RESUMEN
Neurological symptoms of patients suffering from neurodegenerative diseases such as Alzheimer's dementia (AD), Parkinson's disease (PD), or amyotrophic lateral sclerosis (ALS) often worsen during infections. We assessed the disease-modulating effects of recurrent systemic infections with the most frequent respiratory pathogen, Streptococcus pneumoniae, on the course of AD, PD, and ALS in mouse models of these neurodegenerative diseases [transgenic Tg2576 mice, (Thy1)-[A30P]alpha SYN mice, and Tg(SOD1-G93A) mice]. Mice were repeatedly challenged intraperitoneally with live S. pneumoniae type 3 and treated with ceftriaxone for 3 days. Infection caused an increase of interleukin-6 concentrations in brain homogenates. The clinical status of (Thy1)-[A30P]alpha SYN mice and Tg(SOD1-G93A) mice was monitored by repeated assessment with a clinical score. Motor performance was controlled by the tightrope test and the rotarod test. In Tg2576 mice, spatial memory and learning deficits were assessed in the Morris water maze. In none of the three mouse models onset or course of the disease as evaluated by the clinical tests was affected by the recurrent systemic infections performed. Levels of alpha-synuclein in brains of (Thy1)-[A30P]alpha SYN mice did not differ between infected animals and control animals. Plaque sizes and concentrations of A beta 1-40 and A beta 1-42 were not significantly different in brains of infected and uninfected Tg2576 mice. In conclusion, onset and course of disease in mouse models of three common neurodegenerative disorders were not influenced by repeated systemic infections with S. pneumoniae, indicating that the effect of moderately severe acute infections on the course of neurodegenerative diseases may be less pronounced than suspected.
Asunto(s)
Enfermedades Neurodegenerativas/inmunología , Neumonía Bacteriana/complicaciones , Neumonía Bacteriana/inmunología , Infecciones Estreptocócicas/inmunología , Streptococcus pneumoniae/inmunología , Enfermedad Aguda , Enfermedad de Alzheimer/genética , Enfermedad de Alzheimer/inmunología , Enfermedad de Alzheimer/fisiopatología , Péptidos beta-Amiloides/metabolismo , Esclerosis Amiotrófica Lateral/genética , Esclerosis Amiotrófica Lateral/inmunología , Esclerosis Amiotrófica Lateral/fisiopatología , Animales , Antibacterianos/farmacología , Ceftriaxona/farmacología , Modelos Animales de Enfermedad , Progresión de la Enfermedad , Interleucina-6/metabolismo , Aprendizaje por Laberinto/fisiología , Trastornos de la Memoria/genética , Trastornos de la Memoria/inmunología , Trastornos de la Memoria/fisiopatología , Ratones , Ratones Transgénicos , Enfermedades Neurodegenerativas/genética , Enfermedades Neurodegenerativas/fisiopatología , Pruebas Neuropsicológicas , Enfermedad de Parkinson/genética , Enfermedad de Parkinson/inmunología , Enfermedad de Parkinson/fisiopatología , Placa Amiloide/genética , Placa Amiloide/inmunología , Placa Amiloide/metabolismo , Recurrencia , Infecciones Estreptocócicas/complicaciones , Regulación hacia Arriba/genética , Regulación hacia Arriba/inmunología , alfa-Sinucleína/genéticaRESUMEN
Neuronal injury is frequent in bacterial meningitis, resulting in a high rate of death and neurological sequelae. In a search of potential neuroprotective strategies for treatment of bacterial meningitis, the antioxidant melatonin was neuroprotective in cell culture experiments and in a rabbit Streptococcus pneumoniae meningitis model, when treatment was started at the time of infection. In the present study, adjunctive melatonin treatment applied from the beginning of antibiotic therapy 12 hr after infection at a dose of 1.67 mg/kg/hr resulted in plasma concentrations of 451 +/- 198 ng/ml, cerebrospinal fluid (CSF) concentrations of 154 +/- 57 ng/ml and a CSF-to-plasma ratio of 0.38 +/- 0.19 (mean +/- SD). Melatonin therapy had antiinflammatory effects but did not reduce neuronal injury in either a rabbit model of gram-positive Streptococcus pneumoniae or gram-negative Escherichia coli meningitis.