ro13-9904 and Learning-Disabilities

Pneumococcal 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.. Eleven-day-old Wistar rats were infected intracisternally with 6.44 ± 2.17 × 10. We 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.. Combined 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.

Topics: Animals; Animals, Newborn; Anti-Bacterial Agents; Apoptosis; Brain Injuries; Ceftriaxone; Cerebral Cortex; Cytokines; Daptomycin; Disease Models, Animal; Drug Therapy, Combination; Evoked Potentials, Auditory, Brain Stem; Hearing Disorders; Hippocampus; Learning Disabilities; Matrix Metalloproteinase Inhibitors; Matrix Metalloproteinases; Maze Learning; Memory Disorders; Meningitis, Pneumococcal; Rats; Streptococcus pneumoniae

Neonatal Escherichia coli meningitis continues to be an important cause of mortality and morbidity in newborns worldwide. The aim of this study was to investigate the cytokines/chemokines, brain-derived neurotrophic factor (BDNF) levels, blood-brain barrier integrity in neonatal rats following E. coli K1 experimental meningitis infection and subsequent behavioural parameters in adulthood. In the hippocampus, interleukin increased at 96 h, IL-6 at 12, 48 and 96 h, IL-10 at 96 h, cytokine-induced neutrophil chemoattractant-1 at 6, 12, 24, 48 and 96 h, and BDNF at 48 and 96 h. In the cerebrospinal fluid, tumour necrosis factor alpha levels increased at 6, 12, 24, 48 and 96 h. The BBB breakdown occurred at 12 h in the hippocampus, and at 6h in the cortex. We evaluated behavioural parameters in adulthood: habituation to the open-field, step-down inhibitory avoidance, object recognition, continuous multiple-trials step-down inhibitory avoidance and forced swimming tasks. In adulthood, the animals showed habituation and aversive memory impairment. The animals needed a significant increase in the number of training periods to learn and not had depressive-like symptoms.

Topics: Animals; Animals, Newborn; Anti-Bacterial Agents; Avoidance Learning; Blood-Brain Barrier; Brain-Derived Neurotrophic Factor; Ceftriaxone; Cytokines; Disease Models, Animal; Escherichia coli Infections; Gene Expression Regulation, Bacterial; Learning Disabilities; Male; Memory Disorders; Meningitis, Bacterial; Rats; Rats, Wistar; Reaction Time; Recognition, Psychology; Time Factors