- Open Access
Prolyl oligopeptidase is inhibited in relapsing-remitting multiple sclerosis
© Tenorio-Laranga et al; licensee BioMed Central Ltd. 2010
- Received: 17 February 2010
- Accepted: 6 April 2010
- Published: 6 April 2010
Multiple sclerosis (MS) is a complex, inflammatory and neurodegenerative disease of the central nervous system leading to long-term disability. Recent studies indicate a close association between inflammation and neurodegeneration in all lesions and disease stages of MS. Prolyl oligopeptidase (POP) is a proline-specific serine protease that cleaves several neuroactive peptides. This peptidase has been implicated in neurodegeneration, as well as in the modulation of the inflammatory response.
We examined plasma POP and the levels of an endogenous POP inhibitor from relapsing remitting MS patients and compared these with healthy controls, by monitoring the fluorescent changes due to standard fluorescently labelled substrate cleavage. We analysed the data in relationship to patient age and disease disability status.
We observed a significant decrease in POP activity in plasma of relapsing remitting MS patients relative to healthy controls, coupled with an increase of POP endogenous inhibitor. The POP activity was also correlated with patient age and disability status. The lowered POP activity from plasma of MS patients could be rescued by reductants
The decrease in circulating POP activity measured in MS is reverted by reductants. This suggests that POP inactivation in MS might be a result of the oxidative conditions prevailing in the plasma of the diseased patients. Plasma levels of POP activity as well as those of their endogenous inhibitor are suggested as biomarkers of inflammation and oxidative stress in MS.
- Multiple Sclerosis
- Multiple Sclerosis Patient
- Myelin Basic Protein
- Expand Disability Status Scale
- Expand Disability Status Scale Score
Prolyl oligopeptidase (POP) is a proline-specific endopeptidase, highly expressed in brain, that cleaves neuroactive peptides implicated in memory, learning and also in neurodegeneration [1, 2]. The distribution of the enzyme across the brain indicates that POP may be involved in the thalamocortical neurotransmission, memory and learning functions of hippocampal formation and GABAergic regulation of voluntary movements [3–5]. POP inhibitors are neuroprotective in certain experimental settings, for instance in brain ischemia and in T-cell activation-induced cell death . Active POP increases the aggregation rate of α-synuclein in vitro , and serum levels of this activity are lower in different stages of depression and higher in mania . Furthermore, the effect of the mood-stabilizing drugs, lithium, carbamazepine and valproic acid, can be reversed by POP inhibition . Additionally, POP inhibitors can reverse memory loss in rodents under several experimental conditions, such as scopolamine administration  or brain ischemia . A POP endogenous inhibitor has been described  and proposed as a regulator of POP activity in cells, tissues and fluids . Moreover, myelin basic protein has been suggested as a substrate for POP .
Recent studies indicate a close association between inflammation and neurodegeneration in all lesions and disease stages of MS . MS is associated to immunological changes elicited by endogenous myelin-associated antigens such as myelin oligodendrocyte glycoprotein, proteolipoprotein, and myelin basic protein . Acute lesions are thought to result when activated T cells, responsive to these and other potential antigens, traffic to the central nervous system and trigger a cascade of inflammatory events. Widespread axonal degeneration and brain atrophy appear early in the disease course and are prominent in progressive forms of MS. During an acute inflammatory attack, increases in free radicals lead to mitochondrial damage and decreased ATP production, which would be expected to inhibit axonal transport, including the transport of mitochondria . Inflammation also activates signalling pathways that inhibit axonal transport.
Recently a direct role for POP as a modulator of the inflammatory response has been proposed . This response involves a multistep process during matrix metalloproteases (MMPs) mediated collagen degradation, resulting in formation of the peptide, N-acetylated-proline-glycine-proline (N-α-PGP), a POP product. This peptide has been described as a neutrophil chemoattractant and also as a stimulator of superoxide production . In addition, PGP is a biomarker for chronic obstructive pulmonary disease (COPD), an inflammatory disorder . This study has also shown that POP, in conjunction with MMPs, is required for production of PGP. Kamori and collaborators , have showed that POP activity levels are increased in knee joint synovial membrane of patients with rheumatoid arthritis, a systemic inflammatory disorder.
