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The matrix metalloproteinase inhibitor RS-130830 attenuates brain injury in experimental pneumococcal meningitis.

Liechti FD, Bächtold F, Grandgirard D, Leppert D, Leib SL - J Neuroinflammation (2015)

Bottom Line: At 18 hpi, concentrations of interleukin (IL)-1β and IL-10 were significantly lower in the cerebrospinal fluid of treated animals compared to controls.RS-130830 significantly reduced weight loss and leukocyte counts in the cerebrospinal fluid of survivors of PM.This study identifies MMP inhibition, specifically with RS-130830, as an efficient strategy to attenuate disease severity and cortical brain injury in PM.

View Article: PubMed Central - PubMed

Affiliation: Neuroinfection Laboratory, Institute for Infectious Diseases, University of Bern, Friedbühlstr. 51, CH-3010, Bern, Switzerland. fabian.liechti@ifik.unibe.ch.

ABSTRACT

Background: Pneumococcal meningitis (PM) is characterized by high mortality and morbidity including long-term neurofunctional deficits. Neuropathological correlates of these sequelae are apoptosis in the hippocampal dentate gyrus and necrosis in the cortex. Matrix metalloproteinases (MMPs) play a critical role in the pathophysiology of PM. RS-130830 (Ro-1130830, CTS-1027) is a potent partially selective inhibitor of MMPs of a second generation and has been evaluated in clinical trials as an anti-arthritis drug. It inhibits MMPs involved in acute inflammation but has low activity against MMP-1 (interstitial collagenase), MMP-7 (matrilysin) and tumour necrosis factor α converting enzyme (TACE).

Methods: A well-established infant rat model of PM was used where live Streptococcus pneumoniae were injected intracisternally and antibiotic treatment with ceftriaxone was initiated 18 h post infection (hpi). Treatment with RS-130830 (75 mg/kg bis in die (bid) i.p., n = 40) was started at 3 hpi while control littermates received the vehicle (succinylated gelatine, n = 42).

Results: Cortical necrosis was significantly attenuated in animals treated with RS-130830, while the extent of hippocampal apoptosis was not influenced. At 18 hpi, concentrations of interleukin (IL)-1β and IL-10 were significantly lower in the cerebrospinal fluid of treated animals compared to controls. RS-130830 significantly reduced weight loss and leukocyte counts in the cerebrospinal fluid of survivors of PM.

Conclusion: This study identifies MMP inhibition, specifically with RS-130830, as an efficient strategy to attenuate disease severity and cortical brain injury in PM.

No MeSH data available.


Related in: MedlinePlus

Measurements in samples of cerebrospinal fluid. (A) White blood cell count in cerebrospinal fluid samples obtained 18 h after infection (hours post infection (hpi)). No effect after pre-treatment with the MMP inhibitor (RS) was observed when compared to vehicle treated littermates (control (Ctrl)). Leukocyte counts were reduced after treatment with RS in the survivors of the disease (P < 0.05, Mann-Whitney test; squares). (B) Total collagen content was quantified at 18 and 27 hpi (optical density at 550 nm [OD550] was used as arbitrary unit). Concentrations were lower in animals treated with RS compared to control littermates, although this effect did not reach statistical significance (P = ns).
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Fig2: Measurements in samples of cerebrospinal fluid. (A) White blood cell count in cerebrospinal fluid samples obtained 18 h after infection (hours post infection (hpi)). No effect after pre-treatment with the MMP inhibitor (RS) was observed when compared to vehicle treated littermates (control (Ctrl)). Leukocyte counts were reduced after treatment with RS in the survivors of the disease (P < 0.05, Mann-Whitney test; squares). (B) Total collagen content was quantified at 18 and 27 hpi (optical density at 550 nm [OD550] was used as arbitrary unit). Concentrations were lower in animals treated with RS compared to control littermates, although this effect did not reach statistical significance (P = ns).

Mentions: White blood cells (WBC) were counted in CSF at 18 hpi. Five microlitres of the non-centrifuged CSF was diluted 1:20 with 2% acetic acid. Cells were counted after 2 to 3 min in a Neubauer chamber. The difference between treatment groups did not reach statistical significance (RS: 2,044 ± 1,435 cells/μl, n = 13; vehicle: 2,118 ± 1,200 cells/μl, n = 14; P = 0.78; Figure 2A). However, in animals surviving until the endpoint at 42 hpi, leukocyte numbers at 18 hpi were significantly lower (P = 0.026) in RS-treated animals (1,488 ± 488 cells/μl; n = 8) compared to vehicle-treated animals (3,019 ± 1,218 cells/μl; n = 4).Figure 2


The matrix metalloproteinase inhibitor RS-130830 attenuates brain injury in experimental pneumococcal meningitis.

