In pneumococcal meningitis a novel water-soluble inhibitor of matrix metalloproteinases and TNF-α converting enzyme attenuates seizures and injury of the cerebral cortex

Meli, Damian N.; Loeffler, Jutta M.; Baumann, Philippe; Neumann, Ulf; Buhl, Thomas; Leppert, David; Leib, Stephen L.

doi:10.1016/j.jneuroim.2004.01.026

Cited by 63 publications

(61 citation statements)

References 25 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Pneumococcal meningitis has a high level of mortality (up to 30%), and brain and/or cochlear damage occurs in up to 50% of the survivors (2). Inflammatory mediators, such as tumor necrosis factor alpha (TNF-␣) and matrix metalloproteinases (MMPs), are produced during the host response to bacteria and contribute to the pathophysiology that can ultimately lead to death, brain damage, and hearing impairment (23,26,29,36). The role of cytokines and MMPs in the pathophysiology of the cochlear damage associated with pneumococcal meningitis is still unknown.…”

mentioning

confidence: 99%

Doxycycline Reduces Mortality and Injury to the Brain and Cochlea in Experimental Pneumococcal Meningitis

et al. 2006

View full text Add to dashboard Cite

Bacterial meningitis is characterized by an inflammatory reaction to the invading pathogens that can ultimately lead to sensorineural hearing loss, permanent brain injury, or death. The matrix metalloproteinases (MMPs) and tumor necrosis factor alpha-converting enzyme (TACE) are key mediators that promote inflammation, blood-brain barrier disruption, and brain injury in bacterial meningitis. Doxycycline is a clinically used antibiotic with anti-inflammatory effects that lead to reduced cytokine release and the inhibition of MMPs. Here, doxycycline inhibited TACE with a 50% inhibitory dose of 74 M in vitro and reduced the amount of tumor necrosis factor alpha released into the cerebrospinal fluid by 90% in vivo. In an infant rat model of pneumococcal meningitis, a single dose of doxycycline (30 mg/kg) given as adjuvant therapy in addition to ceftriaxone 18 h after infection significantly reduced the mortality, the blood-brain barrier disruption, and the extent of cortical brain injury. Adjuvant doxycycline (30 mg/kg given subcutaneously once daily for 4 days) also attenuated hearing loss, as assessed by auditory brainstem response audiometry, and neuronal death in the cochlear spiral ganglion at 3 weeks after infection. Thus, doxycycline, probably as a result of its anti-inflammatory properties, had broad beneficial effects in the brain and the cochlea and improved survival in this model of pneumococcal meningitis in infant rats. Pneumococcal meningitis has a high level of mortality (up to 30%), and brain and/or cochlear damage occurs in up to 50% of the survivors (2). Inflammatory mediators, such as tumor necrosis factor alpha (TNF-␣) and matrix metalloproteinases (MMPs), are produced during the host response to bacteria and contribute to the pathophysiology that can ultimately lead to death, brain damage, and hearing impairment (23,26,29,36). The role of cytokines and MMPs in the pathophysiology of the cochlear damage associated with pneumococcal meningitis is still unknown. However, it has been demonstrated that MMPs are constitutively expressed at high levels in the cochlea (8) and that in meningitis pneumococci and polymorphonuclear leukocytes (PMNs) extend from the cerebrospinal fluid (CSF) to the perilymph via the cochlear aqueduct (5).Tetracyclines are bacteriostatic agents with broad-spectrum antimicrobial activity (3). Doxycycline is a semisynthetic, longacting, second-generation tetracycline which is absorbed rapidly and penetrates well into the brain and CSF (48). Doxycycline has been shown to have anti-inflammatory effects that are separate and distinct from its antimicrobial action (13,16,35,43). These effects include the reduction of cytokine release and the inhibition of MMPs (7, 38). Experimental and clinical studies have indicated that treatment with doxycycline may be beneficial in inflammatory diseases associated with excessive MMP activity (7,13,35).In pneumococcal meningitis massive subarachnoid and ventricular space inflammation is triggered by the presence of bacteria in the CSF space (7,1...

show abstract

mentioning

confidence: 99%

Doxycycline Reduces Mortality and Injury to the Brain and Cochlea in Experimental Pneumococcal Meningitis

et al. 2006

View full text Add to dashboard Cite

show abstract

“…Nevertheless, our in vitro data indicate that ADAM/MMP inhibition indeed has klotho-dependent effects. This difference could be explained due to a higher local concentration on cells in vitro compared with in vivo, since TNF484 is rapidly metabolized in serum (36). Moreover, the in vivo system is obviously more complex to determine the effect of a specific compound, as compensatory mechanisms may occur.…”

