Roles of matrix metalloproteinase-9 and tissue inhibitors of metalloproteinases 1 in acute encephalopathy following prolonged febrile seizures

Prolonged febrile seizures may be followed by acute encephalopathy with neurological sequelae. To investigate the function of the blood-brain-barrier (BBB) in acute encephalopathy following prolonged febrile seizures with neurological sequelae (AEPFS), the concentrations of serum matrix metalloproteinase-9 (MMP-9) and tissue inhibitors of metalloproteinases 1 (TIMP-1) were measured by ELISA in 10 children with AEPFS, 16 with prolonged febrile seizures without encephalopathy (PFS), 20 with simple febrile seizures (SFS), 23 with convulsive status epilepticus (CSE), and 18 with West syndrome. Serum MMP-9 levels in AEPFS and PFS patients were significantly higher than those in SPS and West syndrome patients and in controls, and those in CSE patients were significantly higher than in controls. Serum TIMP-1 levels in AEPFS patients were significantly lower than those in PFS, SFS, CSE and West syndrome patients and in controls. Serum MMP-9 levels and MMP-9/TIMP-1 ratios in AEPFS patients with motor paralysis were significantly higher than for those without motor paralysis. Our results suggest that prolonged seizures are related to high serum MMP-9 levels, and that an increased MMP-9/TIMP-1 ratio in AEPFS might induce dysfunction of the BBB. Furthermore, an imbalance of serum MMP-9 and TIMP-1 levels in patients with AEPFS may be associated with severe neurological sequelae.     

Serum MMP-9/TIMP-1 and MMP-2/TIMP-2 ratios in multiple sclerosis: relationships with different magnetic resonance imaging measures of disease activity during IFN-beta-1a treatment

Matrix metalloproteinase-9 (MMP-9) is involved in blood-brain barrier (BBB) disruption in active multiple sclerosis (MS), while MMP-2 seems to be associated with the chronic progressive phase of the disease. Recombinant interferon beta-1a (rIFNbeta-1a) is effective in restoring the BBB. We studied the relationships between serum MMP-9, MMP-2, TIMP-1 and TIMP-2 and different magnetic resonance imaging (MRI) measures of disease activity in MS patients during treatment with rIFNbeta-1a. Twenty-one relapsing-remitting (RR) MS patients underwent longitudinally simultaneous blood withdrawals and MRI (before and after standard dose (SD) and triple dose (TD) of gadolinium (Gd)) examinations before and during 48 weeks of rIFNbeta-1a (Rebif 22 mcg three times a week) treatment. Serum MMP-9, MMP-2, TIMP-1 and TIMP-2 were measured, MMP-9 to TIMP-1 and MMP-2 to TIMP-2 ratios were calculated and the numbers of Gd-SD, Gd-TD, new-Gd-SD, new-Gd-TD and new-T2 lesions counted. Serum MMP-9/TIMP-1 ratio (P < 0.0001), as well as the numbers of 'active' lesions (P ranging from 0.0004 to 0.005) decreased during treatment Moreover, serum MMP-9/TIMP-1 ratio proved to be a good positive predictor (estimate = 0.85; P < 0.05) of the numbers of MRI Gd-TD active lesions. These data confirm that serum MMP-9/TMIP-1 ratio may be viewed as a reliable marker and may be predictive of MRI activity in RR MS.     

Serum MMP-9 and TIMP-1 levels are related to MRI activity in relapsing multiple sclerosis.