On the other hand, recent studies have shown that POP is a mediator of the toxic effect that reactive microglia cells have in a neural cell culture model. This effect is reduced by POP inhibitors . The presence of reactive microglia cells has been observed in Alzheimer's, Parkinson's, Pick's and Huntington's diseases, amyotrophic lateral sclerosis, AIDS encephalopathy, and MS . Additionally, microglia are the principal cells that mediate innate immune responses in the CNS.
POP has been found to be responsible for the generation of the thymosin β-4 derived peptide N-acetyl-seryl-aspartyl-lysyl-proline (Ac-SDKP, ). Ac-SDKP is involved in inflammatory cell infiltration, perivascular fibrosis and glomerulosclerosis , and in human malignant tumours . We have evidence that β-thymosin is indeed a physiological substrate of POP in brain .
Alterations in plasma POP activity have been found in several neurological diseases, but to our knowledge, the possible involvement of this peptidase in MS has never been studied. POP has implications in several processes relevant to MS: 1) it has a role in the inflammatory response through generation of key peptides from degradation of extracellular matrix proteins; 2) it is related to microglia activation and T cell response; 3) it is involved in degradation of myelin basic protein; and 4) it has a role in axonal transport. Based in all these clues, we hypothesised that POP activity would be altered in MS. In this study, we have analysed the levels of POP activity, and those of an endogenous POP inhibitor, in a Spanish sample of clinically diagnosed MS patients. We also analysed the results in relation to patient age and disability in search of possible correlations.
Eleven patients, 7 females and 4 males, of an average age of 32 ± 7 years were used in this study. All the patients had confirmed clinical diagnosis of MS according to the modified McDonald criteria . Furthermore, all the subjects were clinically classified as having the relapsing remitting form of MS according to the criteria described by Lublin and Reingold . The time of evolution of the disease from the onset of the dysfunction was between 2 to 156 months (mean 71 ± 60 months), and the Kurtzke Expanded Disability Status Scale (EDSS)  score of the MS patients ranged from 1.5 to 3.5 at the time when the samples were taken. All patients were on interferon-β therapy.
Age-matched healthy volunteers (8 females and 9 males) were recruited for this study. None of the controls had a history of neurological symptoms or of any chronic disease.
Blood was collected from controls and patients by venipuncture from an antecubital vein. Blood (8.5 ml/tube) was directly drawn into two evacuated tubes containing anticoagulants (buffered citrate, EDTA). After collection, blood specimens were spun at 10,000 × g for 1 minute at 4°C. Supernatant plasma was aliquoted and stored at -80°C.
This study was approved by the Ethical Committee of the Centro de Investigación Principe Felipe, Valencia, Spain and followed local and European regulations. All subjects gave their informed consent for the blood collection.
Partial purification of POP
Prolyl oligopeptidase was purified from porcine brain by ion exchange chromatography as described before .
POP endogenous inhibitor
For determination of POP endogenous inhibitor in plasma, purified porcine POP (800 ng) was used in the fluorescence activity assay described above, with or without pre-incubation with 25 μl of plasma. Endogenous POP inhibitor level is reported as the percentage of inhibition caused by the plasma, in these conditions, on purified POP activity. The plasma prolyl endopeptidase activity contribution was less than 10%, and was subtracted in all cases. All assays were done by triplicate.
All analysis was performed using GraphPad Prism 4 software (La Jolla, CA, USA). For comparison between different groups, student's unpaired t test and one-way ANOVA, with Tukey post hoc test, analysis were used. Differences were considered statistically significant when a p value was <0.05. Results are expressed as means ± S.E.M.
