8 research outputs found
Substance P Signaling Contributes to Granuloma Formation in Taenia crassiceps Infection, a Murine Model of Cysticercosis
Cysticercosis is an infection with larval cysts of the cestode Taenia solium. Through pathways that are incompletely understood, dying parasites initiate a granulomatous reaction that, in the brain, causes seizures. Substance P (SP), a neuropeptide involved in pain-transmission, contributes to inflammation and previously was detected in granulomas associated with dead T. crassiceps cysts. To determine if SP contributes to granuloma formation, we measured granuloma-size and levels of IL-1β, TNF-α, and IL-6 within granulomas in T. crassiceps-infected wild type (WT) mice and mice deficient in SP-precursor (SPP) or the SP-receptor (neurokinin 1, NK1). Granuloma volumes of infected SPP- and NK1-knockout mice were reduced by 31 and 36%, respectively, compared to WT mice (P < .05 for both) and produced up to 5-fold less IL-1β, TNF-α, and IL-6 protein. Thus, SP signaling contributes to granuloma development and proinflammatory cytokine production in T. crassiceps infection and suggests a potential role for this mediator in human cystercercosis
Substance P Causes Seizures in Neurocysticercosis
Neurocysticercosis (NCC), a helminth infection of the brain, is a major cause of seizures. The mediators responsible for seizures in NCC are unknown, and their management remains controversial. Substance P (SP) is a neuropeptide produced by neurons, endothelial cells and immunocytes. The current studies examined the hypothesis that SP mediates seizures in NCC. We demonstrated by immunostaining that 5 of 5 brain biopsies from NCC patients contained substance P (SP)-positive (+) cells adjacent to but not distant from degenerating worms; no SP+ cells were detected in uninfected brains. In a rodent model of NCC, seizures were induced after intrahippocampal injection of SP alone or after injection of extracts of cysticercosis granuloma obtained from infected wild type (WT), but not from infected SP precursor-deficient mice. Seizure activity correlated with SP levels within WT granuloma extracts and was prevented by intrahippocampal pre-injection of SP receptor antagonist. Furthermore, extracts of granulomas from WT mice caused seizures when injected into the hippocampus of WT mice, but not when injected into SP receptor (NK1R) deficient mice. These findings indicate that SP causes seizures in NCC, and, suggests that seizures in NCC in humans may be prevented and/or treated with SP-receptor antagonists
Development and validation of an algorithm to recalibrate mental models and reduce diagnostic errors associated with catheter-associated bacteriuria
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
Effect of SP receptor antagonist (SPra) pre-treatment on granuloma extract-induced seizure activity in rats.
<p>Representative EEG recordings in rats after intrahippocampal injection of an early granuloma extract pretreated without (A) or with SPra (B) are shown; double black lines indicate the period of extract injection (A and B) or SP receptor antagonist injection (B only). The behavioral seizure grade (C), seizure amplitude (D), and seizure duration (E) in rats following intrahippocampal injection of early granuloma extracts pre-treated without (Control) or with SPra (SPra; n = 6 each) are depicted graphically (*, p≤0.001, Mann-Whitney). Results are pooled data from two independent experiments.</p
Effect of deletion of the NK1R gene or the SP gene in mice on granuloma extract-induced seizure activity.
<p>A representative EEG tracing after injection of an early granuloma extract obtained from a wild type mouse into the hippocampus of a wild type mouse (A) or NK1<sup>−/−</sup> (B) mouse is shown. The behavioral seizure grade (C), seizure amplitude (D), and seizure duration (E) in wild type or NK1<sup>−/−</sup> mice following intrahippocampal injection of extracts of early granulomas obtained from wild type mice (n = 4 each) are depicted graphically (*, p≤0.001, Mann-Whitney). EEG recordings shown (F and G) are representative of results obtained after intrahippocampal injection into a wild type mouse of an extract from an early granuloma (F) or late granuloma (G) obtained from an SPP<sup>−/−</sup> mouse. Results are pooled data from two independent experiments.</p
SP immunostaining of brain tissue samples from NCC-infected and uninfected patients.
<p>Photomicrographs of brain biopsy specimens of NCC-infected patients (P1 through P5) and brain autopsy specimens of NCC-uninfected patients (N1 and N2) are shown. Specimen slides were stained with specific polyclonal rabbit anti-SP antibody (α-SP) or control rabbit serum. Fields shown are either adjacent to the parasite (indicated by red arrow) or distant from parasite [when specimen size permitted (P1 and P2)], as indicated. SP+ cells are indicated by black arrows, 1000× magnification. Data shown is representative of one independent experiment.</p