Combined effect of non-bacteriolytic antibiotic and inhibition of matrix metalloproteinases prevents brain injury and preserves learning, memory and hearing function in experimental paediatric pneumococcal meningitis

Abstract

BackgroundPneumococcal meningitis is associated with high mortality and morbidity rates. Up to 50% of survivors show neurologic sequelae including hearing loss, cognitive impairments and learning disabilities, being particularly detrimental in affected infants and children where adjuvant therapy with dexamethasone has no proven beneficial effect. We evaluated the effect of concomitantly targeting specific pathophysiological mechanisms responsible for brain damage—i.e. matrix-metalloproteinase (MMP) activity and the exacerbated cerebral inflammation provoked through antibiotic-induced bacterial lysis. Here, we combined adjunctive therapies previously shown to be neuroprotective when used as single adjuvant therapies.MethodsEleven-day-old Wistar rats were infected intracisternally with 6.44 ± 2.17 × 103 CFU Streptococcus pneumoniae and randomised for treatment with ceftriaxone combined with (a) single adjuvant therapy with daptomycin (n = 24), (b) single adjuvant therapy with Trocade (n = 24), (c) combined adjuvant therapy (n = 66) consisting of daptomycin and Trocade, or (d) ceftriaxone monotherapy (n = 42). Clinical parameters and inflammatory CSF cytokine levels were determined during acute meningitis. Cortical damage and hippocampal apoptosis were assessed 42 h after infection. Morris water maze and auditory brainstem responses were used to assess neurofunctional outcome 3 weeks after infection.ResultsWe found significantly reduced apoptosis in the hippocampal subgranular zone in infant rats receiving adjuvant Trocade (p < 0.01) or combined adjuvant therapy (p < 0.001). Cortical necrosis was significantly reduced in rats treated with adjuvant daptomycin (p < 0.05) or combined adjuvant therapy (p < 0.05) compared to ceftriaxone monotherapy. Six hours after treatment initiation, CSF cytokine levels were significantly reduced for TNF-α (p < 0.01), IL-1β (p < 0.01), IL-6 (p < 0.001) and IL-10 (p < 0.01) in animals receiving combined adjuvant intervention compared to ceftriaxone monotherapy. Importantly, combined adjuvant therapy significantly improved learning and memory performance in infected animals and reduced hearing loss (77.14 dB vs 60.92 dB, p < 0.05) by preserving low frequency hearing capacity, compared to ceftriaxone monotherapy.ConclusionCombined adjuvant therapy with the non-bacteriolytic antibiotic daptomycin and the MMP inhibitor Trocade integrates the neuroprotective effects of both single adjuvants in experimental paediatric pneumococcal meningitis by reducing neuroinflammation and brain damage, thereby improving neurofunctional outcome. This strategy represents a promising therapeutic option to improve the outcome of paediatric patients suffering from pneumococcal meningitis.

MMPs and ADAMs in neurological infectious diseases and multiple sclerosis

“…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]. The early inhibition of MMPs during bacterial meningitis might be responsible for an overall reduction of the neuroinflammatory reaction with reduced BBB breakdown and cytokine production, thereby limiting the pathophysiological consequences of the disease [116].…”

“…However, other ADAM17 inhibitors were unable to prevent neural cell death in the hippocampus [132]. On the other hand, Trocade-without having a specific ADAM17-inhibitory profile-successfully prevented hippocampal apoptosis [167,174]. As MMP-9 is directly involved in hippocampal cell death via the degradation of laminin [136,137], inhibition of MMP-9-rather than ADAM17-might explain this neuroprotective effect of Trocade during bacterial meningitis.…”

“…As MMP-9 is directly involved in hippocampal cell death via the degradation of laminin [136,137], inhibition of MMP-9-rather than ADAM17-might explain this neuroprotective effect of Trocade during bacterial meningitis. The protective effect on hippocampal neurons is lowerbut still present-when BB1001 or Trocade therapy is initiated together with antibiotics at time of symptom onset [127,167,174].…”

“…Protection from hippocampal apoptosis by BB1001 improved learning performance in rats with PM [127]. Similarly, in PM-infected rats treated with Trocade plus daptomycin, the observed reduction in hippocampal apoptosis was associated with a significant improvement of learning and memory function [174]. GM6001 therapy significantly protected hippocampal neurons and prevented PM-induced learning and memory impairments in neonatal rats [177].…”

“…GM6001 therapy significantly protected hippocampal neurons and prevented PM-induced learning and memory impairments in neonatal rats [177]. Notably, all three therapies also significantly protected from cortical necrosis [127,174,177], which might also positively influence learning and memory performance after PM. Correspondingly, in adult rats, MMP-2 and -9 inhibition further prevented cognitive impairment after PM possibly due to the observed successful preservation of BBB integrity during acute infection [178].…”