Erythropoietin in the Locus coeruleus attenuates the ventilatory response to CO2 in rats

Abstract

The Locus coeruleus (LC) is a pontine area that contributes to the CO/pH chemosensitivity. LC cells express erythropoietin (Epo) receptors (EpoR), and Epo in the brainstem is a potent normoxic and hypoxic respiratory stimulant. However, a recent study showed that the intra-cisternal injection (ICI) of Epo antagonist does not alter the hypercapnic ventilatory response in mice. As ICI leads to a widespread dispersal of the product throughout the brainstem, in this work we evaluated the specific impact of Epo in the LC-mediated ventilatory response to CO (by whole body plethysmography) in juvenile male Wistar rats. Normocapnic and hypercapnic ventilation were evaluated before and after unilateral microinjection of Epo (1ng/100nL) into the LC. To evaluate the long-term effect of Epo, the HcVR was re-evaluated 24h later. Our results show that Epo attenuates the hypercapnic ventilation. We conclude that Epo in the LC tunes the hypercapnia-induced hyperpnea.

The Vitamin D, IL-6 and the eGFR Markers a Possible Way to Elucidate the Lung–Heart–Kidney Cross-Talk in COVID-19 Disease: A Foregone Conclusion

“…Therefore, a forthcoming therapy would advocate the rationale use of vitamin D. However, based on our clinical experience, we propose that this strategic approach would include a combined approach that allow us to act on the immune system, on the respiratory system, and on the nervous system, contributing to a better respiration via brainstem centers and phrenic nerve. For instance, the use of vitamin D, vitamin K, and erythropoietin (EPO) showed to modulate the ventilator response in the locus coeruleus to CO 2 in rats, positively adjusting the hypercapnia-induced hyperpnoea [ 3 , 40 , 41 , 42 ]. Vitamin D was shown to mediate the intracellular oxidative stress, increasing superoxide dismutase 1 and 2 (SOD1-2) (as seen in cancer hypoxic cancer microenvironment).…”

“…The EPO-mediated regulation of the central respiratory command, which involves both MEK1/2 and PI3K pathways, was seen as crucial for phrenic motor facilitation, suggestive of a spinal plasticity in respiratory motor control in prolonged poor oxygen condition. On the other hand, the vitamin K not only allows the activation of D via the hydroxylation mechanism, but also prevents cell mitochondrial dysfunction, restores oxidative phosphorylation and the aerobic glycolysis, and eventually supports the cleansing hypoxic microenvironment typical of tissues analyzed in cancers and lung and cardiovascular necrosis due to massive thromboembolism [ 3 , 4 , 5 , 41 , 43 , 44 , 45 , 46 , 47 , 48 ] ( Figure 7 ).…”

Erythropoietin as candidate for supportive treatment of severe COVID-19

“…For instance, EPO in the locus coeruleus attenuates the ventilatory response to CO 2 in rats, i.e. it tunes the hypercapnia-induced hyperpnoea (Silva et al 2017). EPO-mediated regulation of the central respiratory command involves MEK1/2 and PI3K (Caravagna and Soliz 2015).…”

In Transgenic Erythropoietin Deficient Mice, an Increase in Respiratory Response to Hypercapnia Parallels Abnormal Distribution of CO2/H+-Activated Cells in the Medulla Oblongata

“…Indeed, absence or drastic reduction of the CO 2 /H + sensitivity leads to central hypoventilation syndromes such as Ondine’s curse ( Weese-Mayer et al, 2010 ; Ramanantsoa et al, 2011 ). Conclusions of the few studies conducted on this topic do not reach consensus ( Ballot et al, 2015b ; Khemiri et al, 2016 ; Laouafa et al, 2016 , 2017 ; Menuet et al, 2016 ; Silva et al, 2017 ). Menuet and collaborators reported a decrease in HcVR in adult transgenic mice over-expressing brain Epo, suggesting that an excess of Epo limits the CO 2 /H + respiratory response ( Menuet et al, 2016 ).…”