OBJECTIVE: To 1) compare monthly serum levels of matrix metalloproteinase-9 (MMP-9) and tissue inhibitor of MMP-type 1 (TIMP-1) in patients with relapsing-remitting MS (RRMS) versus healthy controls and 2) determine the relationship among monthly serum levels of MMP-9 and TIMP-1 and MRI activity. BACKGROUND: Activated T-cells and macrophages secrete MMPs that may facilitate their migration across vascular subendothelial basement membranes into the CNS. The serum concentration of MMP-9 is reported to be higher in patients with RRMS than healthy controls. METHODS: Monthly evaluations including gadolinium-enhanced (Gd+) brain MRI and measures of serum MMP-9 and TIMP-1 were performed for up to 15 months in 24 patients with RRMS and for up to 4 months in 10 controls. RESULTS: Serum MMP-9 but not TIMP-1 levels are elevated in RRMS patients compared to healthy controls (p = 0.025, p = 0.61). In a univariate analysis, high MMP-9 and low TIMP-1 levels precede appearance of new Gd+ lesions (respectively; odds ratio = 3.3, p = 0.008; odds ratio = 2.2, p = 0.086). In a multivariate analysis, in comparison to months when MMP-9 is low and TIMP-1 high, MRI scans obtained the month following high MMP-9 and low TIMP-1 serum concentrations are more likely to report new Gd+ lesions (p = 0.0006, odds ratio = 21.5). CONCLUSION: An increase in the activity of matrix metalloproteinase-9 (MMP-9) relative to tissue inhibitor of MMP-type 1 (TIMP-1) may be related to formation of new MS lesions, suggesting that serum levels of MMP-9 and TIMP-1 may be surrogate markers of disease activity in relapsing-remitting MS.     

Serum levels of matrix metalloproteinase-9 and its tissue inhibitor (TIMP-1) in acute disseminated encephalomyelitis

In multiple sclerosis, there have been many reports on matrix metalloproteinases (MMPs) and their tissue inhibitors (TIMPs). However, MMPs and TIMPs have not been reported in acute disseminated encephalomyelitis (ADEM). We determined the relationship between the serum concentrations of MMP-9 and TIMP-1 and activity of lesions on MRI in 14 patients with ADEM to investigate the roles of MMP-9 and TIMP-1 in the pathogenesis of ADEM. Serum MMP-9 and TIMP-1 levels, measured by ELISA and gadolinium-enhanced (Gd+) brain MRI, were analyzed. Serum MMP-9 and TIMP-1 levels at the acute stage were higher than controls, and the serum MMP-9 levels at the acute stage were higher than those at the convalescent stage in ADEM. In seven patients with Gd+ lesions on brain MRI, serum MMP-9 levels and the MMP-9/TIMP-1 ratio at the acute stage were higher than those at the convalescent stage, and serum TIMP1 levels at the acute stage were lower than those at the convalescent stage. In seven patients without Gd+ lesions on brain MRI, serum TIMP-1 levels at the acute stage were higher than those at the convalescent stage. We speculated that MMP-9 is related to lesion formation at the early stage in ADEM and that TIMP-1 is induced to modulate MMP-9 activity. These findings suggest that MMP-9 and TIMP-1 secondarily play some roles in the inflammatory cascade of ADEM.     

Matrix metalloproteinase-9 and tissue inhibitor of metalloproteinase-1 in perinatal asphyxia

Matrix metalloproteinase-9 (MMP-9) and tissue inhibitor of metalloproteinase-1 (TIMP-1) play important roles in the function of the blood–brain-barrier (BBB). We investigated the roles of MMP-9 and TIMP-1 in the pathogenesis of hypoxic–ischemic encephalopathy following perinatal asphyxia. Serum concentrations of MMP-9 and TIMP-1 were determined by ELISA in 12 neonates with perinatal asphyxia and 15 controls on the birth day and the next day. Serum MMP-9 concentrations in asphyxiated neonates with neurological sequelae (n = 5) were significantly higher than concentration in asphyxiated neonates without sequelae (n = 7) and controls on birth day (p = 0.003 and p < 0.001, respectively). The ratios of serum MMP-9/TIMP-1 on birth day in asphyxiated neonates with neurological sequelae were significantly higher than those in asphyxiated neonates without sequelae (p = 0.048). There were no significant differences in the serum MMP-9 concentrations or the ratios of MMP-9/TIMP-1 between asphyxiated neonates with and without neurological sequelae on the day after birth. Our preliminary study suggests that serum MMP-9 levels on birth day are important for predicting neurological prognosis of neonates with asphyxia.     