Plasma collection conditions affect prolyl endopeptidase activity and stability
Important variations in activity and stability of POP due to preparation and assay conditions have been noticed before . On the other hand, two different enzymes in plasma, with prolyl endopeptidase activity, have been described . Apart from classical POP, the alternative activity is insensitive to POP-specific inhibitors, and is called Z-Pro-Prolinal insensitive peptidase or ZIP. This activity has been attributed to the action of fibrinogen activated protein α (FAPα) or seprase . On the other hand, Breen and collaborators  have reported that cation chelators, which are currently used during plasma preparation, affect POP activity. Our experiments indicate that while neither citrate nor EDTA in the plasma affected the levels of ZIP activity (Fig. 1A), activity of POP, or the Z-pro-prolinal sensitive activity level, was found to be substantially lower in the presence of citrate (p < 0.05). EDTA-containing plasma seems to have higher levels of POP (Fig. 1B). To verify the sensitivity to these chelators, we directly assayed their effect on the activity of purified POP (Fig. 1C). We observed that both compounds inhibit POP activity. However, at the concentrations found in the plasma samples (1.8 mg/ml EDTA and 3.2 mg/ml citrate), POP activity is practically unaffected by EDTA while citrate produces an inhibition of nearly 50% (Fig. 1C). Accordingly, only EDTA-containing plasma was used for further experiments.
POP activity is altered in remitting-relapsing multiple sclerosis and it is related to disease disability status
POP endogenous inhibitor levels in plasma are increased in RR-MS patients
Lower POP levels in RR-MS are due to reversible POP oxidation
Many aspects of MS aetiology and pathophysiology are unresolved, but there is increasing evidence that the relapsing-remitting phase and the progressive phase of the disease are caused by two distinct mechanisms. Focal inflammation is believed to be the cause of relapses, whereas diffuse axonal degeneration appears to be the main contributor to progression . The accumulation of disability in MS is thus caused by neuronal damage at inflammatory foci and by diffuse axonal degeneration. Current treatments of MS can reduce the number of relapses but are ineffective in the progressive phase.
POP is a peptidase which cleaves peptides of less than 30 amino acids from the C-side of an internal proline. Since POP is the only proline-specific endopeptidase in humans, and since several proline-containing bioactive peptides are shorter that 30 amino acids, POP has been suggested to specifically modulate the levels of these peptides . Circulating POP levels have been found to be modified in psychiatric [42–47] and mood disorders , and these facts have suggested a relationship between these conditions and disturbances in bioactive peptide levels. On the other hand, POP has been found to be related to inflammatory processes through thymosin  or collagen degradation . Furthermore, POP has been found to be increased in inflamed tissues , and has been found to be secreted from microglia-like cells upon activation . Reactive microglia play an important role in a number of neurodegenerative diseases, including MS . POP has also been reported to interact with cytoskeletal elements with relation to secretion in neural cells , suggesting a role in axonal transport. Accordingly, we here hypothesise that POP activity is modified in plasma from MS patients.
In summary, we have found in this study that levels of POP activity in plasma from RR-MS patients are substantially reduced compared with healthy controls (Fig. 2A). Analysing this data, we also find that there is a significant decrease of POP activity with increasing age in healthy subjects. However, this age-associated pattern is not observed for RR-MS patients, where the activity was already substantially lower at early ages (Fig. 2B). Furthermore, we find that the decrease observed in POP activity in diseased plasma is more pronounced in cases with more severe symptoms (Fig. 3). We suggest that the decline in POP activity is related to the molecular mechanism of the disease, and to its severity. In trying to understand the reasons for the low levels of POP which we found to prevail in RR-MS plasma, we analysed plasma looking for inhibitory factors. We found that plasma contained a POP endogenous inhibitor. We observed that levels of this inhibitor are substantially increased in RR-MS, probably partially explaining the low activities found in the disease (Fig 4A). However, we did not find any relationship between the plasma content of this endogenous inhibitor, and the low POP activity observed in diseased plasma (Fig. 4B), which suggests the existence of other factor(s) contributing to this decline. Measures of oxidative stress in blood and cerebrospinal fluid (CSF) of patients with MS have consistently found increases in a number of studies [49, 50]. POP is sensitive to the oxidative environment, and it has been reported that oxidation of specific cysteines in this enzyme arrest activity [35, 36]. We observed that addition of DTT to plasma from RR-MS patients increases POP to control levels (Fig. 5). This suggests that the higher degree of oxidative stress prevailing in MS inactivates POP.
