Neurocysticercosis (NCC) is the most important cause of secondary epilepsy in endemic countries around the world, and is thus a significant global health problem. In Peru, around 30% of epilepsy is attributable to this zoonotic disease. Larval cysts of this parasite establish in the brain parenchyma and eventually degenerate by natural involution or after anti-parasitic treatment. Frequently this process results in a residual brain calcification which becomes a foci for seizures. A chain of evidence suggests that calcified lesions play a role in the pathophysiology of seizure activity, such as focal seizure semiology compatible with the localization of the calcified lesion, edema surrounding the calcifications at the time of a seizure, etc. In patients with a single degenerating cyst, seizures are significantly more frequent in those who develop a residual calcification by one year compared with those whose infection does not result in calcification. Under these assumptions, reduction or avoidance of cyst calcification could potentially decrease epilepsy activity. Bisphosphonates have shown an inhibitory effect on ectopic calcification in human studies and in animal models. The inhibitory effect on calcification is probably due to three processes; including, inhibiting precipitation of calcium phosphate, blocking transformation of amorphous calcium phosphate into hydroxyapatite and reducing hydroxyapatite crystal aggregation. Through these processes bisphosphonates inhibit calcium phosphate crystal growth. Our objective is to evaluate whether bisphosphonates decrease the likelihood and degree of residual calcification resulting from degeneration of muscular and cerebral cysts in animal models. Our approach includes four consecutive phases: (1) we will begin by standardizing the experimental intramuscular infection in rodents (rats, guinea pigs and rabbits) to allow a practical model with enough repeatability for further studies, (2) we will then characterize the calcification process of the cyst after antiparasitic treatment in the best models obtained in the preceding phase, as well as in an previously standardized brain model infection in rats, (3) once we have defined the usual process of calcifications, we will then evaluate the ability of three different bisphosphonates (etidronate, alendronate, and ibandronate) to reduce calcification in rodent brain and muscles, and (4) in a final study we will attempt to replicate these findings in naturally-infected pigs as more natural model. This project could provide essential evidence needed to support development of an anti- calcification treatment in NCC patients, with the goal of reducing seizure occurrence. Since our intervention drugs are FDA-approved, positive findings could be rapidly translated into clinical trials. In addition, the new animal models we develop could be used to test new anti-parasitic and anti-inflammatory drugs and also new candidate vaccines.

Public Health Relevance

Neurocysticercosis (NCC) is a major cause of seizures in vast regions of the world. Parasitic larvae establish in the human brain, degenerate, and eventually leave a calcified scar. These calcified lesions seem to play a role in the pathophysiology of seizures. Bisphosphonates are currently used in humans for prevention and treatment of osteopenia and osteoporosis. In some cases, bisphosphonates are also used to avoid ectopic calcifications. We will establish appropriate animal models for cyst infection and calcification an then evaluate whether bisphosphonates decrease the likelihood and degree of residual calcification resulting from dying muscular and cerebral cysticercosis cysts in these animal models.

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Research Project (R01)
Project #
5R01AI116456-05
Application #
9638518
Study Section
Special Emphasis Panel (ZRG1)
Program Officer
Pesce, John T
Project Start
2015-03-01
Project End
2020-02-29
Budget Start
2019-03-01
Budget End
2020-02-29
Support Year
5
Fiscal Year
2019
Total Cost
Indirect Cost
Name
Universidad Peruana Cayetano Heredia
Department
Type
DUNS #
934798430
City
Lima
State
Country
Peru
Zip Code
15102
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