Authors

Discussion

An anti-morbidity effect of the second-generation tetracycline (SGT), doxycycline (DOX), has been identified in clinical filarial lymphoedema. Here we explore potential mechanisms of anti-morbidity effects of SGT using pre-clinical filarial inflammation and infection models.

Direct anti-angiogenic effects of SGTs (DOX), minocycline (MIN) and their hepatic metabolites epi-DOX and epi-MIN were assessed by suppression of adult dermal blood or lymphatic endothelial cell (BEC/LEC) proliferation. Modulation of filarial inflammatory pathology was assessed by oral treatment with MIN during maintenance of localised filarial inflammation with serial injections of Brugia malayi adult female extract in inbred wild type (WT) mice. Modulation of filarial infection-driven immune responses, is being examined in WT or SCID mice infected B. malayi infectious larvae (BmL3) and orally dosed with DOX or MIN during the larval or adult stage of development. MIN, DOX and their 4’-epi non-microbial metabolites induced anti-proliferative effects on BEC and LEC in a micromolar dose-dependent manner. MIN suppression of LEC proliferation was more effective than DOX at low doses. Oral dosing of MIN significantly ameliorated skin thickening, and modulated myeloid inflammatory recruitment. Impact on infection-related immune responses are currently being evaluated.Preliminary evidence promotes a non-microbial antiangiogenic mechanism of SGTs in ameliorating filarial morbidity.