Neuroscientist. 2002 Dec;8(6):586-95.
Matrix metalloproteinases and neuroinflammation in multiple sclerosis.
Matrix metalloproteinases (MMPs) are extracellular matrix remodeling neutral proteases that are important in normal development, angiogenesis, wound repair, and a wide range of pathological processes.
Growing evidence supports a key role of the MMPs in many neuroinflammatory conditions, including meningitis, encephalitis, brain tumors, cerebral ischemia, Guillain-Barré, and multiple sclerosis (MS).
The MMPs attack the basal lamina macromolecules that line the blood vessels, opening the blood-brain barrier (BBB).
They contribute to the remodeling of the blood vessels that causes hyalinosis and gliosis, and they attack myelin.
During the acute inflammatory phase of MS, they are involved in the injury to the blood vessels and may be important in the disruption of the myelin sheath and axons.
Normally under tight regulation, excessive proteolytic activity is detected in the blood and cerebrospinal fluid in patients with acute MS.
Because they are induced in immunologic and nonimmunologic forms of demyelination, they act as a final common pathway to exert a "bystander" effect.
Agents that block the action of the MMPs have been shown to reduce the damage to the BBB and lead to symptomatic improvement in several animal models of neuroinflammatory diseases, including experimental allergic encephalomyelitis.
Such agents may eventually be useful in the control of excessive proteolysis that contributes to the pathology of MS and other neuroinflammatory conditions.
PMID: 12467380 [PubMed - indexed for MEDLINE]
N Engl J Med. 1998 Jan 29;338(5):278-85.
Axonal transection in the lesions of multiple sclerosis.
Trapp BD, Peterson J, Ransohoff RM, Rudick R, Mörk S, Bö L.
Multiple sclerosis is an inflammatory demyelinating disease of the central nervous system and is the most common cause of neurologic disability in young adults. Despite antiinflammatory or immunosuppressive therapy, most patients have progressive neurologic deterioration that may reflect axonal loss. We conducted pathological studies of brain tissues to define the changes in axons in patients with multiple sclerosis.
Brain tissue was obtained at autopsy from 11 patients with multiple sclerosis and 4 subjects without brain disease. Fourteen active multiple-sclerosis lesions, 33 chronic active lesions, and samples of normal-appearing white matter were examined for demyelination, inflammation, and axonal pathologic changes by immunohistochemistry and confocal microscopy. Axonal transection, identified by the presence of terminal axonal ovoids, was detected in all 47 lesions and quantified in 18 lesions.
Transected axons were a consistent feature of the lesions of multiple sclerosis, and their frequency was related to the degree of inflammation within the lesion. The number of transected axons per cubic millimeter of tissue averaged 11,236 in active lesions, 3138 at the hypocellular edges of chronic active lesions, 875 in the hypocellular centers of chronic active lesions, and less than 1 in normal-appearing white matter from the control brains.
Transected axons are common in the lesions of multiple sclerosis, and axonal transection may be the pathologic correlate of the irreversible neurologic impairment in this disease.
Demyelinating diseases--new pathological insights, new therapeutic targets. [N Engl J Med. 1998]
PMID: 9445407 [PubMed - indexed for MEDLINE] Free full text
Curr Med Chem. 2012;19(9):1295-9.
Glutamate and multiple sclerosis.
Frigo M1, Cogo MG, Fusco ML, Gardinetti M, Frigeni B.
1Department of Neurology, S. Gerardo Hospital, Monza (MB), Italy.
Multiple sclerosis (MS) has been considered for a long time a typical inflammatory demyelinating disease of the central nervous system due to autoimmunity targeting oligodendrocytes with sparing of axons until advanced stages of the disease. For this reason, most of the earliest experimental studies focused on the role of cytokines and chemokines at the site of oligodendrocytes loss and on the importance in MS pathogenesis of classical inflammatory mechanisms. As a result, several attempts to treat MS through reduction of the local inflammatory milieau have been performed, leading to the current "immunomodulatory" treatment of the disease. However, more recently the importance of axonal loss and neurodegeneration even in the earliest stages of MS has been also recognized, and additional or concomitant players have been therefore searched. Evidence is now increasing that excessive glutamate is released at the site of demyelination and axonal degeneration in MS plaques, and the most probable candidates for this cellular release are infiltrating leukocytes and activated microglia. These observations are no longer simply preclinical results obtained in the MS animal model, i.e. experimental allergic encephalomyelitis, but have already been partially confirmed by post-mortem studies and in vivo analysis in MS patients, thus raising the possibility that modulation of glutamate release and transport as well as receptors blockade might be relevant targets for the development of future therapeutic interventions.