We report here that RR-MS patients show decreased circulating POP activity, and that this reduction might be correlated with the higher oxidative environment of plasma of these patients. Additionally, our data indicate that the amount of plasma endogenous POP inhibitor is augmented in this disease, but that this factor is only partially responsible for the decreased POP activities found. We suggest that low amounts of POP activity in MS plasma are contributing to symptoms of the disease. Remarkably, we also found that POP activity is decreased in old age to levels comparable to those found in MS.
On the other hand, the increases observed in levels of POP inhibitory factor in diseased plasma is probably not correlated with increased oxidant levels, since there was no influence of DTT on inhibitory activity in plasma. The relevance of this endogenous inhibitor increase is still not known, and further experimentation is required to answer this question.
Our study is the first to relate POP to MS and indicates that most probably there is a change in peptidase homeostasis in the disease. Further work is being conducted in order to define the proteolytic cascades and the peptides involved in the changes observed in MS. This would contribute to our understanding of disease mechanisms and its symptomatology. According to the results reported here, it can be suggested that levels of plasma POP, and of POP inhibitory factor, could be used as novel tools for early MS diagnosis and also as an indicator of disease severity.
JTL was supported by the Fundación Centro de Investigación Príncipe Felipe. JAGH was supported by a fellowship from the Ramón y Cajal Programme of the Spanish Ministry of Education and Science. This work was financed by a grant from Fundación Centro de Investigación Príncipe Felipe (I19) to JAGH, and in part by the European Commission 7th Work Programme of Health to JAGH (FP7- HEALTH-F2-2008-223077).
- García-Horsman JA, Männistö PT, Venäläinen JI: On the role of prolyl oligopeptidase in health and disease. Neuropeptides. 2007, 41: 1-24. 10.1016/j.npep.2006.10.004.View ArticlePubMedGoogle Scholar
- Männistö PT, Venäläinen J, Jalkanen A, García-Horsman JA: Prolyl oligopeptidase: a potential target for the treatment of cognitive disorders. Drug News Perspect. 2007, 20: 293-305. 10.1358/dnp.2007.20.5.1120216.View ArticlePubMedGoogle Scholar
- Myöhänen TT, Venäläinen JI, García-Horsman JA, Piltonen M, Männistö PT: Cellular and subcellular distribution of rat brain prolyl oligopeptidase and its association with specific neuronal neurotransmitters. J Comp Neurol. 2008, 507: 1694-1708. 10.1002/cne.21642.View ArticlePubMedGoogle Scholar
- Myöhänen TT, Venäläinen JI, Tupala E, García-Horsman JA, Miettinen R, Männistö PT: Distribution of immunoreactive prolyl oligopeptidase in human and rat brain. Neurochem Res. 2007, 32: 1365-1374. 10.1007/s11064-007-9316-y.View ArticlePubMedGoogle Scholar
