Comment on Melatonin as a potential adjuvant treatment for COVID-19.

We read the interesting proposal of Zhang et al. in the paper entitled COVID-19: Melatonin as a potential adjuvant treatment, recently published in Life Sciences [1] that summarizes clearly the essential pleiotropic effects of melatonin in several pathologies, regarding its antioxidant, anti-inflammatory and immunomodulatory properties.

Considering the urgency of finding an efficient treatment to the current COVID-19 pandemic, we would like to highlight the relevance of this manuscript and add more data to support the use of melatonin in respiratory diseases, particularly due to its vasoactive properties. On the last years we have studied the effects of melatonin as a treatment for the pulmonary arterial hypertension of the newborn (PAHN). Our results show the antioxidant properties of melatonin and support its pulmonary vasodilator effects. The effects of melatonin appear to be very fast since our findings describe that at the first day of oral administration (1 mg/kg), melatonin reduced in 5 mmHg the pulmonary arterial pressure in neonatal lambs born under hypoxia, without side effects such as systemic hypotension or sleepiness [2,3]. Additionally, with either 7 or 21 days of treatment, small pulmonary arteries showed improved endothelial function ex vivo with a greater vasodilator capacity [2,3]. The latter was associated with increased nitric oxide -dependent and -independent vasodilator functions. Interestingly, one of the nitric oxide independent affected mechanisms, was the enhanced expression of the prostacyclin vasodilator pathway [3,4]. The aforementioned findings were also associated with increased expression and/or activity of the endogenous antioxidant enzymes, superoxide dismutase and catalase, an enhanced plasma antioxidant capacity and a marked decreased in pulmonary oxidative stress markers [2,3]. Furthermore, these effects were associated with a diminished vascular remodeling of the pulmonary circulation after 1 week of treatment [5].

The vasodilatory effects of melatonin are in part a consequence of the antioxidant and anti-inflammatory effects that reverberates on an improved vascular structure and function, but as well they can be due to its direct effects as a vasodilator (Fig. 1 , unpublished data). Although it gives a mild ex vivo vasodilation, the global in vivo effects of melatonin offer a better pulmonary function.

Fig. 1

Vasodilator effect of melatonin on neonatal pulmonary arteries. Cumulative concentration response to melatonin (Mel) of small pulmonary arteries from PAHN lambs (n = 29).

Values are shown as mean ± SEM.

Melatonin pulmonary effects have also been tested in adult animals. For instance, Maarman et al. [6] demonstrated that melatonin improved right ventricular function and reduced cardiac remodeling in pulmonary hypertensive (PAH) rats, suggesting a pressure decrease in the pulmonary artery. In addition, melatonin has been tested in rats with chronic obstructive pulmonary disease [7], where it attenuated pulmonary hypertension by antagonizing the oxidative injury and restore nitric oxide production. Moreover, the anti-inflammatory effects of melatonin restore vascular homeostasis in PAH mice and improve endothelial integrity [8]. Finally, the direct vasodilator effects of melatonin in pulmonary arteries and vein on adult animals (sheep) have also been reported [9].

Although there are no studies that evaluate the vasoactive properties of melatonin in humans, the evidence of its beneficial effects in animals is convincing.

Based on the similarities of COVID-19 with hypoxic pulmonary hypertension and edema [10], melatonin may be a possible alternative as it may aid to promote pulmonary vascular protection. In conclusion, the proposal by Zhang et al. [1] is supported by several scientific data, and given the global medical urgency, melatonin sounds as a sensible adjuvant treatment.