Matrix metalloproteinase-9 (MMP-9) and tissue inhibitor of matrix metalloproteinase (TIMP-1) in patients with relapsing-remitting multiple sclerosis treated with interferon beta

OBJECTIVES: Matrix metalloproteinases (MMPs), particularly MMP-9, facilitate T-cell migration into the central nervous system. They play a key role in the disruption of the blood-brain barrier (BBB) and thus in the pathogenesis of multiple sclerosis. Interferon beta's (IFNbeta) ability to alter the balance between MMP-9 and MMP-9s natural inhibitor, tissue inhibitor of matrix metalloproteinase-1 (TIMP-1), may play a role in stabilizing the BBB. The aim of this study, was to evaluate serum MMP-9 and TIMP-1 and cerebrospinal fluid (CSF) TIMP-1 levels in patients with relapsing-remitting multiple sclerosis (RRMS) treated with IFNbeta-1a. PATIENTS AND METHODS: Blood and CSF samples from 14 patients with RRMS before and 6 months after IFNbeta therapy and 14 age and sex-matched controls were obtained. Levels of MMP-9 and TIMP-1 were measured using ELISA. RESULTS: Before treatment, patients with MS had higher levels of serum MMP-9 and a higher MMP-9/TIMP-1 ratio than the controls. Although serum levels of TIMP-1 were lower in RRMS patients than in the controls, the differences did not reach statistical significance. CSF levels of TIMP-1 were significantly lower in RRMS patients. In the sixth month of IFNbeta therapy serum MMP-9 and the MMP-9/TIMP-1 ratio were significantly decreased, whereas the changes in serum TIMP-1 were not statistically significant. There was a significant increase in CSF TIMP-1 levels in the sixth month of IFNbeta therapy. CONCLUSIONS: Our result shows that RRMS patients have an impaired MMP-9 and TIMP-1 balance, and that 6 months of IFNbeta therapy is beneficial in restoring this balance.     

Serum matrix metalloproteinase-9 and tissue inhibitor of metalloproteinase-1 levels in non-herpetic acute limbic encephalitis

The pathogenesis of non-herpetic acute limbic encephalitis (NHALE) has been not clear. Matrix metalloproteinase-9 (MMP-9) and tissue inhibitor of metalloproteinase 1 (TIMP-1) play important roles in the function of the blood–brain barrier. We measured the serum concentrations of MMP-9 and TIMP-1 by using enzyme-linked immunosorbent assay (ELISA) in 23 patients with NHALE in the acute and convalescent stages. Serum MMP-9 concentrations and ratios of serum MMP-9/TIMP-1 were significantly higher (1) in patients with NHALE in acute and convalescent stages than in control patients (all P < 0.001); (2) in patients with NHALE at the acute stage compared with those at the convalescent stage (P = 0.004, and P = 0.014, respectively). In contrast, serum TIMP-1 concentrations were significantly lower in patients with NHALE in the acute and convalescent stages than in control patients (both P < 0.001) but did not differ in patients with NHALE in the acute and convalescent stages. Our preliminary study suggests that the prolonged imbalance of MMP-9 and TIMP-1 is associated with the pathogenesis of NHALE.     

Cerebrospinal fluid and serum levels and intrathecal production of active matrix metalloproteinase-9 (MMP-9) as markers of disease activity in patients with multiple sclerosis

