Cyclooxygenase-2 inhibitors alleviated depressive and anxious-like behaviors in mice exposed to lipopolysaccharide: Involvement of oxidative stress and neuroinflammation

Article

Author: Oliveira, João Victor Souza ; Capibaribe, Victor Celso Cavalcanti ; de Sousa, Francisca Cléa Florenço ; Macêdo, Danielle Silveira ; de Carvalho, Michele Albuquerque Jales ; Sales, Iardja Stéfane Lopes ; da Silva, Daniel Moreira Alves ; Valentim, José Tiago ; Rebouças, Manoela de Oliveira ; de Aquino, Pedro Everson Alexandre ; Vale, Larice de Carvalho ; Dos Santos Júnior, Manuel Alves

Depression and anxiety disorders have their pathophysiologies linked to inflammation and oxidative stress. In this context, celecoxib (CLX) and etoricoxib (ETR) inhibit cyclooxygenase 2 (COX-2), an enzyme expressed by cells involved in the inflammatory process and found in the brain. Studies have been using CLX as a possible drug in the treatment of depression, although its mechanisms at the central nervous system level are not fully elucidated. In this study, the effects of CLX and ETR on behavioral, oxidative, and inflammatory changes induced by systemic exposure to Escherichia coli lipopolysaccharide (LPS) were evaluated in adult male swiss mice. For ten days, the animals received intraperitoneal injections of LPS at 0.5 mg/kg. From the sixth to the tenth day, one hour after LPS exposure, they were treated orally with CLX (15 mg/kg), ETR (10 mg/kg), or fluoxetine (FLU) (20 mg/kg). Twenty-four hours after the last oral administration, the animals underwent evaluation of locomotor activity (open field test), predictive tests for depressive-like behavior (forced swim and tail suspension tests), and anxiolytic-like effect (elevated plus maze and hole board tests). Subsequently, the hippocampus, prefrontal cortex and striatum were dissected for the measurement of oxidative and nitrosative parameters (malondialdehyde, nitrite, and glutathione) and quantification of pro-inflammatory cytokines (IL-1β and IL-6). LPS induced depressive and anxious-like behavior, and treatment with CLX or ETR was able to reverse most of the behavioral changes. It was evidenced that nitrosative stress and the degree of lipid peroxidation induced by LPS were reduced in different brain areas after treatment with the drugs, as well as the endogenous defense system against free radicals was strengthened. CLX and ETR also significantly reduced LPS-induced cytokine levels. These data are expected to expand information on the role of inflammation in depression and anxiety and provide insights into possible mechanisms of COX-2 inhibitors in psychiatric disorders with a neurobiological basis in inflammation and oxidative stress.

01 Jun 2024·Macromolecular Bioscience

Synthesis and Characterization of Cassava Gum Hydrogel Associated with Chlorhexidine and Evaluation of Release and Antimicrobial Activity

Article

Author: Barreto, Humberto Medeiros ; Argôlo Neto, Napoleão Martins ; Morais, Alan Ícaro Sousa ; Cuevas, Maria Del Mar Orta ; Peña‐Garcia, Ramón ; de Oliveira, Luís Humberto ; Nascimento, Ariane Maria Silva Santos ; da Silva‐Filho, Edson Cavalcanti ; Silva, Albert Santos ; Muniz, Edvani Curti ; Lima, Idglan Sá de ; Osajima, Josy Anteveli

AbstractHydrogels from natural sources are attracting increasing interest due to their ability to protect biologically active molecules. Starch extracted from cassava tubers is a promising material for synthesizing these hydrogels. Copolymerization of cassava gum and incorporation of chlorhexidine digluconate (CLX) into the hydrogels is confirmed by changes in the crystallographic profile, as observed through X‐ray diffraction, and a shift in the 1000 cm−1 band in the Fourier‐transform infrared spectroscopy spectrum. The differential scanning calorimetry reveals changes in the decomposition temperature of the synthesized hydrogels related to CLX volatility. Micrographs illustrate the material's porosity. Release tests indicate a constant linear release over 72 h, while antimicrobial activity against Staphylococcus aureus, Escherichia coli, and Candida albicans is satisfactory, with 100% effectiveness from 0.5% CLX and the formation of inhibition halos. Toxicity and biocompatibility studies show no cytotoxicity. The continuous release of chlorhexidine is promising for components of biomedical implants and applications as it can ensure antimicrobial action according to specific therapeutic needs.

01 Jun 2024·International Journal of Pharmaceutics: X

Repurposing celecoxib for colorectal cancer targeting via pH-triggered ultra-elastic nanovesicles: Pronounced efficacy through up-regulation of Wnt/β-catenin pathway in DMH-induced tumorigenesis

Article

Author: Abou Alazayem, Mahmoud A. ; Shalaby, Khaled ; Elkarmalawy, Marwa ; Aboud, Heba M. ; Elkomy, Mohammed H. ; Abdelmeged, Abdelmeged A. ; El Sisi, Amani M. ; Ahmed, Yasmin M. ; El Menshawe, Shahira F.

Celecoxib (CLX), a selective inhibitor for cyclooxygenase 2 (COX-2), has manifested potential activity against diverse types of cancer. However, low bioavailability and cardiovascular side effects remain the major challenges that limit its exploitation. In this work, we developed ultra-elastic nanovesicles (UENVs) with pH-triggered surface charge reversal traits that could efficiently deliver CLX to colorectal segments for snowballed tumor targeting. CLX-UENVs were fabricated via a thin-film hydration approach. The impact of formulation factors (Span 80, Tween 80, and sonication time) on the nanovesicular features was evaluated using Box-Behnken design, and the optimal formulation was computed. The optimum formulation was positively coated with polyethyleneimine (CLX-PEI-UENVs) and then coated with Eudragit S100 (CLX-ES-PEI-UENVs). The activity of the optimized nano-cargo was explored in 1,2-dimethylhydrazine-induced colorectal cancer in Wistar rats. Levels of COX-2, Wnt-2 and β-catenin were assessed in rats' colon. The diameter of the optimized CLX-ES-PEI-UENVs formulation was 253.62 nm, with a zeta potential of -23.24 mV, 85.64% entrapment, and 87.20% cumulative release (24 h). ES coating hindered the rapid release of CLX under acidic milieu (stomach and early small intestine) and showed extended release in the colon section. In colonic environments, the ES coating layer was removed due to high pH, and the charge on the nanovesicular corona was shifted from negative to positive. Besides, a pharmacokinetics study revealed that CLX-ES-PEI-UENVs had superior oral bioavailability by 2.13-fold compared with CLX suspension. Collectively, these findings implied that CLX-ES-PEI-UENVs could be a promising colorectal-targeted nanoplatform for effective tumor management through up-regulation of the Wnt/β-catenin pathway.

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Indication	Highest Phase	Country/Location	Organization	Date
Digestive System Neoplasms	Preclinical	-	Roche Holdings, Inc.	05 Jun 2023
Digestive System Neoplasms	Preclinical	-	Cytosinlab Pharmaceutical Technology Co., Ltd.Startup	05 Jun 2023

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