• Users Online: 1403
  • Home
  • Print this page
  • Email this page

 Table of Contents  
Year : 2015  |  Volume : 10  |  Issue : 3  |  Page : 391-393

A new look at auranofin, dextromethorphan and rosiglitazone for reduction of glia-mediated inflammation in neurodegenerative diseases

Department of Biology, University of British Columbia Okanagan Campus, Kelowna, British Columbia, V1V 1V7, Canada

Date of Acceptance30-Jan-2015
Date of Web Publication31-Mar-2015

Correspondence Address:
Andis Klegeris
Department of Biology, University of British Columbia Okanagan Campus, Kelowna, British Columbia, V1V 1V7
Login to access the Email id

Source of Support: This work was supported by a grant from the Jack Brown and Family Alzheimer's Disease Research Foundation., Conflict of Interest: None

DOI: 10.4103/1673-5374.153686

Rights and Permissions

Neurodegenerative disorders including Alzheimer's disease are characterized by chronic inflammation in the central nervous system. The two main glial types involved in inflammatory reactions are microglia and astrocytes. While these cells normally protect neurons by providing nutrients and growth factors, disease specific stimuli can induce glial secretion of neurotoxins. It has been hypothesized that reducing glia-mediated inflammation could diminish neuronal loss. This hypothesis is supported by observations that chronic use of non-steroidal anti-inflammatory drugs (NSAIDs) is linked with lower incidences of neurodegenerative disease. It is possible that the NSAIDs are not potent enough to appreciably reduce chronic neuroinflammation after disease processes are fully established. Gold thiol compounds, including auranofin, comprise another class of medications effective at reducing peripheral inflammation. We have demonstrated that auranofin inhibits human microglia- and astrocyte-mediated neurotoxicity. Other drugs which are currently used to treat peripheral inflammatory conditions could be helpful in neurodegenerative disease. Three different classes of anti-inflammatory compounds, which have a potential to inhibit neuroinflammation are highlighted below.

Keywords: auranofin; dextromethorphan; rosiglitazone; Alzheimer′s disease; neuroinflammation; neurodegeneration; microglia; astrocytes

How to cite this article:
Madeira JM, Schindler SM, Klegeris A. A new look at auranofin, dextromethorphan and rosiglitazone for reduction of glia-mediated inflammation in neurodegenerative diseases. Neural Regen Res 2015;10:391-3

How to cite this URL:
Madeira JM, Schindler SM, Klegeris A. A new look at auranofin, dextromethorphan and rosiglitazone for reduction of glia-mediated inflammation in neurodegenerative diseases. Neural Regen Res [serial online] 2015 [cited 2022 Jan 24];10:391-3. Available from: http://www.nrronline.org/text.asp?2015/10/3/391/153686

  Introduction Top

Inflammation in the central nervous system (CNS) contributes to several neurodegenerative diseases (Jonsson et al., 2013). Gene mutations affecting inflammatory pathways have been linked to poorer cognitive functioning in elderly patients and to date no effective treatments for preventing or reducing this inflammation exist (Jonsson et al., 2013). CNS inflammation is driven by two glial cell types: microglia and astrocytes (Gonzalez et al., 2014; Hostenbach et al., 2014); therefore, these cells are the primary targets for novel anti-inflammatory drugs (Lee et al., 2013). Under normal physiological conditions these cells provide trophic support to neurons; however, in neuroinflammation, increased secretion of proinflammatory mediators, glial toxins, excitatory molecules, such as glutamate, as well as decreased release of neurotrophic factors from glia can damage healthy surrounding neurons (Lee et al., 2013). Drugs that counteract these pathological changes without affecting the physiological activity of glia, such as clearing amyloid beta deposits, are excellent candidates for the treatment of neuroinflammatory conditions (Lee et al., 2013).

Several classes of anti-inflammatory drugs have been well studied and are considered safe. They include non-steroidal anti-inflammatory drugs (NSAIDs), which inhibit cyclooxygenase (COX) enzymes; glucocorticoids; and disease modifying anti-rheumatic drugs (DMARDs), such as methotrexate, which have several mechanisms of action (Dinarello, 2010). While most of these drugs have been studied extensively as inhibitors of peripheral inflammation, few have been investigated for their effects on neuroinflammation (Tansey and Goldberg, 2010). This brief highlight will summarize the available evidence of anti-neuroinflammatory activity of three drugs currently approved for use in other disorders.

