Background: The chronic inflammation associated with multiple sclerosis (MS) may lead to the upregulation of pentosidine.
Objectives: This cross-sectional study compares plasma pentosidine levels among healthy controls (HCs) and patients with MS at different disease stages. The study also determines pentosidine's usefulness as a biomarker of MS disease activity and/or severity via its correlation with a number of indicators of MS disease.
Methods: Pentosidine levels were analyzed in 98 MS patients and 43 HCs using reverse-phase high-pressure liquid chromatography with fluorescence detection.
Results: Plasma pentosidine levels were significantly higher in MS patients when compared with HCs (p=0.02). Patients on disease-modifying therapies (DMTs) had lower plasma pentosidine levels when compared with DMT-naïve patients (p= 0.01). Pentosidine plasma levels correlated with indicators of MS disease severity, including Extended Disability Status Scale (p = 0.03), MS Severity Scale (p = 0.01), and MS Functional Composite (p = 0.03). No correlation between pentosidine levels and age, rate of clinical relapse, and disease duration was observed.
Conclusions: Our results suggest that pentosidine could be a novel, inflammatory biomarker in MS clinical practice. Longitudinal studies are warranted to determine any causal relationship between changes in plasma pentosidine levels and MS disease pathology. These studies may pave the way for use of advanced glycation end product (AGE) inhibitors and AGE-breaking agents as new therapeutic modalities in MS.
OdettiPAragnoIGaribaldiSValentiniSPronzatoMARolandiR. Role of advanced glycation end products in aging collagen. Gerontology1998; 44: 187–191.
2.
MiyataTUedaYYamadaY. Accumulation of carbonyls accelerates the formation of pentosidine, an advanced glycosylation end product: carbonyl stress in uremia. J Am Soc Nephrol1998; 9: 2349–2356.
3.
SalmanAGMansourDESwelemAHAl-ZawaharyWMRadwanAA. Pentosidine – a new biochemical marker in diabetic retinopathy. Ophthalmic Res2009; 42: 96–98.
4.
KoyamaYTakeishiYArimotoTNiizekiTShishidoTTakahashiH. High serum level of pentosidine, an advanced glycation end product (AGE), is a risk factor of patients with heart failure. J Card Fail2007; 13: 199–206.
5.
JanuszewskiASAldersonNLMetzTOThorpeSRBaynesJW. Role of lipids in chemical modification of proteins and development of complications in diabetes. Biochem Soc Trans2003; 31: 1413–1416.
6.
GrandheeSKMonnierVM. Mechanism of formation of the Maillard protein cross-link pentosidine. Glucose, fructose, and ascorbate as pentosidine precursors. J Biol Chem1991; 266: 11649–11653.
7.
DyerDGBlackledgeJAThorpeSRBaynesJW. Formation of pentosidine during nonenzymatic browning of proteins by glucose. Identification of glucose and other carbohydrates as possible precursors of pentosidine in vivo. J Biol Chem1991; 266: 11654–11660.
8.
VlassaraH. Advanced glycation end-products and atherosclerosis. [Review] Ann Med1996; 28: 419–426.
9.
SteenvoordenMMHuizingaTWVerzijlNBankRARondayHKLuningHA. Activation of receptor for advanced glycation end products in osteoarthritis leads to increased stimulation of chondrocytes and synoviocytes. Arthritis Rheum2006; 54: 253–263.
10.
BierhausAHaslbeckKMMorcosMSchiekoferSAndrassyMChenJ. Hyperglycaemia increases CML deposition, RAGE expression and NFkappaB activation in peripheral nerves. Exp Clin Endocrinol Diabetes2000; 108: 122–127.
11.
BucciarelliLGWendtTRongLLallaEHofmannMAGoovaMT. RAGE is a multiligand receptor of the immunoglobulin superfamily: implications for homeostasis and chronic disease. Cell Mol Life Sci2002; 59: 1117–1128.
12.
UchimuraTMotomiyaYOkamuraHHashiguchiTMiuraMUjiY. Marked increases in macrophage colony-stimulating factor and interleukin-18 in maintenance hemodialysis patients: Comparative study of advanced glycation end products, carboxymethyllysine and pentosidine. Nephron2002; 90: 401–407.
13.
KarniAKoldzicDNBharanidharanPKhourySJWeinerHL. IL-18 is linked to raised IFN-gamma in multiple sclerosis and is induced by activated CD4(+) T cells via CD40-CD40 ligand interactions. J Neuroimmunol2002; 125: 134–140.
14.
SzczucinskiAKalinowskaALosyJ. CXCL11 (Interferon-inducible T-cell alpha chemoattractant) and interleukin-18 in relapsing-remitting multiple sclerosis patients treated with methylprednisolone. Euro Neurol2007; 58: 228–232.
15.
MeerwaldtRHartogJWGraaffRHuismanRJLinksTPden HollanderNC. Skin autofluorescence, a measure of cumulative metabolic stress and advanced glycation end products, predicts mortality in hemodialysis patients. J Am Soc Nephrol2005; 16: 3687–3693.
16.
HartogJWHummelYMVoorsAASchalkwijkCGMiyataTHuismanRM. Skin autofluorescence, a measure of tissue advanced glycation end-products (AGEs), is related to diastolic function in dialysis patients. J Card Fail2008; 14: 596–602.
