Alternative therapeutic approaches for the control of brain inflammation secondary to antihelminthic therapy in neurocysticercosis using a novel experimental pig model

Alternative therapeutic approaches for the control of brain inflammation secondary to antihelminthic therapy in neurocysticercosis using a novel experimental pig modelPROJECT SUMMARY Neurocysticercosis (NCC) is the infection of the human brain by the larvae of the pork tapeworm Taeniasolium and is a major cause of seizures in most of the world. Antihelminthic therapy induces cyst damage andactivates the host immune response, which results in brain inflammation and edema. Corticosteroids arecommonly administered concomitant with antihelminthic drugs to control the early treatment-inducedinflammatory response. However, an ideal therapeutic scheme using corticosteroids has not been established,corticosteroid therapy is suboptimal in some forms of NCC, and its use may also lead to undesirable side-effects. A better understanding of the immunopathological processes associated with CNS cyst infection and inresponse to antihelminthic therapy is essential to improve the control of the treatment-induced braininflammation and to evaluate potential corticosteroid-sparing/replacing agents. The lack of an appropriateanimal model for NCC has however, limited our ability to achieve these goals.We recently demonstrated that intra-carotid injection of T. solium activated oncospheres in pigs reproducesCNS cyst infection efficiently, thus providing a suitable animal model for the study of NCC. In this proposal, wewill optimize the intra-carotid injection model by determining the number of activated oncospheres required toconsistently reproduce NCC in pigs, as well as to characterize the immunopathological processes associatedwith CNS cyst infection and in response to antihelminthic therapy with albendazole plus praziquantel.Subsequently, we will conduct two trials in pigs with experimental NCC: In the first trial, we will determine theoptimal dose of two alternative anti-inflammatory drugs: etanercept (ETN) or methotrexate (MTX) in the controlof the brain inflammatory response that results from antihelminthic therapy; the second trial will compare theoptimal dose of ETN and MTX versus the wide-spectrum, corticosteroid dexamethasone (DEX) in the control ofpericystic brain inflammation after antihelminthic therapy. We expect that our findings will provide the baseevidence for translational studies testing ETN or MTX in controlled studies in NCC patients.