In this study, we employed a sensitive activity assay system to measure cerebrospinal fluid (CSF) and serum levels of active matrix metalloproteinase-9 (MMP-9) in 37 relapsing-remitting (RR), 15 secondary progressive (SP) and nine primary progressive (PP) multiple sclerosis (MS) patients, grouped according to clinical and magnetic resonance imaging (MRI) evidence of disease activity. We also studied, as neurological controls, 48 patients with other inflammatory neurological disorders (OIND) and 48 with non-inflammatory neurological disorders (NIND). To assess active MMP-9/TIMP-1 circuit, CSF and serum levels of MMP-9 tissue inhibitor TIMP-1 were quantified by ELISA in the same patient population. CSF mean levels of active MMP-9, CSF active MMP-9/TIMP-1 ratios and intrathecal active MMP-9 synthesis, as indicated by specific index, were more elevated in MS than in NIND (P < 0.05, < 0.02 and < 0.02, respectively), serum active MMP-9/TIMP-1 ratio was higher in MS (P < 0.01) and OIND (P < 0.02) than in NIND, and serum TIMP-1 concentrations were lower in MS than in NIND (P<0.05). More importantly, serum active MMP-9 mean levels, serum active MMP-9/TIMP-1 ratio and intrathecal production of active MMP-9 were increased in MS patients with clinical (P < 0.001, < 0.001 and < 0.05, respectively) and MRI (P < 0.001, < 0.001 and < 0.02, respectively) disease activity, whereas CSF mean concentrations of active MMP-9 and CSF active MMP-9/TIMP-1 ratio were enhanced only in MS patients with MRI evidence of disease activity (P < 0.02 and < 0.01, respectively). Altogether, these findings suggest that a shift in MMP-9/TIMP-1 balance towards proteolytic activity of MMP-9 could be relevant in MS immune dysregulation. In addition, our results indicate that CSF and serum levels of active MMP-9 may represent a potential surrogate biomarker for monitoring MS disease activity. In particular, serum active MMP-9/TIMP-1 ratio seems to be a very appropriate indicator of ongoing MS inflammation, since it is easily measurable.     

Profiles of blood biomarkers in alternating hemiplegia of childhood--increased MMP-9 and decreased substance P indicates its pathophysiology

Alternating hemiplegia of childhood (AHC) is a rare disorder characterized by repeated plegic attacks, movement disorders, autonomic phenomena, and developmental delay. To obtain insights into the pathophysiology of AHC, we determined the concentrations of matrix metalloproteinase-9 (MMP-9), tissue inhibitor of MMP-1 (TIMP-1), calcitonin gene-related peptide (CGRP), and substance P (SP) in the serum/plasma of AHC patients (n=6) and control subjects (n=11) by performing enzyme-linked immunosorbent assay (ELISA). Decreased levels of serum SP (382±161 pg/ml), increased levels of plasma MMP-9 (111.0±99.3 ng/mL) and increased MMP-9/TIMP-1 ratio (0.65±0.44) were revealed, compared to those in control subjects (SP: 620±223 pg/mL, p<0.05; MMP-9: 33.5±20.3 ng/mL, p<0.05; MMP-9/TIMP-1 ratio 0.21±0.09, p<0.005). Serum CGRP levels in AHC patients (32.6±14.4 pg/mL) were comparable to those in control subjects (37.0±17.0 pg/mL). Increased MMP-9 levels may be linked to the vascular insult and is common in migraineurs. However, because AHC patients showed different changes in SP and CGRP levels compared to those shown by migraineurs, these results suggest that AHC has a pathomechanism different from the hypothesis of trigeminovascular theory. Decreased SP may represent the autonomic dysfunction in AHC, for which an etiology with progressive neuronal damage can be hypothesized.     

Intrathecal synthesis of matrix metalloproteinase-9 in patients with multiple sclerosis: implication for pathogenesis

