Research Project
10134999
Peru-JHU TMRC Program Principal Investigator/Program Director (Last, First, Middle): GARCIA, Hector H. COMPONENT PROJECT 3 ? IMPROVING THE UNDERSTANDING AND TREATMENT OF BRAIN INFLAMMATION IN NEUROCYSTICERCOSIS PROJECT SUMMARY Human infestation by the larval stage of the pork tapeworm Taenia solium is a major public health problem in most resource-poor countries. Clinical manifestations in humans are predominantly due to central nervous system involvement, known as neurocysticercosis (NCC). Seizures occur in nearly 80% of people with NCC and in about 50% of the patients recurrent seizures occur.10-13 NCC is the most important risk factor for epileptic seizures in many endemic regions, and epidemiologic studies suggest that up to one third of active epilepsy is attributable to NCC. The mechanisms underlying epileptogenesis in NCC patients are still poorly understood. Paradoxically, anti-parasitic treatment often leads to increased edema and inflammatory response, and results in recurrent, sometime severe, seizures.9 Animal models for seizures and epilepsy, in particular models for focal brain inflammation and associated seizures, are scarce and limited. We have recently developed a rat brain NCC model in which rats are intracranially infected with culture-grown T. solium oncospheres and develop brain cysts or metacestodes, with characteristics identical to those developed in the natural host. This novel animal model of NCC is very similar to human NCC because the oncosphere, which is the natural stage of infection that results in cysticercosis, is localized to parenchymal or extraparenchymal (ventricles or meninges) brain tissue and allowed to develop into a metacestode, with identical morphologic characteristics as those found in the natural host. In the proposed study we will test in a comprehensive, quantitative and longitudinal approach the involvement of BBB breakdown, brain inflammatory response and astroglial activation in the development of seizures and epilepsy in the NCC rat model. We hypothesize that a) inflammation-related BBB dysfunction will be associated with the astroglial response in brain tissue and will result in further damage in the surrounding brain, and b) that inhibition of TNF-alpha or MMPs will block the inflammatory response and preserve BBB integrity. Data obtained in Specific Aim 1 will be used to plan the time window of anti-inflammatory treatment, directed to reduce inflammatory signaling, BBB breakdown and glial activation using three (including two recently available) FDA-approved anti-inflammatory approaches, for work under Specific Aim 2.
