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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

Brain injury 42 h after infection. (A) Statistically significant attenuation of cortical necrosis was seen in animals treated with the MMP inhibitor (RS) compared to littermates receiving the vehicle (control (Ctrl)), while no effect was observed on hippocampal apoptosis (B). *P < 0.05 (Mann-Whitney test).
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Fig3: Brain injury 42 h after infection. (A) Statistically significant attenuation of cortical necrosis was seen in animals treated with the MMP inhibitor (RS) compared to littermates receiving the vehicle (control (Ctrl)), while no effect was observed on hippocampal apoptosis (B). *P < 0.05 (Mann-Whitney test).

Mentions: Coronal brain cryosections (45 μm-thick) of animals sacrificed at 42 hpi were stained with cresyl violet. Cortical damage was assessed systematically as previously published [8]. In controls, 11 of 28 animals (39.3%) showed substantial cortical injury (defined as ≥ 1% of the cortex) while this ratio was significantly reduced to 10.3% (3 of 29 animals) in littermates treated with RS (Fisher’s exact test, P = 0.015). In the control group, the mean necrotic area as percentage of the total cortical volume was 3.8% ± 6.5% (median 0.0%, min. 0.0%, max. 26.2%; n = 28) while this area was significantly reduced in the RS group to 0.7% ± 2.8% (median 0.0%, min. 0.0%, max. 14.8%, n = 29; n = 29; P = 0.012; Figure 3A). The number of WBC in CSF at 18 hpi correlated with the extent of cortical brain injury (r = 0.74, P = 0.0056, n = 12).Figure 3


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)

Brain injury 42 h after infection. (A) Statistically significant attenuation of cortical necrosis was seen in animals treated with the MMP inhibitor (RS) compared to littermates receiving the vehicle (control (Ctrl)), while no effect was observed on hippocampal apoptosis (B). *P < 0.05 (Mann-Whitney test).
© Copyright Policy - open-access
Related In: Results  -  Collection

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

Fig3: Brain injury 42 h after infection. (A) Statistically significant attenuation of cortical necrosis was seen in animals treated with the MMP inhibitor (RS) compared to littermates receiving the vehicle (control (Ctrl)), while no effect was observed on hippocampal apoptosis (B). *P < 0.05 (Mann-Whitney test).
Mentions: Coronal brain cryosections (45 μm-thick) of animals sacrificed at 42 hpi were stained with cresyl violet. Cortical damage was assessed systematically as previously published [8]. In controls, 11 of 28 animals (39.3%) showed substantial cortical injury (defined as ≥ 1% of the cortex) while this ratio was significantly reduced to 10.3% (3 of 29 animals) in littermates treated with RS (Fisher’s exact test, P = 0.015). In the control group, the mean necrotic area as percentage of the total cortical volume was 3.8% ± 6.5% (median 0.0%, min. 0.0%, max. 26.2%; n = 28) while this area was significantly reduced in the RS group to 0.7% ± 2.8% (median 0.0%, min. 0.0%, max. 14.8%, n = 29; n = 29; P = 0.012; Figure 3A). The number of WBC in CSF at 18 hpi correlated with the extent of cortical brain injury (r = 0.74, P = 0.0056, n = 12).Figure 3

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