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Triterpenoid modulation of IL-17 and Nrf-2 expression ameliorates neuroinflammation and promotes remyelination in autoimmune encephalomyelitis. Sci Rep 1:201

Department of Pediatrics/Division of Pediatric Hematology-Oncology, University Hospitals Case Medical Center and The Case Comprehensive Cancer Center, Case Western Reserve University, Cleveland, OH 44106, USA.
Scientific Reports (Impact Factor: 5.58). 12/2011; 1:201. DOI: 10.1038/srep00201
Source: PubMed

ABSTRACT Inflammatory cytokines and endogenous anti-oxidants are variables affecting disease progression in multiple sclerosis (MS). Here we demonstrate the dual capacity of triterpenoids to simultaneously repress production of IL-17 and other pro-inflammatory mediators while exerting neuroprotective effects directly through Nrf2-dependent induction of anti-oxidant genes. Derivatives of the natural triterpene oleanolic acid, namely CDDO-trifluoroethyl-amide (CDDO-TFEA), completely suppressed disease in a murine model of MS, experimental autoimmune encephalomyelitis (EAE), by inhibiting Th1 and Th17 mRNA and cytokine production. Encephalitogenic T cells recovered from treated mice were hypo-responsive to myelin antigen and failed to adoptively transfer the disease. Microarray analyses showed significant suppression of pro-inflammatory transcripts with concomitant induction of anti-inflammatory genes including Ptgds and Hsd11b1. Finally, triterpenoids induced oligodendrocyte maturation in vitro and enhanced myelin repair in an LPC-induced non-inflammatory model of demyelination in vivo. These results demonstrate the unique potential of triterpenoid derivatives for the treatment of neuroinflammatory disorders such as MS.