Matrix metalloproteinase-9 (MMP-9) was detected by zymography and enzyme-linked immunosorbent assay (ELISA) in matched serum and cerebrospinal fluid (CSF) samples from patients with neurological diseases. Patients with relapsing-remitting multiple sclerosis (RR-MS) had serum and CSF MMP-9 levels comparable to those from patients with inflammatory neurological diseases (INDs), but higher than patients with non-inflammatory neurological diseases (NINDs) and healthy donors (HDs). MMP-9 increased in active RR-MS in comparison with inactive RR-MS implying that MMP-9 in MS is related with clinical disease activity. A correlation between the CSF/serum albumin (Q(AIb)) and CSF/serum MMP-9 (Q(MMP-9)) was observed in IND and NIND but not in RR-MS patients, indicating that CSF MMP-9 levels in NIND and IND patents could be influenced by serum MMP-9 and blood-brain barrier (BBB) permeability properties. MS patients had higher values of Q(MMP-9):Q(Alb)(MMP-9 index) than IND and NIND patients suggesting that in MS the increase in CSF MMP-9 could be due to intrathecal synthesis of MMP-9. A significant inverse correlation was found between MMP-9 and its endogenous inhibitor TIMP-1 in RR-MS indicating that in MS patients both the increase in MMP-9 and the decrease in TIMP-1 serum levels could contribute to BBB disruption and T-lymphocyte entry into the CNS.     

血清和脑脊液中MMPs与TIMP-1在重症手足口合并脑炎患儿中的诊断意义

目的探讨重症手足口合并脑炎患儿血清及脑脊液中MMPs与TIMP-1变化,为重症手足口合并脑炎患儿早期诊断提供依据。方法以2015-01—2018-03于郑州儿童医院就诊确诊为手足口患儿100例为研究对象,其中普通型55例,重型22例,危重型23例,其中重型及危重型HFMD组均为合并神经系统受累的患儿,统称为脑炎组。统计分析患儿脑脊液蛋白、脑脊液细胞数水平及脑脊液和血清中MMP-2、MMP-9、TIMP-1水平。结果(1)重型和危重型HFMD血清和脑脊液MMP-2、MMP-9、TIMP-1水平较普通型和健康对照组显著增高,危重型增高较为显著,差异有统计学意义(P<0.05);(2)脑炎组血清MMP-2、MMP-9、TIMP-1浓度水平较普通型、健康对照组组显著增高(P<0.05);(3)相关性分析结果显示,HFMD患儿血清MMP-2、MMP-9、TIMP-1浓度水平和脑脊液MMP-2、MMP-9、TIMP-1浓度水平显著正相关,相关系数分别为(r=0.719,P=0.001;r=0.638,P=0.000;r=0.704,P=0.000);(4)血清MMP-2、MMP-9和TIMP-1浓度水平预测脑炎ROC分析,曲线下面积分别为0.95695%CI(0.919、0.994)、0.95195%CI(0.906、0.996)、0.88795%CI(0.852、0.949),最佳截断点分别为103.59、96.34、108.64,相应敏感度和特异度分别为84.4%和94.5%、93.3和87.3%、88.9%和72.7%。结论重型和危重型HFMD合并神经系统受累病例血清和脑脊液中MMP-2、MMP-9、TIMP-1水平升高明显,对于重症手足口病合并脑炎的辅助诊断在临床上具有重要的意义。     

基质金属蛋白酶-2及其抑制剂与颈动脉粥样硬化斑块易损性的关系

目的 探讨基质金属蛋白酶(MMP-2)及其抑制剂金属蛋白酶组织抑制因子(TIMP-2)与颈动脉粥样硬化斑块易损性的关系. 方法 对60例首次前循环型动脉粥样硬化性脑梗死恢复期患者及38名同期门诊体检正常者(无斑块组)行颈动脉超声检查,分别测定颈动脉内中膜厚度(IMT)、Crouse积分(CPI)、斑块总面积(CPA).根据超声病理形态将患者分为易损斑块组(33例)和稳定斑块组(27例).ELISA法测定血清MMP-2、TIMP-2水平. 结果 易损斑块组颈动脉IMT、CPI、CPA均大于稳定斑块组及无斑块组;稳定斑块组颈动脉IMT、CPI、CPA均大于无斑块组,差异均有统计学意义(P<0.05).易损斑块组血清MMP-2、MMP-2/TIMP-2比值均高于稳定斑块组及无斑块组,TIMP-2低于稳定斑块组及无斑块组,差异均有统计学意义(P<0.05).易损斑块组血清MMP-2、MMP-2/TIMP-2比值与IMT、CPI、CPA均呈正相关(r=0.961,r=0.966,r=0.804;r=0.625,r=0.709,r=0.651;P均<0.05).易损斑块组血清TIMP-2与IMT、CPI、CPA均呈负相关(r=0.944,r=-0.996,r=-0.859,P均<0.05).稳定斑块组血清MMP-2、MMP-2/TIMP-2比值与IMT、CPI、CPA均呈正相关(r=0.429,r=0.461,r=0.423;r=0.601,r=0.673,r=0.571;P均<0.05).易损斑块组血清TIMP-2与IMT、CPI、CPA均呈负相关(r=-0.507,r=-0.568,r=-0.554,P均<0.05). 结论 血清MMP-2、TIMP-2水平及MMP-2/TIMP-2比值与颈动脉粥样硬化斑块易损性密切相关.     