PMID: 22304707 [PubMed - indexed for MEDLINE]
1. Transl Stroke Res. 2015 Apr;6(2):156-9. doi: 10.1007/s12975-014-0381-7. Epub 2014 Dec 5.
Effect of simvastatin on MMPs and TIMPs in human brain endothelial cells and experimental stroke.
Reuter B1, Rodemer C, Grudzenski S, Meairs S, Bugert P, Hennerici MG, Fatar M.
•1Department of Neurology, Universitätsmedizin Mannheim, University of Heidelberg, Theodor-Kutzer-Ufer 1-3, 68167, Mannheim, Germany, firstname.lastname@example.org.
Clinical studies demonstrated favorable effects of statins in stroke beyond lipid-lowering effects. In acute stroke, the disruption of the blood-brain barrier (BBB) is mediated by matrix metalloproteinases (MMPs). A modified MMP metabolism may account for the beneficial effects of statins. Cultured human brain microvascular endothelial cells (BMECs) were pretreated with simvastatin and subjected to oxygen glucose deprivation (OGD). Gene expression and protein secretion of MMP-2 and MMP-9 and the tissue inhibitor of metalloproteinase (TIMP)-1 and TIMP-2 were measured by quantitative real-time polymerase chain reaction (PCR) and enzyme-linked immunosorbent assay (ELISA).
Simvastatin significantly dampened the expression but not secretion of MMP-2 under OGD. MMP-9 synthesis rate was low and unaffected by simvastatin treatment, while the gene expression and protein secretion of TIMP-1 and TIMP-2 were both strongly induced.
Our results provide evidence for a positive effect of simvastatin on the MMP metabolism in human BMECs and experimental stroke mainly by means of the increased expression and secretion of TIMP-1 and TIMP-2.
PMID: 25476155 [PubMed - in process]
Neurology. 1999 Oct 22;53(7):1397-401.
Serum MMP-9 and TIMP-1 levels are related to MRI activity in relapsing multiple sclerosis.
Waubant E1, Goodkin DE, Gee L, Bacchetti P, Sloan R, Stewart T, Andersson PB, Stabler G, Miller K.
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.
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.
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.
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).
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.
Matrix metalloproteinases in multiple sclerosis: targets of therapy or markers of injury? [Neurology. 1999]
PMID: 10534241 [PubMed - indexed for MEDLINE]
Clin Neurol Neurosurg. 2006 Feb;108(2):124-8.
Matrix metalloproteinase-9 (MMP-9) and tissue inhibitor of matrix metalloproteinase (TIMP-1) in patients with relapsing-remitting multiple sclerosis treated with interferon beta.
Boz C1, Ozmenoglu M, Velioglu S, Kilinc K, Orem A, Alioglu Z, Altunayoglu V.
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.
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.
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.
1: BMC Med. 2007 Jul 19;5:20.
Simvastatin is associated with a reduced incidence of dementia and Parkinson's disease.
Wolozin B, Wang SW, Li NC, Lee A, Lee TA, Kazis LE.
Boston University School of Medicine, Boston, MA, USA.
BACKGROUND: Statins are a class of medications that reduce cholesterol by inhibiting 3-hydroxy-3-methylglutaryl-coenzyme A reductase. Whether statins can benefit patients with dementia remains unclear because of conflicting results. We hypothesized that some of the confusion in the literature might arise from differences in efficacy of different statins. We used a large database to compare the action of several different statins to investigate whether some statins might be differentially associated with a reduction in the incidence of dementia and Parkinson's disease.
METHODS: We analyzed data from the decision support system of the US Veterans Affairs database, which contains diagnostic, medication and demographic information on 4.5 million subjects. The association of lovastatin, simvastatin and atorvastatin with dementia was examined with Cox proportional hazard models for subjects taking statins compared with subjects taking cardiovascular medications other than statins, after adjusting for covariates associated with dementia or Parkinson's disease.
