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

Endothelial Nitric Oxide Synthase Mediates the Cerebrovascular Effects of Erythropoietin in Traumatic Brain Injury

Background: Erythropoietin (Epo) improves post-traumatic cerebral blood flow (CBF), pressure auto-regulation, and vascular reactivity to L-arginine. This study examines the dependence of these cerebral hemodynamic effects of Epo on nitric oxide (NO) generated by endothelial nitric oxide synthase (eNOS). Methods: Using laser Doppler flow imaging, CBF was monitored in wild-type (WT) and eNOS-deficient mice undergoing controlled cortical impact (CCI) followed by administration of Epo (5000 U/kg) or normal saline. Results: CBF decreased in all groups post-injury with the greatest reductions occurring at the impact site. Epo administration resulted in significantly higher CBF in the peri-contusional sites in the WT mice (70.2 ± 3.35 % in Epo-treated compared to 53 ± 3.3 % of baseline in saline-treated mice (p< .0001), but no effect was seen in the eNOS-deficient mice. No CBF differences were found at the core impact site where CBF dropped to 20-25% of baseline in all groups. Conclusion: These differences between eNOS-deficient and WT mice indicate that the EPO mediated improvement in CBF in TBI is eNOS dependent

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^−/− (B) mouse is shown. The behavioral seizure grade (C), seizure amplitude (D), and seizure duration (E) in wild type or NK1^−/− 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^−/− 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

Severe Monkeypox in Hospitalized Patients - United States, August 10-October 10, 2022.

As of October 21, 2022, a total of 27,884 monkeypox cases (confirmed and probable) have been reported in the United States.§ Gay, bisexual, and other men who have sex with men have constituted a majority of cases, and persons with HIV infection and those from racial and ethnic minority groups have been disproportionately affected (1,2). During previous monkeypox outbreaks, severe manifestations of disease and poor outcomes have been reported among persons with HIV infection, particularly those with AIDS (3-5). This report summarizes findings from CDC clinical consultations provided for 57 patients aged ≥18 years who were hospitalized with severe manifestations of monkeypox¶ during August 10-October 10, 2022, and highlights three clinically representative cases. Overall, 47 (82%) patients had HIV infection, four (9%) of whom were receiving antiretroviral therapy (ART) before monkeypox diagnosis. Most patients were male (95%) and 68% were non-Hispanic Black (Black). Overall, 17 (30%) patients received intensive care unit (ICU)-level care, and 12 (21%) have died. As of this report, monkeypox was a cause of death or contributing factor in five of these deaths; six deaths remain under investigation to determine whether monkeypox was a causal or contributing factor; and in one death, monkeypox was not a cause or contributing factor.** Health care providers and public health professionals should be aware that severe morbidity and mortality associated with monkeypox have been observed during the current outbreak in the United States (6,7), particularly among highly immunocompromised persons. Providers should test all sexually active patients with suspected monkeypox for HIV at the time of monkeypox testing unless a patient is already known to have HIV infection. Providers should consider early commencement and extended duration of monkeypox-directed therapy†† in highly immunocompromised patients with suspected or laboratory-diagnosed monkeypox.§§ Engaging all persons with HIV in sustained care remains a critical public health priority