Hesperetin, a Selective Phosphodiesterase 4 Inhibitor, Effectively Suppresses Ovalbumin-Induced Airway Hyperresponsiveness without Influencing Xylazine/Ketamine-Induced Anesthesia

Abstract

Hesperetin, a selective phosphodiesterase (PDE)4 inhibitor, is present in the traditional Chinese medicine, “Chen Pi.” Therefore, we were interested in investigating its effects on ovalbumin- (OVA-) induced airway hyperresponsiveness, and clarifying its rationale for ameliorating asthma and chronic obstructive pulmonary disease (COPD). Hesperetin was revealed to have a therapeutic (PDE4H/PDE4L) ratio of >11. Hesperetin (10 ~ 30 μmol/kg, intraperitoneally (i.p.)) dose-dependently and significantly attenuated the airway hyperresponsiveness induced by methacholine. It also significantly suppressed the increases in total inflammatory cells, macrophages, lymphocytes, neutrophils, and eosinophils, and levels of cytokines, including interleukin (IL)-2, IL-4, IL-5, interferon-γ, and tumor necrosis factor-α in bronchoalveolar lavage fluid (BALF). It dose-dependently and significantly suppressed total and OVA-specific immunoglobulin E levels in the BALF and serum. However, hesperetin did not influence xylazine/ketamine-induced anesthesia, suggesting that hesperetin has few or no emetic effects. In conclusion, the rationales for ameliorating allergic asthma and COPD by hesperetin are anti-inflammation, immunoregulation, and bronchodilation.

Effects of the Flavanone combination Hesperetin‐Naringenin, and Orange and Grapefruit Juices, on Airway inflammation and Remodeling in a murine asthma model

“…or 3–30 µmol/kg o.p.) reduced all types of inflammatory cells and cytokines, including IL‐5 and tumor necrosis factor‐α (TNF‐α) levels in BAL fluid of methacholine‐sensitized mice (Yang et al ., ; Shih et al ., ). Our study revealed that hesperetin–naringenin, orange, and grapefruit juices each could significantly reduce infiltration of inflammatory cells to airway and mucus plug formation.…”

The role of phosphodiesterase-5 inhibitors in prostatic inflammation: a review

“…Similarly, vardenafil mimics the effect of NO by increasing GMPc levels with a subsequent reduction of histamine release and mast-cell-mediated allergic reactions [ 54 ]. Other studies reported that selective PDE4 inhibitors suppressed hematological and immunological markers of inflammation and were also effective in reducing specific airway resistance [ 55 , 56 ].…”

Hesperetin improves diabetic coronary arterial vasomotor responsiveness by upregulating myocyte voltage‑gated K+ channels

“…HSP contributes to the protective effects of orange juice to the vascular system (8,9). It was reported that HSP possesses antioxidant (10)(11)(12), hypolipidemic (13), anti-inflammatory (14), neuroprotective (15), cardioprotective (16), hypotensive (17) and anti-coagulation (18) properties, in addition to being effective in attenuating airway hypersensitivity (8,19). HSP has been demonstrated to exert vasculoprotective and anti-angiogenic effects in diabetic rats (20), in addition to inhibiting rat aortic smooth muscle cell proliferation (21).…”

“…Suggested mechanisms include the enhancement of endothelial nitric oxide production (23), suppression of reactive oxygen species production (24), inhibition of phosphodiesterases (22) and activation of tetraethylammonium-sensitive K + channels (25). Review of these studies (19,(22)(23)(24)(25) suggests that the effects mediated by HSP are likely to involve multiple targets, where each mechanism may contribute additively to the eventual vasculoprotective effect downstream. A previous study showed that HSP relaxes rat coronary arteries (RCAs) isolated from healthy rats through, at least in part, an increase of myocyte Kv channel currents (26).…”