ABSTRACT
The identification and early development of novel antimicrobial agents for use in veterinary medicine is subject to many of the same business and technical challenges as those found in antimicrobial agent use for human infectious disease. However, as awareness that some of the antimicrobial classes used in veterinary medicine are the same as used in human medicine, concern by multiple stakeholders has increased that this nonhuman use might be contributing to the problem of antimicrobial resistance to pathogens in humans, particularly with regard to food-borne diseases, such as salmonellosis and campylobacteriosis. Consequently, the interface between veterinary and human antibiotic use and resistance, especially with respect to human microbial food safety, has begun to redirect the industry pipeline of novel antimicrobial agents to be commercialized for use in veterinary medicine.
Subject(s)
Anti-Bacterial Agents/therapeutic use , Bacteria/drug effects , Bacterial Infections/veterinary , Veterinary Medicine/methods , Animals , Bacteria/growth & development , Bacterial Infections/drug therapy , Drug Resistance, Bacterial/drug effects , Food Microbiology , Food Safety , Humans , Veterinary Medicine/trendsABSTRACT
Interleukin (IL)-10 is important for regulating inflammation but whether it protects against infection-related deficits in cognitive function is unknown. Therefore, the current study evaluated sickness behavior, hippocampal-dependent matching-to-place performance and several inflammatory cytokines and neurotrophins in wild-type (IL-10(+/+)) and IL-10-deficient (IL-10(-/-)) mice after i.p. injection of lipopolysaccharide (LPS). Additionally, morphology of dendrites of pyramidal neurons in the dorsal CA1 hippocampus was assessed. Treatment with LPS increased IL-1beta, IL-6, and tumor necrosis factor alpha (TNFalpha) mRNA in all brain areas examined including the hippocampus, in both IL-10(+/+) and IL-10(-/-) mice but the increase was largest in IL-10(-/-) mice. Plasma IL-1beta, IL-6 and TNFalpha were also higher in IL-10(-/-) mice compared to IL-10(+/+) mice after LPS. Consistent with increased inflammatory cytokines in IL-10(-/-) mice after LPS treatment, were a more lengthy sickness behavior syndrome and a more prominent reduction in hippocampal levels of nerve growth factor mRNA; brain-derived neurotrophic factor mRNA was reduced similarly in both genotypes after LPS. In a test of hippocampal-dependent learning and memory that required mice to integrate new information with previously learned information and switch strategies to master a task, IL-10(-/-) mice were found to be less efficient after LPS than were similarly treated wild-type mice. LPS did not affect morphology of dendrites of pyramidal neurons in the dorsal CA1 hippocampus in either genotype. Taken together the results are interpreted to suggest that during peripheral infection IL-10 inhibits sickness behavior and tribulations in hippocampal-dependent working memory via its propensity to mitigate inflammation. We conclude that IL-10 is critical for maintaining normal neuro-immune communication during infection.
Subject(s)
Cognition Disorders/psychology , Interleukin-10/genetics , Interleukin-10/physiology , Lipopolysaccharides/pharmacology , Animals , Behavior/physiology , Cognition Disorders/chemically induced , Corticosterone/blood , Cytokines/biosynthesis , Cytokines/genetics , Dendrites/drug effects , Dendrites/ultrastructure , Injections, Intraperitoneal , Lipopolysaccharides/administration & dosage , Male , Maze Learning/drug effects , Mice , Mice, Inbred C57BL , Mice, Knockout , Motor Activity/drug effects , Motor Activity/physiology , Nerve Growth Factors/biosynthesis , Nerve Growth Factors/genetics , Psychomotor Performance/physiology , Pyramidal Cells/drug effects , Pyramidal Cells/ultrastructure , RNA, Messenger/biosynthesis , RNA, Messenger/geneticsABSTRACT
The expression of several inflammatory cytokines that inhibit synaptic plasticity and hippocampal-dependent learning and memory is higher in the brains of aged mice compared to young adults after peripheral injection of lipopolysaccharide (LPS). In this study we investigated whether the exaggerated inflammatory cytokine response in the hippocampus of aged mice after IP injection of LPS is associated with architectural changes to dendrites of pyramidal neurons in the dorsal CA1 hippocampus. Compared to young adults, aged mice had higher basal expression of MHC class II, lower basal expression of two neurotrophins, nerve growth factor (NGF) and brain-derived neurotrophic factor (BDNF), and a decrease in total dendritic length in both the basal and apical tree. After IP LPS administration, expression of IL-1beta, IL-6, and TNFalpha mRNA was higher in hippocampus of aged mice compared to young adults whereas NGF and BDNF mRNA was reduced similarly in both age groups. The basal dendritic tree was not affected by LPS in either adult or aged mice 72h after treatment; however, length and branching of the apical tree was reduced by LPS in aged but not adult mice. The present findings indicate that a peripheral infection in the aged can cause a heightened inflammatory cytokine response in the hippocampus and atrophy of hippocampal neurons. Architectural changes to dorsal CA1 hippocampal neurons may contribute to cognitive disorders evident in elderly patients with an infection.
