Neurocysticercosis (NCC) is a parasitic infection of the human central nervous system caused by the helminth Taenia solium. NCC is recognized as a leading cause of seizures worldwide. Seizures in NCC are evoked by localized granulomatous responses to dying parasites in the brain. The mediators of the seizures are unknown, identification of seizure mediator(s) in NCC may result in treatment with specific antagonists. The neuropeptide substance P (SP) stimulates granuloma growth and Th1 cytokine production. Another neuropeptide, somatostatin, stimulates Th2 cytokine production and impairs granuloma formation. SP evokes epileptiform responses in neurons, whereas, somatostatin has anticonvulsant properties. We divided granulomas associated with murine cysticercosis into 4 stages based on the histologic appearance of the degenerating parasite. Early stage granulomas expressed Th1 cytokines and SP, whereas Th2 cytokines and somatostatin were only expressed in later stages. Preliminary results also noted that behavioral seizures and increased hippocampal activity were induced when extracts from early granulomas were injected into brain of rats. Pretreatment with SP receptor antagonist inhibited these effects. Similarly, injection of SP into rat brain also induced seizures and altered hippocampal activity that was completely blocked by pretreatment with SP receptor antagonist or somatostatin. We hypothesize that SP mediates and somatostatin inhibits the granulomatous response and seizures in NCC.
Specific aim 1 : To test the hypothesis that SP and somatostatin modulate granulomatous responses in cysticercosis. Granuloma size, Th1/Th2 and pro-inflammatory cytokine levels in infected, wildtype mice, SP knockout mice (SP KO), SP receptor KO mice and somatostatin KO mice will be compared.
Specific aim 2 : To determine if SP and somatostatin are respectively responsible for the mediation and modulation of seizure responses in NCC. SP protein expression will be examined in brain biopsies from NCC patients with seizures. Epileptogenic activity of granuloma extracts from infected, SP KO and somatostatin KO mice will be compared to that from wildtype mice.
Specific aim 3 : To determine if seizures in NCC are directly due to SP and/or indirectly due to SP induced cytokines. Epileptogenic activity of early granuloma extracts will be tested with or without inhibition or blocking of SP, IL-1beta, TNF-alpha or IL-6. Also epileptogenic activity of early granulomas from infected IL-1beta, TNF-alpha or IL-6 knockouts will be tested.
Specific aim 4 : To test the hypothesis that somatostatin inhibits seizures in NCC. Epileptogenic activity of early granuloma extracts with or without somatostatin analogues or SOM antagonist will be studied. These studies will determine the importance of SP and SOM in pathogenesis of NCC, and may lead to future use of SP antagonist and SOM analogues as anti-epileptic agents for treatment of seizures in NCC and other seizure related diseases.

National Institute of Health (NIH)
National Institute of Neurological Disorders and Stroke (NINDS)
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Special Emphasis Panel (ZRG1-BDCN-4 (01))
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Nunn, Michael
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Baylor College of Medicine
Internal Medicine/Medicine
Schools of Medicine
United States
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Khumbatta, Mitra; Firozgary, Bahrom; Tweardy, David John et al. (2014) Somatostatin negatively regulates parasite burden and granulomatous responses in cysticercosis. Biomed Res Int 2014:247182
Robinson, Prema; Garza, Armandina; Weinstock, Joel et al. (2012) Substance P causes seizures in neurocysticercosis. PLoS Pathog 8:e1002489
Garza, Armandina; Tweardy, David J; Weinstock, Joel et al. (2010) Substance P signaling contributes to granuloma formation in Taenia crassiceps infection, a murine model of cysticercosis. J Biomed Biotechnol 2010:597086
Garza, Armandina; Weinstock, Joel; Robinson, Prema (2008) Absence of the SP/SP receptor circuitry in the substance P-precursor knockout mice or SP receptor, neurokinin (NK)1 knockout mice leads to an inhibited cytokine response in granulomas associated with murine Taenia crassiceps infection. J Parasitol 94:1253-8
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