Serum MMP-2 and MMP-9 are elevated in different multiple sclerosis subtypes

In multiple sclerosis (MS), matrix metalloproteinase (MMP) activity in tissues is the result of a balance between MMPs and their tissue inhibitors (TIMPs). MMP-9 predominates in acute MS lesions and is inhibited by TIMP-1, while MMP-2 may participate in the remodeling of the extracellular matrix (ECM) such as in chronic disease and is inhibited by TIMP-2. These differences may be reflected in serum and cerebrospinal fluid (CSF). We have tried to characterize MMP-2 and MMP-9 activities, in relation to their respective TIMPs, 2 and 1, as a factor of different types of the disease, as this information was not previously clearly stated. We found the MMP-2/TIMP-2 ratio in serum to show higher values in secondary progressive (SP, p=0.02) and primary progressive (PP, p=0.01) MS than short disease duration (SDD) relapsing-remitting (RR) MS, but not different from the healthy control (HC) group. Whereas the MMP-9/TIMP-1 ratio in serum showed higher (p=0.04) values in SDD RR MS than PP but also in active patients, evaluated either clinically (p=0.006) or from the magnetic resonance imaging (MRI, p<0.05), compared to inactive disease. CSF MMP to TIMP ratios did not differ between MS subtypes, suggesting systemic rather CNS-restricted changes. These results show that an increase in MMP-2/TIMP-2 ratio marks chronic progression in MS, but it is as high as in HC, and also confirm that high MMP-9 activity characterizes short duration relapsing and active forms of the disease.     

Effect of interferon β-1a on serum matrix metalloproteinase—9 (MMP-9) and tissue inhibitor of matrix metalloproteinase (TIMP-1) in relapsing remitting multiple sclerosis patients

There is emerging evidence that matrix metalloproteinases (MMPs) might be involved in blood brain barrier (BBB) breakdown in multiple sclerosis. A group of natural tissue inhibitors of metalloproteinases (TIMPS) regulates proteolytic activity to prevent tissue damage. TIMP-1 and MMP-9 are known to be secreted as heterodimers and TIMP-1 preferentially functions to inhibit MMP-9 activity. In this present study, the effects of IFNbeta-1a on serum MMP-9 and TIMP-1 were evaluated longitudinally during a one-year period. The MMP-9 levels showed no significant changes while TIMP-1 levels gradually and significantly increased during 3rd and 6th months of therapy compared with pretreatment levels.     