  Auranofin Top

Gold compounds including 2, 3, 4, 6-tetra-o-acetyl-l-thio-β-D-glucopyrano-sato-S-(triethyl-phosphine) gold, manufactured as auranofin (AF), are used to treat inflammation associated with rheumatoid arthritis (Kean, 1990). While their exact mechanism of action is unclear, it is known that AF inhibits several inflammatory pathways including nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB) activation and tumor necrosis factor (TNF)-α production and secretion (Madeira et al., 2012).

Our studies indicate that AF possesses both anti-neuroinflammatory and neuroprotective activities. AF at low micromolar concentrations inhibited human microglia- and astrocyte-mediated neurotoxicity (Madeira et al., 2013, 2014). The anti-neuroinflammatory activity of AF was selective; it inhibited priming of phagocyte respiratory burst and microglial secretion of TNF-α and nitric oxide (NO) (Madeira et al., 2014). AF upregulated hemeoxygenase (HOX)-1, an anti-inflammatory and neuroprotective enzyme in astrocytes (Cuadrado and Rojo, 2008; Madeira et al., 2013). Moreover, AF directly protected neuronal cells from toxicity induced by hydrogen peroxide or stimulated glial supernatants; however, it did not inhibit secretion of interleukin (IL)-6 and IL-8 (Madeira et al., 2013, 2014). After oral administration in rats and mice, AF has been shown to reach CNS concentrations above 0.1 μM required for its protective effects (Madeira et al., 2012, 2013); therefore, AF may be useful in the treatment of neuroinflammation.

  Dextromethorphan Top

Dextromethorphan (DM; d-3-methoxy-17-methylmorphinan) is an anti-tussive agent used in cough medicines (Tortella et al., 1989). DM has been shown to inhibit peripheral production and secretion of several inflammatory mediators including TNF-α, IL-6, NO and superoxide anion (O2) (Liu et al., 2003). Several studies have shown that DM reduces glia-mediated neuroinflammation and may have neuroprotective effects (Liu et al., 2003; Keller et al., 2008; Chechneva et al., 2011). DM inhibited microglia-mediated degeneration of dopaminergic neurons in vitro and inhibited the production of TNF-α, NO, and O2 by stimulated microglia (Liu et al., 2003). Furthermore, DM is a known N-methyl-d-aspartate receptor (NMDAR) antagonist (Tortella et al., 1989). In a mouse model of excitotoxic brain damage, DM reduced lesion size and neuronal cell death, possibly by reducing microglial activation. Low concentrations of DM reduced inflammation-primed NMDAR-mediated excitotoxic brain damage without inducing neuronal apoptosis (Keller et al., 2008). In animal models of multiple sclerosis, DM was shown to reduce the transcription of NOX-2 and O2Ľ production in microglia (Chechneva et al., 2011). A phase II clinical trial investigating a combination of DM and quinidine sulfate (a metabolic inhibitor that affects DM concentration in the body) for the treatment of Alzheimer's disease (AD) is currently underway, but results have not yet been released (Misra and Medhi, 2013).

  Rosiglitazone Top

Rosiglitazone (RSG) is currently used in the treatment of type 2 diabetes. RSG is a thiazolidinedione, which activates peroxisome proliferator-activated receptor-γ (PPAR-γ) (Haffner et al., 2002). PPAR-γ agonists are anti-inflammatory by suppressing NF-κB and by directing macrophages towards the anti-inflammatory M2 phenotype (Bouhlel et al., 2007; Gold et al., 2010). RSG may be helpful in the treatment of neuroinflammatory conditions. Hyong et al. (2008) demonstrated that RSG improved neurological status in rats after surgical brain injury. This improvement could be due to decreased IL-1β and TNF-α expression. In a similar study using a stroke model, RSG treatment decreased infarct volume, improved post ischemic neurological function, and reduced neutrophil accumulation in the brain parenchyma of mice. RSG inhibited TNF-α, IL-1β, and IL-6 secretion by cultured cortical microglia (Luo et al., 2006) and has also shown direct neuroprotective activity in the models of traumatic brain injury (Yi et al., 2008). Treatment of mice with RSG enhanced post-traumatic brain expression of neuroprotective heat shock proteins, HOX-1, and anti-oxidant enzymes. Luna-Medina et al. (2005) demonstrated that RSG significantly reduced expression of TNF-α, IL-6, inducible nitric oxide synthase, and COX-2 by stimulated astrocytes through PPAR-γ activation. While complete suppression of COX-2 may cause undesirable CNS effects, such adverse activity has not been reported with RSG treatment (Gold et al., 2010). Studies of the effects of RSG on Alzheimer's disease (AD) progression have yielded mixed results depending on whether or not the patients were carriers of the apolipoprotein E (APOE) allele which is correlated with late-onset AD (Gold et al., 2010).