- Myöhänen TT, García-Horsman JA, Tenorio-Laranga J, Männistö PT: Issues about the physiological functions of prolyl oligopeptidase based on its discordant spatial association with substrates and inconsistencies among mRNA, protein levels, and enzymatic activity. J Histochem Cytochem. 2009, 57: 831-848. 10.1369/jhc.2009.953711.PubMed CentralView ArticlePubMedGoogle Scholar
- Brandt I, Gérard M, Sergeant K, Devreese B, Baekelandt V, Augustyns K, Scharpé S, Engelborghs Y, Lambeir AM: Prolyl oligopeptidase stimulates the aggregation of alpha-synuclein. Peptides. 2008, 29: 1472-1478. 10.1016/j.peptides.2008.05.005.View ArticlePubMedGoogle Scholar
- Brandt I, Scharpé S, Lambeir AM: Suggested functions for prolyl oligopeptidase: a puzzling paradox. Clin Chim Acta. 2007, 377: 50-61. 10.1016/j.cca.2006.09.001.View ArticlePubMedGoogle Scholar
- Cheng L, Lumb M, Polgár L, Mudge AW: How can the mood stabilizer VPA limit both mania and depression?. Mol Cell Neurosci. 2005, 29: 155-161. 10.1016/j.mcn.2004.12.003.View ArticlePubMedGoogle Scholar
- Yoshimoto T, Kado K, Matsubara F, Koriyama N, Kaneto H, Tsura D: Specific inhibitors for prolyl endopeptidase and their anti-amnesic effect. J Pharmacobiodyn. 1987, 10: 730-735.View ArticlePubMedGoogle Scholar
- Shishido Y, Furushiro M, Tanabe S, Nishiyama S, Hashimoto S, Ohno M, Yamamoto T, Watanabe S: ZTTA, a postproline cleaving enzyme inhibitor, improves cerebral ischemia-induced deficits in a three-panel runway task in rats. Pharmacology, biochemistry, and behavior. 1996, 55: 333-338. 10.1016/S0091-3057(96)00102-5.View ArticlePubMedGoogle Scholar
- Salers P: Evidence for the presence of prolyl oligopeptidase and its endogenous inhibitor in neonatal rat pancreatic beta-cells. Regul Pept. 1994, 50: 235-245. 10.1016/0167-0115(94)90004-3.View ArticlePubMedGoogle Scholar
- Brandt I, De Vriendt K, Devreese B, Van Beeumen J, Van Dongen W, Augustyns K, De Meester I, Scharpe S, Lambeir AM: Search for substrates for prolyl oligopeptidase in porcine brain. Peptides. 2005, 26: 2536-2546. 10.1016/j.peptides.2005.05.016.View ArticlePubMedGoogle Scholar
- Frischer JM, Bramow S, Dal-Bianco A, Lucchinetti CF, Rauschka H, Schmidbauer M, Laursen H, Sorensen PS, Lassmann H: The relation between inflammation and neurodegeneration in multiple sclerosis brains. Brain. 2009, 132: 1175-1189. 10.1093/brain/awp070.PubMed CentralView ArticlePubMedGoogle Scholar
- Schmidt S: Candidate autoantigens in multiple sclerosis. Mult Scler. 1999, 5: 147-160.View ArticlePubMedGoogle Scholar
- Rintoul GL, Bennett VJ, Papaconstandinou NA, Reynolds IJ: Nitric oxide inhibits mitochondrial movement in forebrain neurons associated with disruption of mitochondrial membrane potential. J Neurochem. 2006, 97: 800-806. 10.1111/j.1471-4159.2006.03788.x.View ArticlePubMedGoogle Scholar
- Gaggar A, Jackson PL, Noerager BD, O'Reilly PJ, McQuaid DB, Rowe SM, Clancy JP, Blalock JE: A novel proteolytic cascade generates an extracellular matrix-derived chemoattractant in chronic neutrophilic inflammation. J Immunol. 2008, 180: 5662-5669.PubMed CentralView ArticlePubMedGoogle Scholar
