Red wine polyphenols and swallowing reflex in dysphagia

Dear Editor, Aspiration is the most life-threatening medical problem followed by dysphagia, which is experienced by approximately 50% of patients in nursing homes.1,2 Dysphagia is caused not only by a motor impairment, but also by an impairment of the sensory (neural) component of swallowing; that is, an impairment of the swallowing reflex.3 Triggering of the swallowing reflex can be accelerated if swallowed material is warmed up, even in dysphagic patients.4 Furthermore, it has been reported that capsaicin and capsiate, transient receptor potential vanilloid 1 (TRPV1) agonists, accelerated the swallowing reflex in patients with aspiration pneumonia.5,6 Because a hot sensation is sensitized through TRPV1,7 the results show that TRPV1 stimulation, together with pharyngeal food stimuli, accelerate the swallowing reflex in the elderly. Twenty-five hundred years before the beneficial effect of red wine in reducing the incidence of cardiovascular disease became widely known as the "French Paradox",8 Hippocrates, the Greek physician, had already used red wine not only as a medicine for a variety of ailments, such as diarrhea, difficult childbirth and lethargy, but also as a disinfectant, an aid to digestion, a diuretic and as a carrier of other drugs. Here, we report our successful use of red wine as a treatment for dysphagia and also an examination of the cellular mechanism from which this beneficial effect of red wine polyphenolic compounds (RWPC) is derived. We assessed the swallowing reflex in all residents (mean age 84 years [SD 7], n = 42) in a nursing home located in a suburb of Sendai, Japan. Written informed consent was obtained from every subject. The swallowing reflex was provoked by a 1 mL of bolus solution injected into the pharynx through a nasal catheter. The swallowing reflex was quantified from the injection to the onset of swallowing.4–6 In the nursing home, 14 elderly patients with episodes of dysphagia (mean age 86 years [SD 6]) suffered from swallowing reflex impairment (latency >5 s with distilled water).9 Computed tomography showed various degrees of cerebral atrophy and lacunar infarction in these patients. We assessed the swallowing reflex with various stimuli in these 14 elderly patients. Distilled water, red and white wines without alcohol, and red grape juice were applied at intervals of 2 min in a double-blind and randomized manner. A red wine made from Cabernet Sauvignon grapes and a white wine made from Koshu grapes were evaporated under reduced pressure (40°C) to half the original volume in order to remove the ethanol. Red grape juice made from Concord red grapes was not concentrated. The latency of response to red wine was significantly shorter than those of vehicle, white wine and red grape juice (P < 0.001 versus the others by anova with a post-hoc application of Fisher's LSD test; Fig. 1a). Then, we randomly selected seven subjects from the 14 subjects by the envelope method. To confirm the effect of RWPC on improving the latency, we applied purified RWPC to these seven subjects in a double-blind manner. RWPC extracted from Cabernet Sauvignon grapes (>90% purity) was quantified by the Folin–Ciocalteu method (83.3% Gallic acid equivalent). RWPC was dissolved in distilled water at various concentrations. The latency decreased as a function of RWPC (Fig. 1b), suggesting that RWPC facilitated the swallowing reflex in these elderly patients. (a) Effect of red wine, white wine and red grape juice on the swallowing reflex in elderly patients with dysphagia. *P < 0.001 versus the others by anova with a post-hoc application of Fisher's LSD test. (b) The effect of red wine and various concentrations of red wine polyphenolic compounds (RWPC) on the latency of the swallowing reflex in elderly patients with dysphagia. Columns and points are mean (SD). (c) Effect of RWPC and capsazepine on capsaicin-induced inward currents in mouse dorsal root ganglion neurons. Reagents were applied during the period indicated by the horizontal bars. Data are representative of six independent experiments. The rapid effect of RWPC suggests the existence of a neural modification of the swallowing reflex by RWPC. Because the swallowing reflex is mediated by a capsaicin-sensitive neural pathway,5,6 we postulated that the molecular basis for the effect of RWPC is at least partly attributed to activation of TRPV1, the capsaicin receptor. Therefore, we investigated the direct interaction of RWPC and the capsaicin-induced response using mouse dorsal root ganglion (DRG) neurons with TRPV1 as a model system. DRG neurons of adult ddY mice (8 weeks) were enzymatically dissociated in Leibovitz's L-15 Medium (LLM) supplemented by 3 mg/mL collagenase medium at 37°C for 20–30 min. Using a conventional whole-cell patch clamp configuration, mouse DRG neurons with small somata (soma diameter <30 µm) were voltage clamped at −60 mV. The external solution was composed of (in mmol): NaCl, 140; KCl, 5.4; MgCl2, 2; CaCl2, 1; D-glucose, 5; Tris/HCl, 5; pH was adjusted to 7.35. The pipette solution was composed of (in mmol): K-glutamate, 145; MgCl2, 2; Tris/HCl, 5; pH was adjusted to 7.2. The recording pipette resistance was 3–5 MΩ when filled with the pipette solution. Reagents were delivered from a nearby application pipette by weak continuous pressure. All experiments were carried out at room temperature. RWPC dramatically enhanced the current induced by capsaicin (6.8 times [SD 2.0], n = 6), whereas RWPC alone never induced any current (Fig. 1c). Capsazepine, a TRPV1 antagonist,7 completely inhibited the responses by both capsaicin and the combination of capsaicin and RWPC. These results suggest that RWPC enhanced the swallowing reflex by potentiating TRPV1. To the best of our knowledge, this is the first time the direct effect of RWPC on neurotransmissions has been shown. In the pharynx, tonic activation of TRPV1 could be caused by endogeneous activators and local temperature,7 which might be enhanced by RWPC. The precise molecular mechanism by which RWPC facilitates the activation of TRPV1 needs to be elucidated. The present study suggests not only another benefit of consuming red wine with meals, but also the possible use of TRPV1 activators and/or potentiators5 as remedies for dysphagia with neural dysfunction.