Combination therapy with ampicillin and azithromycin in an experimental pneumococcal pneumonia is bactericidal and effective in down regulating inflammation in mice

OBJECTIVES: Emergence of multidrug resistance among Streptococcus pneumoniae (SP), has limited the available options used to treat infections caused by this organism. The objective of this study was to compare the role of monotherapy and combination therapy with ampicillin (AMP) and azithromycin (AZM) in eradicating bacterial burden and down regulating lung inflammation in a murine experimental pneumococcal infection model. METHODS: Balb/C mice were infected with 10(6) CFU of SP. Treatments with intravenous ampicillin (200 mg/kg) and azithromycin (50 mg/kg) either alone or in combination was initiated 18 h post infection, animals were sacrificed from 0 – 6 h after initiation of treatment. AMP and AZM were quantified in serum by microbiological assay. Levels of TNF-α, IFN-γ IL-6, and IL-10 in serum and in lungs, along with myeloperoxidase, inflammatory cell count in broncho alveolar lavage fluid, COX-2 and histopathological changes in lungs were estimated. RESULTS: Combination therapy down regulated lung inflammation and accelerated bacterial clearance. This approach also significantly decreased TNF-α, IFN-γ, IL-6 and increased IL-10 level in serum and lungs along with decreased myeloperoxidase, pulmonary vascular permeability, inflammatory cell numbers and COX-2 levels in lungs. CONCLUSIONS: Combinatorial therapy resulted in comparable bactericidal activity against the multi-drug resistant isolate and may represent an alternative dosing strategy, which may help to alleviate problems with pneumococcal pneumonia

Protective effects of methanolic extract of Adhatoda vasica Nees leaf in collagen-induced arthritis by modulation of synovial toll-like receptor-2 expression and release of pro-inflammatory mediators

RA associated with oxidative stress and chronic inflammation has been a major health problem among the population worldwide. In this study protective effect of methanolic extract of Adhatoda vasica leaf (AVE) was evaluated on Collagen-induced arthritis in male Swiss albino mice. Post oral administration of AVE at 50, 100 and 200 mg/kg body weight doses decreased the arthritic index and footpad swelling. AVE administration diminished pro-inflammatory cytokines in serum and synovial tissues. Reduced chemokines and neutrophil infiltration in synovial tissues after AVE administration dictated its protective effect against RA. Decreased LPO content and SOD activity along with concomitant rise in GSH and CAT activities from liver, spleen and synovial tissues indicated regulation of oxidative stress by AVE. In addition decreased CRP in serum along with suppressed TLR-2 expression in CIA mice after AVE treatment was also observed. Protective effect of AVE in RA is further supported from histopathological studies which showed improvement during bone damage. In conclusion this study demonstrated A. vasica is capable of regulating oxidative stress during CIA and therefore down regulated local and systemic release of pro-inflammatory mediators, which might be linked to mechanism of decreasing synovial TLR-2 expression via downregulating release of its regular endogenous ligands like CRP

Reduced acetylcholinesterase activity downregulates peripheral and central inflammation during glucocorticoid resistance induced by chronic restraint stress and systemic lipopolysaccharide challenge in male mice

859-874Stress sensitizes the neuroinflammatory response to immunogenic challenge and associated behavioral changes in rodents. GlucocorticoidS (GCs) have been well known for their immunosuppressive and anti-inflammatory properties. However, recent advances have uncovered situations wherein they have opposite effects, especially when activated immune cells show resistance to circulating GCs. Under these circumstances, studying the role of the recently described ‘cholinergic anti-inflammatory pathway’ was of considerable interest. In this study, we investigated the level of serum C-reactive protein (CRP), cytokines and reactive oxygen and nitrogen species and antioxidant enzyme activities in the liver, brain and adrenal gland following LPS administration in stressed mice. Hypothalamic acetyl cholinesterase (AChE) enzyme activity and the expression of heat shock proteins 70 and 90, superoxide dismutase-1 and cycloxygenase-2 proteins in the hypothalamus were estimated by immunobloting. Behavioural changes were observed on an elevated plus maze and in an open field. Our results suggest that there exists a synergistic effect between inflammation and stress only when the stress exposure is acute in nature. Immune activation following chronic stress, downregulated inflammation, in spite of the resistant endocrine response to inflammation, via the newly described cholinergic anti-inflammatory pathway. Thus, it indicates that acute immune activation during chronic stress may be beneficial for the host to maintain homeostasis

Exogenous Interleukin-10 and ciprofloxacin treatment reduces inflammation and helps to improve cognitive behaviour in acute and chronic restraint stressed mice infected with <em>Escherichia coli</em>

241-257Recent research focused on the increased level of inflammatory cytokines and decreased the level of anti-inflammatory cytokines in chronically stressed individuals and this physiological state deteriorates further if the individual encounters some pathogens. Few studies have examined the effect of live bacterial infection in a stressed condition and fewer still have examined the effect of exogenous IL-10 and an antibiotic combination as a therapeutic approach to chronic stress and infection. In this study, we evaluated the role of the host’s adrenal-glucocorticoid response to live E. coli infection in the presence of exogenous IL-10 or an antibiotic or both in combination in restraint-stressed mice. Results obtained showed that IL-6, TNF-α and IFN-γ levels were down-regulated, IL-10 level increased significantly (P <0.05), pathogen load from blood was cleared effectively, and these effects were more profound when IL-10 treated stressed animals were administered CIP post-infection compared to the only IL-10 or only CIP treated groups. Moreover, serum C-reactive protein, AChE activity, COX-2 and iNOS expression were also inhibited in these animals. Both IL-10 and CIP treated animals also showed improved exploration and locomotion in OFT and EPM. Thus this study suggests an alternative therapeutic modality where impaired glucocorticoid sensitivity interferes with the appropriate regulation of inflammation