- Weathington NM, van Houwelingen AH, Noerager BD, Jackson PL, Kraneveld AD, Galin FS, Folkerts G, Nijkamp FP, Blalock JE: A novel peptide CXCR ligand derived from extracellular matrix degradation during airway inflammation. Nat Med. 2006, 12: 317-323. 10.1038/nm1361.View ArticlePubMedGoogle Scholar
- O'Reilly P, Jackson PL, Noerager B, Parker S, Dransfield M, Gaggar A, Blalock JE: N-alpha-PGP and PGP, potential biomarkers and therapeutic targets for COPD. Respir Res. 2009, 10: 38-10.1186/1465-9921-10-38.PubMed CentralView ArticlePubMedGoogle Scholar
- Kamori M, Hagihara M, Nagatsu T, Iwata H, Miura T: Activities of dipeptidyl peptidase II, dipeptidyl peptidase IV, prolyl endopeptidase, and collagenase-like peptidase in synovial membrane from patients with rheumatoid arthritis and osteoarthritis. Biochem Med Metab Biol. 1991, 45: 154-160. 10.1016/0885-4505(91)90016-E.View ArticlePubMedGoogle Scholar
- Klegeris A, Li J, Bammler TK, Jin J, Zhu D, Kashima DT, Pan S, Hashioka S, Maguire J, McGeer PL, Zhang J: Prolyl endopeptidase is revealed following SILAC analysis to be a novel mediator of human microglial and THP-1 cell neurotoxicity. Glia. 2008, 56: 675-685. 10.1002/glia.20645.View ArticlePubMedGoogle Scholar
- McGeer PL, Itagaki S, McGeer EG: Expression of the histocompatibility glycoprotein HLA-DR in neurological disease. Acta Neuropathol. 1988, 76: 550-557. 10.1007/BF00689592.View ArticlePubMedGoogle Scholar
- Cavasin MA, Rhaleb NE, Yang XP, Carretero OA: Prolyl oligopeptidase is involved in release of the antifibrotic peptide Ac-SDKP. Hypertension. 2004, 43: 1140-1145. 10.1161/01.HYP.0000126172.01673.84.View ArticlePubMedGoogle Scholar
- Liao TD, Yang XP, D'Ambrosio M, Zhang Y, Rhaleb NE, Carretero OA: N-acetyl-seryl-aspartyl-lysyl-proline attenuates renal injury and dysfunction in hypertensive rats with reduced renal mass: council for high blood pressure research. Hypertension. 55: 459-467. 10.1161/HYPERTENSIONAHA.109.144568.Google Scholar
- Liu JM, Kusinski M, Ilic V, Bignon J, Hajem N, Komorowski J, Kuzdak K, Stepien H, Wdzieczak-Bakala J: Overexpression of the angiogenic tetrapeptide AcSDKP in human malignant tumors. Anticancer Res. 2008, 28: 2813-2817.PubMedGoogle Scholar
- Tenorio-Laranga J, Valero ML, Männistö PT, Sánchez del Pino M, García-Horsman JA: Combination of snap freezing, differential pH two-dimensional reverse-phase high-performance liquid chromatography, and iTRAQ technology for the peptidomic analysis of the effect of prolyl oligopeptidase inhibition in the rat brain. Anal Biochem. 2009, 393: 80-87. 10.1016/j.ab.2009.06.019.View ArticlePubMedGoogle Scholar
- Polman CH, Reingold SC, Edan G, Filippi M, Hartung HP, Kappos L, Lublin FD, Metz LM, McFarland HF, O'Connor PW, Sandberg-Wollheim M, Thompson AJ, Weinshenker BG, Wolinsky JS: Diagnostic criteria for multiple sclerosis: 2005 revisions to the "McDonald Criteria". Ann Neurol. 2005, 58: 840-846. 10.1002/ana.20703.View ArticlePubMedGoogle Scholar
- Lublin FD, Reingold SC: Defining the clinical course of multiple sclerosis: results of an international survey. National Multiple Sclerosis Society (USA) Advisory Committee on Clinical Trials of New Agents in Multiple Sclerosis. Neurology. 1996, 46: 907-911.View ArticlePubMedGoogle Scholar