中青年脑梗死患者颈动脉粥样硬化及其血清基质金属蛋白酶-9、组织基质金属蛋白酶抑制剂-1、超敏C反应蛋白水平的改变

目的研究中青年脑梗死患者颈动脉粥样硬化及其血清基质金属蛋白酶-9(MMP-9)、组织基质金属蛋白酶抑制剂-1(TIMP-1)、超敏C反应蛋白(hs-CRP)水平的改变。方法应用彩色多普勒超声仪探测42例急性脑梗死患者(ACI组)、29例无症状颈动脉硬化患者(ACA组)及17名健康体检者(NC组)的双侧颈动脉粥样硬化的情况。采用酶联免疫吸附法检测各组血清MMP-9和TIMP-1水平,免疫散射比浊法检测血清hs-CRP水平。结果 NC组均未检出颈动脉粥样硬化斑块。ACI组易损斑块的比例(69.2%)及检出率(47.6%)均明显高于ACA组(46.4%,20.7%)(均P<0.05)。ACI组血清MMP-9、TIMP-1、hs-CRP水平及MMP-9/TIMP-1比值均明显高于ACA组(均P<0.05);ACA组血清MMP-9、TIMP-1、hs-CRP水平均明显高于NC组(均P<0.05)。ACI组中,易损斑块亚组血清MMP-9、TIMP-1、hs-CRP水平及MMP-9/TIMP-1比值均明显高于稳定斑块亚组(均P<0.05);稳定斑块亚组血清MMP-9、TIMP-1、hs-CRP水平均明显高于无斑块亚组(均P<0.05)。结论血清MMP-9、TIMP-1、hs-CRP可作为反映颈动脉粥样硬化及斑块稳定性的血清学指标。MMP-9/TIMP-1比值增高及颈动脉易损斑块可能提示中青年脑梗死的风险。     

Serum levels of matrix metalloproteinases-2 and -9 and their tissue inhibitors in inflammatory neuromuscular disorders

We monitored serum levels of matrix metalloproteinases (MMPs) and their tissue inhibitors (TIMPs) before and during intravenously applied immunoglobulin (IVIG) therapy in 33 patients with chronic immune-mediated neuropathies and myopathies and 15 controls. Baseline MMP-2 and TIMP-2 serum levels were lower and MMP-9 and TIMP-1 serum levels higher in all patients compared to age-matched controls. Eight days after IVIG treatment, MMP-2, TIMP-2, and TIMP-1 serum levels increased, while MMP-9 serum levels decreased, indicating tissue repair. After 60 days, MMP-9 levels increased, MMP-2 approached normal levels, while TIMP-1 and TIMP-2 serum levels were below day 8 levels, indicating relapsing tissue damage. Comparing the MMP/TIMP results with the clinical courses, IVIG treatment tended to change MMP/TIMP levels in a way that paralleled clinical improvement and relapse. In sum, during a distinct time period, IVIG therapy seems to be able to modulate MMP-mediated tissue repair.     

Five patients with subacute sclerosing panencephalitis treated with intraventricular alpha-interferon and inosinpranobex

We followed up 5 patients with subacute sclerosing panencephalitis (SSPE) for 14 to 81 months. They were treated with alpha-interferon (INF-alpha) and oral inosinpranobex (INP) in an early stage of Jabbour stage II and within 5 months after the onset. On admission, Ommaya reservoir was implanted for the intrathecal administration of INF-alpha. The dose was 1 x 10(5) U/m2 initially and daily increased to 1 x 10(6) U/m2. A total dose of 30 x 10(6) U/m3 was given to them over a 4-weeks to 6-weeks period. After discharge, a dose of 15 x 10(6) U/m2 in three patients was given weekly and a dose of 30 x 10(6) U/m2 in the other patients. In addition, all patients received oral INP. One patient showed mild progression and remained in early stage of Jabbour stage II. In the remaining 4 patients, the disease progressed to Jabbour stage III. Despite the small number of patients studied here, the results suggest that treatment with INF-alpha plus oral INP is ineffective in an early stage of SSPE.     

Matrix metalloproteinase-9 is elevated in serum of patients with amyotrophic lateral sclerosis

Matrix metalloproteinase-9 (MMP-9) and its specific inhibitor, tissue inhibitor of matrix metalloproteinase-1 (TIMP-1), were analysed by enzyme-linked immunosorbent assay (ELISA) and by zymography in serum and cerebrospinal fluid (CSF) of patients with amyotrophic lateral sclerosis (ALS). In contrast to patients with inflammatory diseases, MMP-9 levels were not elevated in CSF of ALS patients. In serum, however, compared to healthy donors, MMP-9 was significantly (p = 0.0003) increased up to levels as high as those of viral meningoencephalitis (VM) or bacterial meningitis (BM) patients. MMP-9 levels remained elevated during long-term observation of ALS patients. In the absence of an inflammatory response, the results indicate that the increase of MMP-9 in serum of ALS patients might be caused by upregulation of MMP-9 in denervated muscles or in degenerating peripheral nerves following motor neurone loss.     