17.
TakedaAYasudaTMiyataTGotoYWakaiMWatanabeM. Advanced glycation end products co-localized with astrocytes and microglial cells in Alzheimer’s disease brain. Acta Neuropathol1998; 95: 555–558.
18.
MeliMPerierCFerronCParssegnyFDenisCGonthierR. Serum pentosidine as an indicator of Alzheimer’s disease. J Alzheimers Dis2002; 4: 93–96.
19.
BarKJFrankeSWendaBMullerSKientsch-EngelRSteinG. Pentosidine and N(epsilon)-(carboxymethyl)-lysine in Alzheimer’s disease and vascular dementia. Neurobiol Aging2003; 24: 333–338.
20.
YanSSWuZYZhangHPFurtadoGChenXYanSF. Suppression of experimental autoimmune encephalomyelitis by selective blockade of encephalitogenic T-cell infiltration of the central nervous system. Nat Med2003; 9: 287–293.
21.
SidotiAAntognelliCRinaldiCD’AngeloRDattolaVGirlandaP. Glyoxalase I A111E, paraoxonase 1 Q192R and L55M polymorphisms: susceptibility factors of multiple sclerosis?Mult Scler2007; 13: 446–453.
22.
PiwowarAKnapik-KordeckaMSzczecinskaJWarwasM. Plasma glycooxidation protein products in type 2 diabetic patients with nephropathy. Diabetes Metab Res Rev2008; 24: 549–553.
23.
RysavaRKalousovaMZimaTDostalCMertaMTesarV. Does renal function influence plasma levels of advanced glycation and oxidation protein products in patients with chronic rheumatic diseases complicated by secondary amyloidosis?Kidney Blood Press Res2007; 30: 1–7.
24.
CalkinACGiuntiSSheehyKJChewCBoolellVRajaramYS. The HMG-CoA reductase inhibitor rosuvastatin and the angiotensin receptor antagonist candesartan attenuate atherosclerosis in an apolipoprotein E-deficient mouse model of diabetes via effects on advanced glycation, oxidative stress and inflammation. Diabetologia2008; 51: 1731–1740.
25.
MiyataTIshiguroNYasudaYItoTNangakuMIwataH. Increased pentosidine, an advanced glycation end product, in plasma and synovial fluid from patients with rheumatoid arthritis and its relation with inflammatory markers. Biochem Biophys Res Commun1998; 244: 45–49.
26.
PortaccioEZipoliVGorettiBDe StefanoNAmatoMP. Gray matter atrophy correlates with MS disability progression measured with MSFC but not EDSS. J Neurol Sci2009; 284: 223–224.
27.
KochMMostertJArutjunyanAVStepanovMTeelkenAHeersemaD. Plasma lipid peroxidation and progression of disability in multiple sclerosis. Euro J Neurol2007; 14: 529–533.
28.
ClynesRMoserB. Receptor for AGE (RAGE): weaving tangled webs within the inflammatory response. Curr Mol Med2007; 7: 743–751.
29.
NienhuisHLWestraJSmitAJLimburgPCKallenbergCGBijlM. AGE and their receptor RAGE in systemic autoimmune diseases: an inflammation propagating factor contributing to accelerated atherosclerosis. [Review] Autoimmunity2009; 42: 302–304.
30.
OchiHOsoegawaMWuXMMinoharaMHoriuchiIMuraiH. Increased IL-13 but not IL-5 production by CD4-positive T cells and CD8-positive T cells in multiple sclerosis during relapse phase. J Neurol Sci2002; 201: 45–51.
31.
WheelerTTJordanTWFordHC. Double-label two-dimensional electrophoresis of serum and plasma proteins from patients with multiple sclerosis. J Neurol Sci1987; 78: 87–92.
32.
FigarolaJLShanmugamNNatarajanRRahbarS. Anti-inflammatory effects of the advanced glycation end product inhibitor LR-90 in human monocytes. Diabetes2007; 56: 647–655.
33.
TanimotoMGohdaTKanekoSHagiwaraSMurakoshiMAokiT. Effect of pyridoxamine (K-163), an inhibitor of advanced glycation end products, on type 2 diabetic nephropathy in KK-A(y)/Ta mice. Metabolism Clin Exp2007; 56: 160–167.
34.
ForbesJMSoulisTThallasVPanagiotopoulosSLongDMVasanS. Renoprotective effects of a novel inhibitor of advanced glycation. Diabetologia2001; 44: 108–114.
35.
SoulisTCooperMVranesDBucalaRJerumsG. Effects of aminoguanidine in preventing experimental diabetic nephropathy are related to the duration of treatment. Kidney Int1996; 50: 627–627.
36.
VasanSFoilesPFoundsH. Therapeutic potential of breakers of advanced glycation end product-protein crosslinks. [Review] Arch Biochem Biophys2003; 419: 89–96.
37.
MunchGDeuther-ConradWGasic-MilenkovicJ. Glycoxidative stress creates a vicious cycle of neurodegeneration in Alzheimer’s disease – a target for neuroprotective treatment strategies? [Review]. J Neural Transm Suppl2002; 62: 303–307.