- Kurtzke JF: Rating neurologic impairment in multiple sclerosis: an expanded disability status scale (EDSS). Neurology. 1983, 33: 1444-1452.View ArticlePubMedGoogle Scholar
- Tenorio-Laranga J, Venäläinen JI, Männistö PT, García-Horsman JA: Characterization of membrane-bound prolyl endopeptidase from brain. Febs J. 2008, 275: 4415-4427. 10.1111/j.1742-4658.2008.06587.x.View ArticlePubMedGoogle Scholar
- Momeni N, Yoshimoto T, Ryberg B, Sandberg-Wollheim M, Grubb A: Factors influencing analysis of prolyl endopeptidase in human blood and cerebrospinal fluid: increase in assay sensitivity. Scand J Clin Lab Invest. 2003, 63: 387-395. 10.1080/00365510310001951.View ArticlePubMedGoogle Scholar
- Breen G, Harwood AJ, Gregory K, Sinclair M, Collier D, St Clair D, Williams RS: Two peptidase activities decrease in treated bipolar disorder not schizophrenic patients. Bipolar Disord. 2004, 6: 156-161. 10.1111/j.1399-5618.2004.00100.x.View ArticlePubMedGoogle Scholar
- Collins PJ, McMahon G, O'Brien P, O'Connor B: Purification, identification and characterisation of seprase from bovine serum. Int J Biochem Cell Biol. 2004, 36: 2320-33. 10.1016/j.biocel.2004.05.006.View ArticlePubMedGoogle Scholar
- Yoshimoto T, Tsukumo K, Takatsuka N, Tsuru D: An inhibitor for post-proline cleaving enzyme; distribution and partial purification from porcine pancreas. J Pharmacobiodyn. 1982, 5: 734-740.View ArticlePubMedGoogle Scholar
- Soeda S, Yamakawa N, Ohyama M, Shimeno H, Nagamatsu A: An inhibitor of proline endopeptidase: purification from rat brain and characterization. Chem Pharm Bull (Tokyo). 1985, 33: 24445-24451.View ArticleGoogle Scholar
- Fülöp V, Szeltner Z, Polgár L: Catalysis of serine oligopeptidases is controlled by a gating filter mechanism. EMBO Rep. 2000, 1: 277-281. 10.1093/embo-reports/kvd048.PubMed CentralView ArticlePubMedGoogle Scholar
- Szeltner Z, Renner V, Polgár L: The noncatalytic beta-propeller domain of prolyl oligopeptidase enhances the catalytic capability of the peptidase domain. J Biol Chem. 2000, 275: 15000-15005. 10.1074/jbc.M000942200.View ArticlePubMedGoogle Scholar
- Gilgun-Sherki Y, Melamed E, Offen D: The role of oxidative stress in the pathogenesis of multiple sclerosis: the need for effective antioxidant therapy. J Neurol. 2004, 251: 261-268. 10.1007/s00415-004-0348-9.View ArticlePubMedGoogle Scholar
- Karg E, Klivényi P, Németh I, Bencsik K, Pintér S, Vécsei L: Nonenzymatic antioxidants of blood in multiple sclerosis. J Neurol. 1999, 246: 533-539. 10.1007/s004150050399.View ArticlePubMedGoogle Scholar
- LeVine SM: The role of reactive oxygen species in the pathogenesis of multiple sclerosis. Med Hypotheses. 1992, 39: 271-274. 10.1016/0306-9877(92)90121-R.View ArticlePubMedGoogle Scholar
- Naidoo R, Knapp ML: Studies of lipid peroxidation products in cerebrospinal fluid and serum in multiple sclerosis and other conditions. Clin Chem. 1992, 38: 2449-2454.PubMedGoogle Scholar
