalawy, 1999; Gorelick, 2010; Marchetti & Abbracchio, 2005; Raber et al., 1998). In line with this notion, researchers have begun to explore the use of marijuana in the reduction of inflammatory processes (Albayram et al., 2011; Cabral & Griffin-Thomas, 2009; Jackson, Diemel, Pryce, & Baker, 2005). "
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    ABSTRACT: The purpose of the current study was to determine if self-reported lifetime marijuana use moderates the relationship between interleukin-6 (IL-6) and neurocognitive performance. Participants included 161 African American adults (50.3% women), with a mean age of 45.24 (SD=11.34). Serum was drawn upon entry into the study and participants completed a demographic questionnaire, which included drug use history, and a battery of neuropsychological tests. Using multiple regression analyses and adjusting for demographic covariates, the interaction term comprised of IL-6 and self-reported lifetime marijuana use was significantly associated with poorer performance on the Written (β=-.116; SE=.059; p=.049) and Oral trials (β=-.143; SE=.062; p=.022) of the Symbol Digit Modalities Test, as well as the Trail Making Test trial A (β=.157; SE=.071; p=.028). Current findings support previous literature, which presents the inverse relationship between IL-6 and neurocognitive dysfunction. The potential protective properties of marijuana use in African Americans, who are at increased risk for inflammatory diseases, are discussed. (JINS, 2014, 20, 773-783).
    Journal of the International Neuropsychological Society 09/2014; 20(8):773-83. DOI:10.1017/S1355617714000691 · 2.96 Impact Factor
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    • "Several previous studies have demonstrated that both astrocytes and microglia were activated under PD conditions, and their roles are very dynamic and cell-type dependent [41]–[43]. Astrocytes and microglia may exert harmful effects by producing pro-inflammatory and cytotoxic mediators that kill neurons or form scars that barricade axonal regeneration, but in certain circumstances, these cells can turn into highly protective cells, and produce anti-inflammatory cytokines, express and release a panel of pro-survival, neurotrophic and pro-regenerative factors, thereby facilitating neuronal recovery and repair [44]–[46]. To understand the different cell type interactions and to elucidate the molecular mechanism underlying the neuroprotective effect of SalB, we used an in vitro system containing the three main PD-related cell types, namely neurons, microglia, and astrocytes. "
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    ABSTRACT: Salvianolic acid B (SalB), a bioactive compound isolated from the plant-derived medicinal herb Danshen, has been shown to exert various anti-oxidative and anti-inflammatory activities in several neurological disorders. In this study, we sought to investigate the potential protective effects and associated molecular mechanisms of SalB in Parkinson's disease (PD) models. To determine the neuroprotective effects of SalB in vitro, MPP+- or lipopolysaccharide (LPS)-induced neuronal injury was achieved using primary cultures with different compositions of neurons, microglia and astrocytes. Our results showed that SalB reduced both LPS- and MPP+-induced toxicity of dopamine neurons in a dose-dependent manner. Additionally, SalB treatment inhibited the release of microglial pro-inflammatory cytokines and resulted in an increase in the expression and release of glial cell line-derived neurotrophic factor (GDNF) from astrocytes. Western blot analysis illustrated that SalB increased the expression and nuclear translocation of nuclear factor (erythroid-derived 2)-like 2 (Nrf2). The knockdown of Nrf2 using specific small interfering RNA (siRNA) partially reversed the SalB-induced GDNF expression and anti-inflammatory activity. Moreover, SalB treatment significantly attenuated dopaminergic (DA) neuronal loss, inhibited neuroinflammation, increased GDNF expression and improved the neurological function in MPTP-treated mice. Collectively, these findings demonstrated that SalB protects DA neurons by an Nrf-2 -mediated dual action: reducing microglia activation-mediated neuroinflammation and inducing astrocyte activation-dependent GDNF expression. Importantly the present study also highlights critical roles of glial cells as targets for developing new strategies to alter the progression of neurodegenerative disorders.
    PLoS ONE 07/2014; 9(7):e101668. DOI:10.1371/journal.pone.0101668 · 3.23 Impact Factor
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    • "Activation of microglia was reported to be neuroprotective in ischemic models (Lalancette-Hébert et al., 2007), despite its harmful effects to neurons when activation is excessive (Heppner et al., 2005; Marchetti and Abbracchio, 2005). A proper control of microglial reactivity by SERMs may represent a potential therapeutic strategy in brain injuries. "
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    ABSTRACT: Following brain injury, microglia assume a reactive-like state and secrete pro-inflammatory molecules that can potentiate damage. A therapeutic strategy that may limit microgliosis is of potential interest. In this context, selective estrogen receptor modulators, such as raloxifene and tamoxifen, are known to reduce microglia activation induced by neuroinflammatory stimuli in young animals. In the present study, we have assessed whether raloxifene and tamoxifen are able to affect microglia activation after brain injury in young and aged animals in time points relevant to clinics, which is hours after brain trauma. Volume fraction of MHC-II(+) microglia was estimated according to the point-counting method of Weibel within a distance of 350 μm from the lateral border of the wound, and cellular morphology was measured by fractal analysis. Two groups of animals were studied: (1) young rats, ovariectomized at 2 months of age; and (2) aged rats, ovariectomized at 18 months of age. Fifteen days after ovariectomy animals received a stab wound brain injury and the treatment with estrogenic compounds. Our findings indicate that raloxifene and tamoxifen reduced microglia activation in both young and aged animals. Although the volume fraction of reactive microglia was found lower in aged animals, this was accompanied by important changes in cell morphology, where aged microglia assume a bushier and hyperplasic aspect when compared to young microglia. These data suggest that early regulation of microglia activation provides a mechanism by which selective estrogen receptors modulators (SERMs) may exert a neuroprotective effect in the setting of a brain trauma.
    Frontiers in Aging Neuroscience 07/2014; 6:132. DOI:10.3389/fnagi.2014.00132 · 4.00 Impact Factor
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