  Conclusion Top

Neuroinflammation contributes to the pathogenesis of a wide range of neurodegenerative disorders especially during their early stages before irreversible changes, such as plaque formation, have occured (Lucas et al., 2006). Currently no effective treatments directed at reducing this inflammation exist (Klegeris et al., 2007). Development of novel therapeutics is a lengthy process, which can be expedited by developing new applications for drugs that are already approved for use in humans. A number of such approved drugs with known peripheral anti-inflammatory activity have yet to be studied for their effects on neuroinflammation (Dinarello, 2010). By re-purposing old drugs, the time it takes for an effective anti-neuroinflammatory drug to be found and put into clinical trials could be significantly reduced[25].

  References Top

Bouhlel MA, Derudas B, Rigamonti E, Dievart R, Brozek J, Haulon S, Zawadzki C, Jude B, Torpier G, Marx N, Staels B, Chinetti-Gbaguidi G (2007) PPARgamma activation primes human monocytes into alternative M2 macrophages with anti-inflammatory properties. Cell Metab 6:137-143.  Back to cited text no. 1
Chechneva OV, Mayrhofer F, Daugherty DJ, Pleasure DE, Hong JS, Deng W (2011) Low dose dextromethorphan attenuates moderate experimental autoimmune encephalomyelitis by inhibiting NOX2 and reducing peripheral immune cells infiltration in the spinal cord. Neurobiol Dis 44:63-72.  Back to cited text no. 2
Cuadrado A, Rojo AI (2008) Heme oxygenase-1 as a therapeutic target in neurodegenerative diseases and brain infections. Curr Pharm Des 14:429-442.  Back to cited text no. 3
Dinarello CA (2010) Anti-inflammatory agents: Present and future. Cell 140:935-950.  Back to cited text no. 4
Gold M, Alderton C, Zvartau-Hind M, Egginton S, Saunders AM, Irizarry M, Craft S, Landreth G, Linnamagi U, Sawchak S (2010) Rosiglitazone monotherapy in mild-to-moderate Alzheimer's disease: results from a randomized, double-blind, placebo-controlled phase III study. Dement Geriatr Cogn Disord 30:131-146.  Back to cited text no. 5
Gonzalez H, Elgueta D, Montoya A, Pacheco R (2014) Neuroimmune regulation of microglial activity involved in neuroinflammation and neurodegenerative diseases. J Neuroimmunol 274:1-13.  Back to cited text no. 6
Haffner SM, Greenberg AS, Weston WM, Chen H, Williams K, Freed MI (2002) Effect of rosiglitazone treatment on nontraditional markers of cardiovascular disease in patients with type 2 diabetes mellitus. Circulation 106:679-684.  Back to cited text no. 7
Hostenbach S, Cambron M, D'Haeseleer M, Kooijman R, De Keyser J (2014) Astrocyte loss and astrogliosis in neuroinflammatory disorders. Neurosci Lett 565:39-41.  Back to cited text no. 8
Hyong A, Jadhav V, Lee S, Tong W, Rowe J, Zhang JH, Tang J (2008) Rosiglitazone, a PPAR gamma agonist, attenuates inflammation after surgical brain injury in rodents. Brain Res 1215:218-224.  Back to cited text no. 9
Jonsson T, Stefansson H, Steinberg S, Jonsdottir I, Jonsson PV, Bjornsson S, Huttenlocber J, Levey AI, Lah JJ, Rujescu D, Hampel H, Giegling I, Andreassen OA, Engedasl K, Ulstein I, Djurovic S, Ibrahim-Verbaas C, Hofman A, Ikram MA, van Duijn CM, et al. (2013) Variant of TREM2 associated with the risk of Alzheimer's disease. N Engl J Med 368:107-116.  Back to cited text no. 10