- Rovaris M, Confavreux C, Furlan R, Kappos L, Comi G, Filippi M: Secondary progressive multiple sclerosis: current knowledge and future challenges. Lancet Neurol. 2006, 5: 343-354. 10.1016/S1474-4422(06)70410-0.View ArticlePubMedGoogle Scholar
- Maes M, Goossens F, Lin A, De Meester I, Van Gastel A, Scharpé S: Effects of psychological stress on serum prolyl endopeptidase and dipeptidyl peptidase IV activity in humans: higher serum prolyl endopeptidase activity is related to stress-induced anxiety. Psychoneuroendocrinology. 1998, 23: 485-495. 10.1016/S0306-4530(98)00020-1.View ArticlePubMedGoogle Scholar
- Maes M, Goossens F, Scharpé S, Calabrese J, Desnyder R, Meltzer HY: Alterations in plasma prolyl endopeptidase activity in depression, mania, and schizophrenia: effects of antidepressants, mood stabilizers, and antipsychotic drugs. Psychiatry Res. 1995, 58: 217-225. 10.1016/0165-1781(95)02698-V.View ArticlePubMedGoogle Scholar
- Maes M, Goossens F, Scharpé S, Meltzer HY, D'Hondt P, Cosyns P: Lower serum prolyl endopeptidase enzyme activity in major depression: further evidence that peptidases play a role in the pathophysiology of depression. Biol Psychiatry. 1994, 35: 545-552. 10.1016/0006-3223(94)90101-5.View ArticlePubMedGoogle Scholar
- Maes M, Libbrecht I, Van Hunsel F, Lin AH, Bonaccorso S, Goossens F, De Meester I, De Clerck L, Biondi M, Scharpé S, Janca A: Lower serum activity of prolyl endopeptidase in fibromyalgia is related to severity of depressive symptoms and pressure hyperalgesia. Psychol Med. 1998, 28: 957-965. 10.1017/S0033291798006801.View ArticlePubMedGoogle Scholar
- Maes M, Lin AH, Bonaccorso S, Goossens F, Van Gastel A, Pioli R, Delmeire L, Scharpé S: Higher serum prolyl endopeptidase activity in patients with post-traumatic stress disorder. J Affect Disord. 1999, 53: 27-34. 10.1016/S0165-0327(98)00086-X.View ArticlePubMedGoogle Scholar
- Maes M, Monteleone P, Bencivenga R, Goossens F, Maj M, van West D, Bosmans E, Scharpé S: Lower serum activity of prolyl endopeptidase in anorexia and bulimia nervosa. Psychoneuroendocrinology. 2001, 26: 17-26. 10.1016/S0306-4530(00)00032-9.View ArticlePubMedGoogle Scholar
- Schulz I, Zeitschel U, Rudolph T, Ruiz-Carrillo D, Rahfeld JU, Gerhartz B, Bigl V, Demuth HU, Rossner S: Subcellular localization suggests novel functions for prolyl endopeptidase in protein secretion. J Neurochem. 2005, 94: 970-979. 10.1111/j.1471-4159.2005.03237.x.View ArticlePubMedGoogle Scholar
- Koch M, Mostert J, Arutjunyan AV, Stepanov M, Teelken A, Heersema D, De Keyser J: Plasma lipid peroxidation and progression of disability in multiple sclerosis. Eur J Neurol. 2007, 14: 529-533. 10.1111/j.1468-1331.2007.01739.x.View ArticlePubMedGoogle Scholar
- Koch M, Ramsaransing GS, Arutjunyan AV, Stepanov M, Teelken A, Heersema DJ, De Keyser J: Oxidative stress in serum and peripheral blood leukocytes in patients with different disease courses of multiple sclerosis. J Neurol. 2006, 253: 483-487. 10.1007/s00415-005-0037-3.View ArticlePubMedGoogle Scholar
This article is published under license to BioMed Central Ltd. This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/2.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.