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

Abstract

BackgroundPneumococcal 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).MethodsA 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).ResultsCortical 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.ConclusionThis study identifies MMP inhibition, specifically with RS-130830, as an efficient strategy to attenuate disease severity and cortical brain injury in PM.

Bacterial meningitis: an update of new treatment options

“…pneumoniae meningitis, subcutaneous injections of lithium chloride started 5 days prior to infection reduced neuronal apoptosis in the dentate gyrus and improved spatial memory function as assessed by Morris water maze 3 weeks after infection [191]. In the same model, intraperitoneal treatment with fluoxetine (10 mg/kg/day) reduced the number of animals with relevant hippocampal apoptosis when compared to untreated infected littermates and also tended to reduce neocortical injury without influencing the parameters of inflammation [190]. Because of their relatively high rate of side effects, both lithium and fluoxetine will not qualify for prophylaxis for community-acquired meningitis.…”

“…Several classes of MMP inhibitors including the second-generation MMP inhibitor RS-130830, which proved to be safe in clinical trials for osteoarthritis and hepatitis C, were able to reduce neocortical but not hippocampal injury when given 3 h after the induction of Str. pneumoniae meningitis [189,190]. The second-generation MMP inhibitors Ro 32-3555 and Ro 32-7315 started 3 h after infection (antibiotic treatment started 15 h later) decreased hippocampal apoptosis and cortical injury in the infant rat model of Str.…”

MMPs and ADAMs in neurological infectious diseases and multiple sclerosis

“…Matrix metalloproteinases and ADAMs function as ECM degrading enzymes and sheddases, thereby controlling BBB breakdown and production of inflammatory cytokines [15]. In experimental bacterial meningitis, MMP and ADAM inhibitors significantly reduce CSF levels of MMPs and pro-inflammatory cytokines (TNF-α, IL-6, IL-1β, IL-10) [128,132,[167][168][169]. Notably, CSF levels of TNF-α are also significantly reduced by MMP inhibitors (MMPIs) without specificity for ADAM17 (i.e., Trocade) [167], indicating that MMPIs are able to indirectly reduce pro-inflammatory cytokine production apart from direct ADAM17 inhibition.…”

“…Since metalloproteinases are central regulators of BBB breakdown during bacterial meningitis (discussed above), their inhibition during the acute disease is a valuable therapeutic strategy to reduce cortical necrosis. Pre-treatment or treatment early in the course of disease with MMPIs is associated with reduced cortical necrosis in pneumococcal meningitis [128,132,167,168,172,173] and with lower rates of intracerebral hemorrhage in meningococcal meningitis [169]. This neuroprotective effect is, however, reduced when the application of the inhibitors is delayed until the time of antibiotic therapy at the first appearance of disease symptoms [127,174].…”

TRPV1 inhibits smooth muscle cell phenotype switching in a mouse model of abdominal aortic aneurysm

“…The main function of MMPs is to degrade various protein components in the extracellular matrix [4,5]. In total, 24 members of the MMP family have been identified according to their structure and function and classified into 6 classes according to their substrates: collagenases [6], gelatinases [7], stromelysins [7,8], matrilysins [9] and other secretory MMPs. Vascular smooth muscle cells (VSMCs) in the media and adventitia of the aortic wall are the main source of MMP-2 [10,11].…”