GHRH Antagonists Protect Against Hydrogen Peroxide-Induced Breakdown of Brain Microvascular Endothelium Integrity

Abstract

Growth hormone releasing hormone is a hypothalamic neuropeptide, which regulates the release of growth hormone from the anterior pituitary gland. Growth hormone releasing hormone antagonists are anticancer agents, associated with strong anti-inflammatory activities. In the present study, we investigated the effects of the GHRH antagonist MIA-602 in the integrity of the brain microvascular endothelium in vitro. Our observations suggest that MIA-602 protects against the H2O2-induced breakdown of the brain endothelium and enhances its integrity by inducing P53, deactivating cofilin, and suppressing the RhoA inflammatory pathway. Thus, GHRH antagonists may offer an exciting possibility for the treatment of pathologies related to the blood brain barrier dysfunction, including the Parkinson’s and Alzheimer’s diseases.

P53 deficiency potentiates LPS-Induced acute lung injury in vivo

“…P53 induction due to Tunicamycin revealed the negative regulation of APE1/Ref1 by this transcription factor ( Uddin et al., 2019a ). Indeed, P53 may hold the capacity to mediate the supportive effects of UPR in lung endothelial barrier function ( Barabutis, 2019b ); in the context of Hsp90 inhibition ( Barabutis, 2020c ; Kubra et al., 2020b ) and the effects of GHRH antagonists in the vasculature ( Uddin et al., 2019b ; Barabutis et al., 2020 ). Hsp90 inhibition in the lungs was not associated to lethal effects, as it was indicated by cellular viability measurements ( Uddin et al., 2020 ), partially due to the fact that the activated (inflamed) Hsp90 presents a higher affinity for Hsp90 inhibitors compared to normal cells ( Barabutis, 2020c ).…”

“…The upregulation of P53 due to Hsp90 inhibition contributed towards the protective role of those compounds in the inflamed lungs ( Barabutis et al., 2015 , 2019 bib_Barabutis_et_al_2019 bib_Barabutis_et_al_2015 ). Interestingly, growth hormone-releasing hormone (GHRH) antagonists have also been reported to exert anti-inflammatory activities in normal and cancer lungs partially due to P53 induction ( Barabutis, 2020d ; Uddin et al., 2019b ; Barabutis et al., 2020 ).…”

P53 in the impaired lungs

“…UPR directly regulates the expression levels of P53 in the lung endothelium [ 60 ]. Recent studies suggested that the endothelial barrier enhancing effects of Hsp90 inhibitors and growth hormone-releasing hormone (GHRH) antagonists might be associated with UPR mediated P53 expression [ [69] , [70] , [71] ]. GHRH antagonist induces the expression of P53 and suppresses the major inflammatory extracellular signal-regulated kinases 1/2 (ERK1/2), Janus kinase 2 (JAK2), and signal transducer and activator of transcription 3 (STAT3) pathways in lung microvascular endothelial cells which express GHRH receptors [ 37 ].…”

Suppression of reactive oxygen species in endothelial cells by an antagonist of growth hormone‐releasing hormone

“…[32] In the context of endothelial biology, we introduced the ability of GHRHAnt to strengthen the endothelial barrier integrity of lung cells [6] and brain microvascular endothelial cells. [8] The effects of GHRHAnt and GHRH in the ROS generation of BPAEC, hCMEC/D3, and HMVEC-L cells were unknown. It was previously reported in cancers that GHRH antagonists suppress the generation of ROS, cyclooxygenase 2 (COX-2), and cytochrome c oxidase IV (COX-IV).…”

“…[6,7] The anti-inflammatory effects of GHRHAnt also occurred in human cerebral microvascular endothelial cells (hCMEC/D3), which express GHRH-Rs. [8] MIA-602 (GHRH antagonist) suppressed the hydrogen peroxide (H 2 O 2 )-induced blood-brain barrier (BBB) breakdown and supported the transendothelial resistance of those cells.…”