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    • "They showed that induction of eAe in Nrf2-deficient mice resulted in more severe disease symptoms and an increase in infiltrated immune cells (Johnson et al. 2010). Sulforaphane and derivatives of the natural triterpene oleanolic acid, both well-known Nrf2 activators, suppressed disease in a murine model of MS by inhibiting the immune system and inducing antioxidant genes (Pareek et al. 2011; li et al. 2013). In addition, there is ample evidence that fumaric acid esters are able to boost the production of endogenous antioxidant enzymes via activation of the Nrf2 pathway (Scannevin et al. 2012). "
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    ABSTRACT: Activation of microglial cells and impaired mitochondrial function are common pathological characteristics of many neurological diseases and contribute to increased generation of reactive oxygen species (ROS). It is nowadays accepted that oxidative damage and mitochondrial dysfunction are key hallmarks of classical neuroinflammatory and neurodegenerative diseases, such as multiple sclerosis, Alzheimer's disease, Parkinson's disease and Huntington's disease. To counteract the detrimental effects of ROS and restore the delicate redox balance in the central nervous system (CNS), cells are equipped with an endogenous antioxidant defense mechanism consisting of several antioxidant enzymes. The production of many antioxidant enzymes is regulated at the transcriptional level by the transcription factor nuclear factor E2-related factor 2 (Nrf2). Although evidence is accumulating that activation of the Nrf2 pathway represents a promising therapeutic approach to restore the CNS redox balance by reducing ROS-mediated neuronal damage in experimental models of neurodegenerative disorders, only a few Nrf2-activating compounds have been tested in a clinical setting. We here provide a comprehensive synopsis on the role of ROS in common neurodegenerative disorders and discuss the therapeutic potential of the Nrf2 pathway.
    Archive für Toxikologie 08/2014; 88(10). DOI:10.1007/s00204-014-1338-z · 5.08 Impact Factor
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    • "The combination of immunomodulatory and antioxidants is expected to improve the prognosis of patients with optic neuritis. Recently, Triterpenoids (oleanolic acid derived) were reported to have the dual capacity of simultaneously repressing production of IL-17 and other pro-inflammatory mediators while exerting neuroprotective effects through antioxidation by activating the Nrf2/ARE pathway in experimental optic neuritis [25]. Gypenosides with an aglycone mainly of dammarane-type tetracyclic triterpenoids, also has a dual capacity of immune regulation and antioxidation [21] [22] [23]. "
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    ABSTRACT: Optic neuritis is a common disease in young adults, inducing apoptosis of retinal ganglion cells, which leads to varying degree of visual function damages, even blindness. As the standard treatment, methylprednisolone pulse therapy can only promote the recovery of visual acuity but not prevent retinal ganglion cell degeneration. It cannot help improve the ultimate visual outcome. Both inflammatory response and endogenous oxidative stress play crucial roles in the progression of optic neuritis. The combination of immunomodulatory and antioxidant is expected to improve the prognosis of the disease by preventing the apoptosis of retinal ganglion cells. Triterpenoids (oleanolic acid derived) were reported to have the dual capacity of simultaneously repressing production of pro-inflammatory mediators and exerting neuroprotective effects through induction of anti-oxidant genes in experimental optic neuritis. Gypenosides with an aglycone mainly of dammarane-type tetracyclic triterpenoids, also has the dual capacity of immune regulation and antioxidation. Both gypenosides and oleanolic acid were reported to have similar roles in hepatoprotection. Beside, gypenosides were reported to have the capacity of modulating the activation of immune cells and the expression of cytokines. In addition, gypenosides showed neuroprotective effect against oxidative injury in dopaminergic neurons and mouse model of Parkinson's disease. Accordingly, we propose that gypenosides have potential neuroprotective and immunomodulatory effects on optic neuritis through antioxidation and immune regulation. The application of gypenosides might prevent the apoptosis of retinal ganglion cells and improve the ultimate visual outcome in patients with optic neuritis.
    Medical Hypotheses 03/2014; 82(5). DOI:10.1016/j.mehy.2014.02.030 · 1.07 Impact Factor
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    • "Restoring balanced levels of redox - sensitive transcription fac - tors and enzymes through Nrf2 induction has been demonstrated in a number of mouse models of neurodegenerative disease ( Jakel et al . , 2007 ; Kanninen et al . , 2009 ; Neymotin et al . , 2011 ; Pareek et al . , 2011 ) but perhaps confusing a downstream antioxidant ac - tivity with the upstream activation of redox controls , as shown here . The strategy of a combination of energy precursor and redox stimulators to induce multiple targets including NADH , NADPH , signaling pathways , metabolism , and so forth shown here to be effective in vitro may p"
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    ABSTRACT: To determine whether glutathione (GSH) loss or increased reactive oxygen species (ROS) are more important to neuron loss, aging, and Alzheimer's disease (AD), we stressed or boosted GSH levels in neurons isolated from aging 3xTg-AD neurons compared with those from age-matched nontransgenic (non-Tg) neurons. Here, using titrating with buthionine sulfoximine, an inhibitor of γ-glutamyl cysteine synthetase (GCL), we observed that GSH depletion increased neuronal death of 3xTg-AD cultured neurons at increasing rates across the age span, whereas non-Tg neurons were resistant to GSH depletion until old age. Remarkably, the rate of neuron loss with ROS did not increase in old age and was the same for both genotypes, which indicates that cognitive deficits in the AD model were not caused by ROS. Therefore, we targeted for neuroprotection activation of the redox sensitive transcription factor, nuclear erythroid-related factor 2 (Nrf2) by 18 alpha glycyrrhetinic acid to stimulate GSH synthesis through GCL. This balanced stimulation of a number of redox enzymes restored the lower levels of Nrf2 and GCL seen in 3xTg-AD neurons compared with those of non-Tg neurons and promoted translocation of Nrf2 to the nucleus. By combining the Nrf2 activator together with the NADH precursor, nicotinamide, we increased neuron survival against amyloid beta stress in an additive manner. These stress tests and neuroprotective treatments suggest that the redox environment is more important for neuron survival than ROS. The dual neuroprotective treatment with nicotinamide and an Nrf2 inducer indicates that these age-related and AD-related changes are reversible.
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