RESULTS: We observed that simvastatin is associated with a significant reduction in the incidence of dementia in subjects > or =65 years, using any of three models. The first model incorporated adjustment for age, the second model included adjusted for three known risk factors for dementia, hypertension, cardiovascular disease or diabetes, and the third model incorporated adjustment for the Charlson index, which is an index that provides a broad assessment of chronic disease. Data were obtained for over 700,000 subjects taking simvastatin and over 50,000 subjects taking atorvastatin who were aged >64 years. Using model 3, the hazard ratio for incident dementia for simvastatin and atorvastatin are 0.46 (CI 0.44-0.48, p < 0.0001) and 0.91 (CI 0.80-1.02, p = 0.11), respectively. Lovastatin was not associated with a reduction in the incidence of dementia. Simvastatin also exhibited a reduced hazard ratio for newly acquired Parkinson's disease (HR 0.51, CI 0.4-0.55, p < 0.0001).
CONCLUSION: Simvastatin is associated with a strong reduction in the incidence of dementia and Parkinson's disease, whereas atorvastatin is associated with a modest reduction in incident dementia and Parkinson's disease, which shows only a trend towards significance.
PMID: 17640385 [PubMed - in process]
Cholesterol Drug Zocor May Lower Risk of Both Alzheimer's, Parkinson's Diseases
By Daniel J. DeNoon
WebMD Medical News
Reviewed by Louise Chang, MD
July 18, 2007 -- Zocor -- but not sister cholesterol-lowering drugs Lipitor or Mevacor -- may cut the risk of both Alzheimer's and Parkinson's disease, a new study suggests.
It's not the first time that the cholesterol-lowering drugs known as statins have been linked to Alzheimer's disease. A small clinical trial in 2005 suggested that Lipitor might improve mental function in people with early Alzheimer's disease.
Both Lipitor and Zocor are in clinical trials to see whether they really do help people with Alzheimer's disease. But now there's compelling evidence that Zocor may actually prevent not only Alzheimer's disease, but Parkinson's disease, too.
The provocative new data come from Boston University researcher Benjamin Wolozin, MD, and colleagues.
"Many people are looking at whether statins might prevent the progression of dementia in people with Alzheimer's disease," Wolozin tells WebMD. "But a lot of people in the field think that if you start statin treatment at the time you already have the disease, it might be the wrong time. It might be nice to talk about how to prevent the disease."
To see whether taking statins had any effect on Alzheimer's disease, Wolozin's team used the immense U.S. Veterans Affairs database, with detailed information on 4.5 million patients. Some 727,000 of these patients took Zocor, about 54,000 took Lipitor, and about 54,000 took Mevacor.
In patients over age 64, those who took Zocor were 54% less likely to get Alzheimer's disease and 49% less likely to get Parkinson's disease than were matched patients not taking statin drugs.
Those who took Lipitor were 9% less likely to get Alzheimer's disease, a finding that was not statistically significant. Lipitor did not affect Parkinson's disease risk.
Mevacor had no effect on risk of either Alzheimer's disease or Parkinson's disease.
D. Larry Sparks, PhD, director of the Roberts Laboratory for Neurodegenerative Disease Research at the Sun Health Research Institute in Sun City, Ariz., is involved in clinical trials of statins for Alzheimer's disease but was not involved in the Wolozin study.
"This study keeps alive the idea that statins may be of benefit in the treatment of Alzheimer's disease and maybe even in mild cognitive impairment," Sparks tells WebMD. "But the most important part is that this addresses the role of cholesterol-lowering medications as a way to combat Parkinson's disease."
The study does not offer answers to the question of why Zocor seems to work better than Lipitor in preventing Alzheimer's and Parkinson's diseases.
Is it time to start taking Zocor to prevent neurodegenerative diseases? Wolozin says people should take statins only to lower high cholesterol levels.
"If your parents got Alzheimer's disease and you have high cholesterol, you might want to talk with your doctor about whether you should take Zocor or Lipitor," Wolozin says. "If your parents don't have Alzheimer's disease, but, say, your dad had a heart attack, you should probably take Lipitor, because it is somewhat better at preventing some of the [problems ] associated with heart disease. You have to look at your own personal risk factors."
Proof of whether statins affect risk of Alzheimer's disease or Parkinson's disease can come only from controlled clinical trials. But as such trials would be extremely lengthy and expensive, Wolozin doubts they will be undertaken.
Help may come from ongoing trials looking at whether Lipitor or Zocor can help people who already have Alzheimer's disease. Those trials are nearly over; results are expected next year.
The Wolozin study appears in the July issue of the online journal BioMed Central Medicine.
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