Alternative therapeutic approaches for the control of brain inflammation secondary to antihelminthic therapy in neurocysticercosis using a novel experimental pig model PROJECT SUMMARY Neurocysticercosis (NCC) is the infection of the human brain by the larvae of the pork tapeworm Taenia solium and is a major cause of seizures in most of the world. Antihelminthic therapy induces cyst damage and activates the host immune response, which results in brain inflammation and edema. Corticosteroids are commonly administered concomitant with antihelminthic drugs to control the early treatment-induced inflammatory 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 in response to antihelminthic therapy is essential to improve the control of the treatment-induced brain inflammation and to evaluate potential corticosteroid-sparing/replacing agents. The lack of an appropriate animal 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 reproduces CNS cyst infection efficiently, thus providing a suitable animal model for the study of NCC. In this proposal, we will optimize the intra-carotid injection model by determining the number of activated oncospheres required to consistently reproduce NCC in pigs, as well as to characterize the immunopathological processes associated with 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 the optimal dose of two alternative anti-inflammatory drugs: etanercept (ETN) or methotrexate (MTX) in the control of the brain inflammatory response that results from antihelminthic therapy; the second trial will compare the optimal dose of ETN and MTX versus the wide-spectrum, corticosteroid dexamethasone (DEX) in the control of pericystic brain inflammation after antihelminthic therapy. We expect that our findings will provide the base evidence for translational studies testing ETN or MTX in controlled studies in NCC patients.
Alternative therapeutic approaches for the control of brain inflammation secondary to antihelminthic therapy in neurocysticercosis using a novel experimental pig model PROJECT NARRATIVE Neurocysticercosis (NCC) is the infection of the human brain by the larval cyst of Taenia solium. Antihelminthic therapy in NCC damages the parasite and induces brain inflammation as consequence of the acute immune response. Corticosteroids are commonly used to blunt the inflammatory response, although no ideal therapy scheme exists, the efficacy of corticosteroids is also suboptimal in some forms of NCC, and its use may lead to undesirable side-effects. An ideal NCC animal that closely resembles the human pathology may help to understand the immunohistopathological processes associated with CNS cyst infection and brain inflammation. We have developed a novel NCC pig model by intra-carotid oncosphere injection that consistently produces viable brain cyst infection, thus providing a valuable tool for the study of NCC. This proposal aims to optimize this model and to characterize the immune responses and histological changes associated with experimental CNS cyst infection and in response to antihelminthic therapy. Subsequently, this model will be used to determine optimal doses of two anti-inflammatory drugs: etanercept (ETN) or methotrexate (MTX) for the control of the treatment-induced brain inflammation, and the optimal dose of ETN and MTX will be compared with the wide-spectrum corticosteroid dexamethasone (DEX) for assessment of potential corticosteroid- sparing/replacing agents for use in NCC