Interferon-β-1 b decreased matrix metalloproteinase-9 serum levels in primary progressive multiple sclerosis

Recent reports have shown that matrix-metalloproteinases (MMPs) facilitate T-cell migration into the CNS and play a role in disruption of the blood-brain-barrier and myelin break-down. An increase of MMP-9 serum levels predicts disease activity in relapsing remitting multiple sclerosis (RRMS). Interferon-beta (IFN-beta), which is an established treatment for RRMS, inhibits T-cell migration in vitro in parallel with the downregulation of MMP expression. Only limited data are available for primary progressive multiple sclerosis (PPMS) which differs in demographic and immunological aspects as well as in MRI criteria from RRMS. In this study, 19 patients with laboratory-supported definite PPMS were treated with 8 x 10(6) IU IFN-beta1b (Betaferon) subcutaneously every other day. Serum was collected before treatment and on months 1, 2, 3, 6 and 9 during treatment. Levels of MMP-9 and of its natural inhibitor known as tissue-inhibitor of matrix-metalloproteinase-1 (TIMP-1) were quantified by ELISA. In addition MMP-2 serum levels were determined by zymography. 19 healthy volunteers served as controls. Before treatment serum levels of MMP-9 were elevated in patients with PPMS compared with controls, whereas there was no difference in TIMP-1 serum levels. During treatment with IFN- beta1b the concentration of MMP-9 in the serum of 18 out of 19 PPMS patients decreased,whereas serum levels of MMP-2 and TIMP-1 remained nearly unaffected. Our results demonstrate that the MMP-9 to TIMP-1 ratio in patients with PPMS is elevated in comparison with healthy controls. The suppression of MMP-9 by IFN-beta1b indicates that this drug is immunomodulatory active in PPMS patients. Further studies are necessary to test if IFN-beta exerts a beneficial effect in PPMS.     

Profiles of matrix metalloproteinases and their inhibitors in plasma of patients with dementia

BACKGROUND: Matrix metalloproteinases (MMPs) are elevated in the brain tissue of patients with dementia and may play a role in the pathophysiology of dementia. MMP-9 and tissue inhibitors of MMPs (TIMPs) are elevated in postmortem brain tissue of patients with Alzheimer's disease (AD). In a previous study we showed that circulating levels of MMP-9 are elevated in AD patients. The aim of the present study was to examine circulating levels of MMP-1, MMP-2, MMP-9, TIMP-1 and TIMP-2 in the plasma of patients with mild cognitive impairment (MCI), AD, vascular dementia (VaD), dementia with Lewy bodies (DLB) and frontotemporal dementia (FTD), to determine, whether plasma profiles of MMPs and TIMPs differ in various types of dementia. METHODS: Gelatinolytic activity (MMP-2 and MMP-9) was measured in all plasma samples by zymography. Levels of MMP-2, MMP-9, MMP-1 as well as TIMP-1 and TIMP-2 were measured by ELISA. RESULTS: We found constitutive expression of MMP-1, -2 and -9 as well as TIMP-1 and -2 in all the samples investigated. As shown previously, MMP-9 was significantly elevated in the plasma of AD patients (p = 0.004) as compared to controls and MCI patients. Plasma levels of TIMP-1 were significantly lower in VD samples as compared to all other groups. Levels of TIMP-2 were significantly lower in patients with FTD as compared to AD, VaD and MCI patients. There were no significant changes of MMP-1 and MMP-2 levels in the samples. CONCLUSION: These findings suggest that circulating levels of MMP-9, TIMP-1 and TIMP-2 and changes in the MMP/TIMP balance in plasma differ in various types of dementia.