Kean WF (1990) Intramuscular versus oral gold therapy. Baillieres Clin Rheumatol 4:219-246.  Back to cited text no. 11
Keller M, Griesmaier E, Auer M, Schlager G, Urbanek M, Simbruner G, Gressens P, Sarkozy G (2008) Dextromethorphan is protective against sensitized N-methyl-D-aspartate receptor-mediated excitotoxic brain damage in the developing mouse brain. Eur J Neurosci 27:874-883.  Back to cited text no. 12
Klegeris A, McGeer EG, McGeer PL (2007) Therapeutic approaches to inflammation in neurodegenerative disease. Curr Opin Neurol 20:351-357.  Back to cited text no. 13
Lee M, McGeer E, Kodela R, Kashfi K, McGeer PL (2013) NOSH- aspirin (NBS-1120), a novel nitric oxide and hydrogen sulfide releasing hybrid, attenuates neuroinflammation induced by microglial and astrocytic activation: a new candidate for treatment of neurodegenerative disorders. Glia 61:1724-1734.  Back to cited text no. 14
Liu Y, Qin L, Li G, Zhang W, An L, Liu B, Hong JS (2003) Dextromethorphan protects dopaminergic neurons against inflammation-mediated degeneration through inhibition of microglial activation. J Pharmacol Exp Ther 305:212-218.  Back to cited text no. 15
Lucas SM, Rothwell NJ, Gibson RM (2006) The role of inflammation in CNS injury and disease. Br J Pharmacol 147 Suppl 1:S232-240.  Back to cited text no. 16
Luna-Medina R, Cortes-Canteli M, Alonso M, Santos A, Martinez A, Perez-Castillo A (2005) Regulation of inflammatory response in neural cells in vitro by thiadiazolidinones derivatives through peroxisome proliferator-activated receptor gamma activation. J Biol Chem 280:21453-21462.  Back to cited text no. 17
Luo Y, Yin W, Signore AP, Zhang F, Hong Z, Wang S, Graham SH, Chen J (2006) Neuroprotection against focal ischemic brain injury by the peroxisome proliferator-activated receptor-gamma agonist rosiglitazone. J Neurochem 97:435-448.  Back to cited text no. 18
Madeira JM, Gibson DL, Kean WF, Klegeris A (2012) The biological activity of auranofin: implications for novel treatment of diseases. Inflammopharmacology 20:297-306.  Back to cited text no. 19
Madeira JM, Bajwa E, Stuart MJ, Hashioka S, Klegeris A (2014) Gold drug auranofin could reduce neuroinflammation by inhibiting microglia cytotoxic secretions and primed respiratory burst. J Neuroimmunol 276:71-79.  Back to cited text no. 20
Madeira JM, Renschler CJ, Mueller B, Hashioka S, Gibson DL, Klegeris A (2013) Novel protective properties of auranofin: inhibition of human astrocyte cytotoxic secretions and direct neuroprotection. Life Sci 92:1072-1080.  Back to cited text no. 21
Misra S, Medhi B (2013) Drug development status for Alzheimer's disease: present scenario. Neurol Sci 34:831-839.  Back to cited text no. 22
Tansey MG, Goldberg MS (2010) Neuroinflammation in Parkinson's disease: its role in neuronal death and implications for therapeutic intervention. Neurobiol Dis 37:510-518.  Back to cited text no. 23
Tortella FC, Pellicano M, Bowery NG (1989) Dextromethorphan and neuromodulation: old drug coughs up new activities. Trends Pharmacol Sci 10:501-507.  Back to cited text no. 24
Yi JH, Park SW, Brooks N, Lang BT, Vemuganti R (2008) PPARgamma agonist rosiglitazone is neuroprotective after traumatic brain injury via anti-inflammatory and anti-oxidative mechanisms. Brain Res 1244:164-172.  Back to cited text no. 25

