Suppression of cytokine storm and associated inflammatory mediators by salicylaldehyde derivative of pregabalin: An innovative perspective for alleviating airway inflammation and lung remodeling

Abstract

Objectives: Pregsal is a novel salicylaldehyde derivative of pregabalin, a structural analogue of gamma-aminobutyric acid approved for treating epilepsy, neuropathic pain and diabetic peripheral neuropathy but not trialled to date for airway inflammatory diseases. The current study evaluated a preclinical model of airway inflammation and lung remodelling induced by ovalbumin (OVA) for the potential benefits of pregsal. Methods: Wistar rats (N = 10 per group) were divided into four groups sensitized intraperitoneally (i.p.) and then challenged intranasally with OVA, with or without i.p. pregsal (100 mg/kg) or methylprednisolone (MP) (15 mg/kg). Airway inflammation was assessed through inflammatory cell infiltration in the lungs, delayed-type hypersensitivity (DTH), and nitric oxide (NO) level using bronchoalveolar lavage fluid (BALF) and lung tissues. The mRNA expression levels of a panel of inflammatory mediators (cytokines, chemokine and growth factors) in the lungs were measured by the reverse transcription-polymerase chain reaction (RT-PCR). Systemic inflammation was assessed using splenocyte proliferation and total and differential leucocyte count in blood and BALF. Lung remodelling was assessed by wet/dry lung weight ratio, epithelial thickness and goblet cell hyperplasia, hydroxyproline and osteopontin (OPN) levels, arginase activity in lungs, and ornithine decarboxylase (ODC) activity in lung mitochondria. Results: Pregsal significantly alleviated the total and differential leucocyte count in blood and BALF, NO production in BALF and recruitment of inflammatory cells in the lungs. It suppressed the T-cell response and attenuated the OVA-induced lung epithelial thickness, goblet cell hyperplasia, wet/dry lung weight ratio, hydroxyproline and OPN levels, arginase and ODC activity. Levels of inflammatory mediators were also downregulated in the lungs by pregsal. Conclusions: The key findings of this study indicate that pregsal significantly reduces the development of airway inflammation and lung remodelling by suppression of cytokine storm and associated inflammatory mediators.

Keywords

• Pregabalin
• Salicylaldehyde
• Airway inflammation
• Lung remodelling
• Inflammatory mediators