Section: Discussionmentioning

confidence: 99%

Shedding of klotho by ADAMs in the kidney

Loon

Pulskens

Hagen

et al. 2015

American Journal of Physiology-Renal Physiology

View full text Add to dashboard Cite

The anti-aging gene klotho plays an important role in Ca 2ϩ and phosphate homeostasis. Membrane-bound klotho is an essential coreceptor for fibroblast growth factor-23 and can be cleaved by proteases, including a disintegrin and metalloproteinase (ADAM)10 and ADAM17. Cleavage of klotho occurs at a site directly above the plasma membrane (␣-cut) or between the KL1 and KL2 domain (␤-cut), resulting in soluble full-length klotho or KL1 and KL2 fragments, respectively. The aim of the present study was to gain insights into the mechanisms behind klotho cleavage processes in the kidney. Klotho shedding was demonstrated using a Madin-Darby canine kidney cell line stably expressing klotho and human embryonic kidney-293 cells transiently transfected with klotho. Here, we report klotho expression on both the basolateral and apical membrane, with a higher abundance of klotho at the apical membrane and in the apical media. mRNA expression of ADAM17 and klotho were enriched in mouse distal convoluted and connecting tubules. In vitro ADAM/matrix metalloproteinase inhibition by TNF484 resulted in a concentration-dependent inhibition of the ␣-cut, with a less specific effect on ␤-cut shedding. In vivo TNF484 treatment in wild-type mice did not change urinary klotho levels. However, ADAM/matrix metalloproteinase inhibition did increase renal and duodenal mRNA expression of phosphate transporters, whereas serum phosphate levels were significantly decreased. In conclusion, our data show that renal cells preferentially secrete klotho to the apical side and suggest that ADAMs are responsible for ␣-cut cleavage.klotho; a disintegrin and metalloproteinase 10; a disintegrin and metalloproteinase 17; klotho shedding; a disintegrin and metalloproteinase/matrix metalloproteinase inhibitor CA 2ϩ AND PHOSPHATE HOMEOSTASIS is a tightly regulated process involving several hormones. Klotho is emerging as a key factor in this process (5,18,51). Initially, the klotho gene was discovered as an anti-aging gene, since lack of klotho in mice resulted in early aging and a premature death (23, 26), whereas overexpression of klotho led to an increased lifespan (28).Klotho is a single-pass type 1 transmembrane protein consisting of two extracellular domains, which are the KL1 and KL2 subunits. Full-length klotho has potential enzymatic activity (30, 49), and in the body, it exists in two forms, namely, membrane-bound and soluble klotho. Membrane-bound klotho is predominantly present in the renal distal convolution, consisting of the distal convoluted tubule (DCT) and connecting tubule (CNT), parathyroid glands, and choroid plexus in the brain (26,31). A key function of membrane-bound klotho is to act as an obligate cofactor for the fibroblast growth factor (FGF) receptor, thereby enabling binding and downstream signaling of FGF23 via the ERK1/2 MAPK pathway (27, 51). In the kidney, binding of FGF23 to the receptor complex results in enhanced phosphate excretion via reduced expression of the Na ϩ -phosphate transporters NaPi-IIa and NaPiIIc (12). Moreov...

show abstract

“…The procedure that does not produce structural brain damage was well tolerated by all animals and no deaths were observed during the Wrst 12 h after injection. On postnatal day 11, when the rats (n = 97) weighed 26.5 § 3.9 g, they were infected by a direct intracisternal injection, with a 32-gauge needle of 10 l of saline containing Aspergillus conidia [1,10,22,23,28]. In preliminary experiments, the rats (n = 12) were given inocula of 5.0, 6.0 and 7.0 log 10 CFU (n = 4 per group).…”

Section: To Produce Cerebral Aspergillus Infectionmentioning

confidence: 99%

“…Building on our experience with experimental CNS infection in rats, we have established a model of cerebral aspergillosis in non-immunosuppressed nursing rats that mimics important aspects of human disease [1,10,22,23,28]. To allow suYcient time to study disease progression and potential treatment eVects, CNS infection in untreated animals was intended to be universally and reproducibly lethal within several days.…”

Section: Introductionmentioning

confidence: 99%

A model of cerebral aspergillosis in non-immunosuppressed nursing rats

2007

View full text Add to dashboard Cite

Central nervous system aspergillosis is an often fatal complication of invasive Aspergillus infection. Relevant disease models are needed to study the pathophysiology of cerebral aspergillosis and to develop novel therapeutic approaches. This study presents a model of central nervous system aspergillosis that mimics important aspects of human disease. Eleven-day-old non-immunosuppressed male Wistar rats were infected by an intracisternal injection of 10 l of a conidial suspension of Aspergillus fumigatus. An inoculum of 7.18 log 10 colony-forming units (CFU) consistently produced cerebral infection and resulted in death of all animals (n = 25) within 3-10 days. Median survival time was 3 days. Histomorphologically, all animals developed intracerebral abscesses (2-26 per brain) containing abundant fungal hyphae and neutrophils. Fungal culture of cortical homogenates yielded maximal growth on day 3 after infection (5.4 log 10 CFU/g, n = 15) that declined over time. Galactomannan concentrations in cortical homogenates, assessed as an index for hyphal burden, peaked on days 3-5. Fungal infection spread to peripheral organs in 83% of animals. Fungal burden in lung, liver, spleen and kidney was two orders of magnitude lower than in the brain. The successful establishment of a model of cerebral aspergillosis in a non-immunosuppressed host provides the opportunity to investigate mechanisms of disease and to develop novel treatment regimens for this commonly fatal infection.

show abstract

In pneumococcal meningitis a novel water-soluble inhibitor of matrix metalloproteinases and TNF-α converting enzyme attenuates seizures and injury of the cerebral cortex

Cited by 63 publications

References 25 publications

Doxycycline Reduces Mortality and Injury to the Brain and Cochlea in Experimental Pneumococcal Meningitis

Doxycycline Reduces Mortality and Injury to the Brain and Cochlea in Experimental Pneumococcal Meningitis

Shedding of klotho by ADAMs in the kidney

A model of cerebral aspergillosis in non-immunosuppressed nursing rats

Contact Info

Product

Resources

About