This article has been cited by
1 Repurposing auranofin for treatment of Experimental Cerebral Toxoplasmosis
Iman Fathy Abou-El-Naga,Nermine Mogahed Fawzy Hussein Mogahed
Acta Parasitologica. 2021;
[Pubmed] | [DOI]
2 Excitotoxicity as a Target Against Neurodegenerative Processes
Octavio Binvignat,Jordi Olloquequi
Current Pharmaceutical Design. 2020; 26(12): 1251
[Pubmed] | [DOI]
3 Auranofin Attenuates Non-Alcoholic Fatty Liver Disease by Suppressing Lipid Accumulation and NLRP3 Inflammasome-Mediated Hepatic Inflammation In Vivo and In Vitro
Hyun Hwangbo,Min Yeong Kim,Seon Yeong Ji,So Young Kim,Hyesook Lee,Gi-Young Kim,Cheol Park,Young-Sam Keum,Su Hyun Hong,Jaehun Cheong,Yung Hyun Choi
Antioxidants. 2020; 9(11): 1040
[Pubmed] | [DOI]
4 Dextromethorphan Analgesia in a Human Experimental Model of Hyperalgesia
E. Martin,C. Narjoz,X. Decleves,L. Labat,C. Lambert,M.-A. Loriot,G. Ducheix,C. DualÚ,B. Pereira,G. Pickering
Anesthesiology. 2019; 131(2): 356
[Pubmed] | [DOI]
5 Antiparasitic Activity of Auranofin against Pathogenic Naegleria fowleri
Nathan Peroutka-Bigus,Bryan H. Bellaire
Journal of Eukaryotic Microbiology. 2019;
[Pubmed] | [DOI]
6 Inávitro and inávivo anti-tumor activity of two gold(III) complexes with isoquinoline derivatives as ligands
Taj-Malook Khan,Noor Shad Gul,Xing Lu,Jian-Hua Wei,Yan-Cheng Liu,Hongbin Sun,Hong Liang,Chris Orvig,Zhen-Feng Chen
European Journal of Medicinal Chemistry. 2019; 163: 333
[Pubmed] | [DOI]
7 The effect of dextromethorphan use in ParkinsonŠs disease: A 6-hydroxydopamine rat model and population-based study
Cheng-Tsung Liu,Li-Ting Kao,Jui-Hu Shih,Wu-Chien Chien,Chuang-Hsin Chiu,Kuo-Hsing Ma,Yuahn-Sieh Huang,Cheng-Yi Cheng,Chyng-Yann Shiue,I-Hsun Li
European Journal of Pharmacology. 2019; : 172639
[Pubmed] | [DOI]
8 Counteraction of HCV-Induced Oxidative Stress Concurs to Establish Chronic Infection in Liver Cell Cultures
Simona Anticoli,Donatella Amatore,Paola Matarrese,Marta De Angelis,Anna Teresa Palamara,Lucia Nencioni,Anna Ruggieri
Oxidative Medicine and Cellular Longevity. 2019; 2019: 1
[Pubmed] | [DOI]
9 Interaction of DCF1 with ATP1B1 induces impairment in astrocyte structural plasticity via the P38 signaling pathway
Jiao Wang,Fangfang Zhou,Dong Wang,Jie Li,Dongfang Lu,Qian Li,Hong Zhou,Weihao Li,Qian Wang,Yiliu Wu,Jiang Xie,Tieqiao Wen
Experimental Neurology. 2018; 302: 214
[Pubmed] | [DOI]
10 Combined Rosiglitazone and Forskolin Have Neuroprotective Effects in SD Rats after Spinal Cord Injury
Qing-qi Meng,Wei Lei,Hao Chen,Zhen-cheng Feng,Li-qiong Hu,Xing-liang Zhang,Siming Li
PPAR Research. 2018; 2018: 1
[Pubmed] | [DOI]
11 Combination of methylprednisolone and rosiglitazone promotes recovery of neurological function after spinal cord injury
Xi-gong Li,Xiang-jin Lin,Jun-hua Du,San-zhong Xu,Xian-feng Lou,Zhong Chen
Neural Regeneration Research. 2016; 11(10): 1678
[Pubmed] | [DOI]
12 A systems pharmacology approach to decipher the mechanism of danggui-shaoyao-san decoction for the treatment of neurodegenerative diseases
Yunxia Luo,Qi Wang,Yongbin Zhang
Journal of Ethnopharmacology. 2016; 178: 66
[Pubmed] | [DOI]


Similar in PUBMED
   Search Pubmed for
   Search in Google Scholar for
 Related articles
Access Statistics
Email Alert *
Add to My List *
* Registration required (free)

  In this article

 Article Access Statistics
    PDF Downloaded419    
    Comments [Add]    
    Cited by others 12    

Recommend this journal