Liechti FD, Bächtold F, Grandgirard D, Leppert D, Leib SL - J Neuroinflammation (2015)

Measurements in samples of cerebrospinal fluid. (A) White blood cell count in cerebrospinal fluid samples obtained 18 h after infection (hours post infection (hpi)). No effect after pre-treatment with the MMP inhibitor (RS) was observed when compared to vehicle treated littermates (control (Ctrl)). Leukocyte counts were reduced after treatment with RS in the survivors of the disease (P < 0.05, Mann-Whitney test; squares). (B) Total collagen content was quantified at 18 and 27 hpi (optical density at 550 nm [OD550] was used as arbitrary unit). Concentrations were lower in animals treated with RS compared to control littermates, although this effect did not reach statistical significance (P = ns).
© Copyright Policy - open-access
Related In: Results  -  Collection

License 1 - License 2
Show All Figures
getmorefigures.php?uid=PMC4352253&req=5

Fig2: Measurements in samples of cerebrospinal fluid. (A) White blood cell count in cerebrospinal fluid samples obtained 18 h after infection (hours post infection (hpi)). No effect after pre-treatment with the MMP inhibitor (RS) was observed when compared to vehicle treated littermates (control (Ctrl)). Leukocyte counts were reduced after treatment with RS in the survivors of the disease (P < 0.05, Mann-Whitney test; squares). (B) Total collagen content was quantified at 18 and 27 hpi (optical density at 550 nm [OD550] was used as arbitrary unit). Concentrations were lower in animals treated with RS compared to control littermates, although this effect did not reach statistical significance (P = ns).
Mentions: White blood cells (WBC) were counted in CSF at 18 hpi. Five microlitres of the non-centrifuged CSF was diluted 1:20 with 2% acetic acid. Cells were counted after 2 to 3 min in a Neubauer chamber. The difference between treatment groups did not reach statistical significance (RS: 2,044 ± 1,435 cells/μl, n = 13; vehicle: 2,118 ± 1,200 cells/μl, n = 14; P = 0.78; Figure 2A). However, in animals surviving until the endpoint at 42 hpi, leukocyte numbers at 18 hpi were significantly lower (P = 0.026) in RS-treated animals (1,488 ± 488 cells/μl; n = 8) compared to vehicle-treated animals (3,019 ± 1,218 cells/μl; n = 4).Figure 2

Bottom Line: At 18 hpi, concentrations of interleukin (IL)-1β and IL-10 were significantly lower in the cerebrospinal fluid of treated animals compared to controls.RS-130830 significantly reduced weight loss and leukocyte counts in the cerebrospinal fluid of survivors of PM.This study identifies MMP inhibition, specifically with RS-130830, as an efficient strategy to attenuate disease severity and cortical brain injury in PM.

View Article: PubMed Central - PubMed

Affiliation: Neuroinfection Laboratory, Institute for Infectious Diseases, University of Bern, Friedbühlstr. 51, CH-3010, Bern, Switzerland. fabian.liechti@ifik.unibe.ch.

ABSTRACT

Background: Pneumococcal meningitis (PM) is characterized by high mortality and morbidity including long-term neurofunctional deficits. Neuropathological correlates of these sequelae are apoptosis in the hippocampal dentate gyrus and necrosis in the cortex. Matrix metalloproteinases (MMPs) play a critical role in the pathophysiology of PM. RS-130830 (Ro-1130830, CTS-1027) is a potent partially selective inhibitor of MMPs of a second generation and has been evaluated in clinical trials as an anti-arthritis drug. It inhibits MMPs involved in acute inflammation but has low activity against MMP-1 (interstitial collagenase), MMP-7 (matrilysin) and tumour necrosis factor α converting enzyme (TACE).

Methods: A well-established infant rat model of PM was used where live Streptococcus pneumoniae were injected intracisternally and antibiotic treatment with ceftriaxone was initiated 18 h post infection (hpi). Treatment with RS-130830 (75 mg/kg bis in die (bid) i.p., n = 40) was started at 3 hpi while control littermates received the vehicle (succinylated gelatine, n = 42).

Results: Cortical necrosis was significantly attenuated in animals treated with RS-130830, while the extent of hippocampal apoptosis was not influenced. At 18 hpi, concentrations of interleukin (IL)-1β and IL-10 were significantly lower in the cerebrospinal fluid of treated animals compared to controls. RS-130830 significantly reduced weight loss and leukocyte counts in the cerebrospinal fluid of survivors of PM.

Conclusion: This study identifies MMP inhibition, specifically with RS-130830, as an efficient strategy to attenuate disease severity and cortical brain injury in PM.

No MeSH data available.


Related in: MedlinePlus