Tumor necrosis factor-alpha, prostaglandin-E2 and interleukin-1ß targeted anti-arthritic potential of fluvoxamine: drug repurposing.

Fluvoxamine, a selective serotonin re uptake inhibitor, is used to treat depression. The aim of present study was to evaluate fluvoxamine in acute (egg albumin-induced inflammation) and chronic inflammatory rat models (formaldehyde and complete Freund's adjuvant (CFA)-induced arthritis). Fluvoxamine showed highly significant (p<0.001) protective effect at dose of 50 mg/kg orally with percentage suppression 21.3% as compared to disease control group in acute model. Likewise, formaldehyde-induced arthritic experiment confirmed the significant (p<0.001) anti-arthritic behavior, showed by fluvoxamine (50 mg/kg orally) throughout the study. Moreover, In CFA-induced model, the higher dose (fluvoxamine 50 mg/kg) exhibited highly significant (p<0.001) decrease in paw thickness and arthritic score with significant increase in weight of animals from 123.8± 1.934 g to 130.2± 1.655 g, significantly decreased the level of RF and CRP to level of 12.0±0.707 and 11.40±0.50 respectively and restoration of SOD, CAT (69.8±1.5, 72.0±1.4 respectively). Furthermore, the level of TNF-α, PGE2, and IL-1ß (147.0±2.0, 406.8±2.5, and 93.8±1.3 respectively) in arthritic animals was reduced to significant (p<0.001) level (53.8±1.3, 205±3.6, and 42.0±1.4 respectively) after treatment with fluvoxamine. Furthermore, molecular docking of fluvoxamine against TNF-α, PGE2, and IL-1ß protein targets showed good binding energies which hereby from computational studies proves our compound anti-inflammatory potential. In addition, absorption, distribution, metabolism, excretion, and toxicity (ADMET) studies reveled that fluvoxamine has very good pharmacokinetic profile with no specific hepatic toxicity and good absorption level. In addition, the skin sensitization test in vitro human cell line activation test (h-CLAT) and KeratinoSens have revealed that isolated flavone is not skin sensitive with confidence score of 59.6% and 91.6%. The current findings validated the anti-arthritic potential of fluvoxamine but it should be recommended for clinical investigation in future research.

Identification and characterization of the SIFamide receptor in the hemimetabolous Chagas disease vector, Rhodnius prolixus Stål, 1859, (Hemiptera, Reduviidae, Triatominae).

Within arthropods, the SIFamide family of neuropeptides appears to be involved in the modulation of a range of physiological and behavioral events. In Rhodnius prolixus, we have previously shown the presence of SIFamidergic-like processes in neurohemal release sites and provided evidence for a role for Rhopr-SIFa in modulating heartbeat frequency and feeding behaviors. Here, the R. prolixus SIFamide receptor (RhoprSIFR) has been identified, cloned, and sequenced. Sequence analyses show high similarity and identity between the RhoprSIFR and other cloned SIFamide receptors. Quantitative PCR shows that the RhoprSIFR transcript is found in a variety of tissues, including those involved in feeding and reproduction. In unfed insects, high transcript expression is observed in the central nervous system and midgut, suggesting a role of Rhopr-SIFa in various processes related to feeding and digestion. Expression of the RhoprSIFR transcript changes between unfed, 24 h post-fed, and 7 d post-fed conditions. Expression of the RhoprSIFR transcript significantly increases in the anterior midgut and posterior midgut 7 d post-feeding and knockdown of the RhoprSIFR transcript significantly reduces the size of blood meal consumed. This data suggests a possible role for Rhopr-SIFa in regulating long-term post-feeding osmotic balance and digestion of the blood meal. Lastly, transcript expression of Rhopr-SIFa and RhoprSIFR also varies temporally in relation to the reproductive stage, suggesting an involvement of this signaling pathway in reproductive activities. Identification of the RhoprSIFR and its expression profile now provide tools for a more detailed understanding into the precise coordination of feeding and other physiological processes in R. prolixus.

SIFamide Influences Feeding in the Chagas Disease Vector, Rhodnius prolixus.

SIFamides are a family of highly conserved neuropeptides in arthropods, and in insects are mainly expressed in four medial neurons in the pars intercerebralis of the brain. Although SIFamide has been shown to influence sexual behavior, feeding, and sleep regulation in holometabolous insects such as Drosophila melanogaster, little is known about its role in hemimetabolous insects, including the blood-sucking bug, Rhodnius prolixus. In this study, we confirm the nucleotide sequence for R. prolixus SIFamide (Rhopr-SIFa) and find characteristic phenotypic expression of SIFamide in four cells of the pars intercerebralis in the brain. In addition to extensive SIFa projections throughout the entire central nervous system, SIFamidergic processes also enter into the corpus cardiacum, and project along the dorsal vessel, suggestive of Rhopr-SIFa acting as a neurohormone. Physiologically, Rhopr-SIFamide induces dose-dependent increases in heartbeat frequency in vitro suggesting the presence of peripheral receptors, and thereby indicating Rhopr-SIFa is released to act upon peripheral targets. We also explore the function of Rhopr-SIFa in R. prolixus, specifically in relation to feeding, since R. prolixus is a blood-gorging insect and a vector for Chagas disease. The intensity of SIFamide-like staining in the neurons in the brain is diminished 2 h following feeding, and restocking of those cells is finished 24 h later, indicating Rhopr-SIFa may be released at feeding. The results of temporal qPCR analysis were consistent with the immunohistochemical findings, showing an increase in Rhopr-SIFa transcript expression in the brain 2 h after feeding. We also observed enhanced feeding (size of meal) in insects injected with Rhopr-SIFa whereas insects with RNAi-mediated knockdown of the Rhopr-SIFa transcript consumed a significantly smaller blood meal relative to controls. These data suggest that the four SIFamidergic neurons and associated arborizations may play an important function in the neuronal circuitry controlling R. prolixus feeding, with Rhopr-SIFa acting as a central and peripheral neuromodulator/neurohormone.