Bromocriptine-QR Therapy Reduces Sympathetic Tone and Ameliorates a Pro-Oxidative/Pro-Inflammatory Phenotype in Peripheral Blood Mononuclear Cells and Plasma of Type 2 Diabetes Subjects

Abstract

Bromocriptine-QR is a sympatholytic dopamine D2 agonist for the treatment of type 2 diabetes that has demonstrated rapid (within 1 year) substantial reductions in adverse cardiovascular events in this population by as yet incompletely delineated mechanisms. However, a chronic state of elevated sympathetic nervous system activity and central hypodopaminergic function has been demonstrated to potentiate an immune system pro-oxidative/pro-inflammatory condition and this immune phenotype is known to contribute significantly to the advancement of cardiovascular disease (CVD). Therefore, the possibility exists that bromocriptine-QR therapy may reduce adverse cardiovascular events in type 2 diabetes subjects via attenuation of this underlying chronic pro-oxidative/pro-inflammatory state. The present study was undertaken to assess the impact of bromocriptine-QR on a wide range of immune pro-oxidative/pro-inflammatory biochemical pathways and genes known to be operative in the genesis and progression of CVD. Inflammatory peripheral blood mononuclear cell biology is both a significant contributor to cardiovascular disease and also a marker of the body’s systemic pro-inflammatory status. Therefore, this study investigated the effects of 4-month circadian-timed (within 2 h of waking in the morning) bromocriptine-QR therapy (3.2 mg/day) in type 2 diabetes subjects whose glycemia was not optimally controlled on the glucagon-like peptide 1 receptor agonist on (i) gene expression status (via qPCR) of a wide array of mononuclear cell pro-oxidative/pro-inflammatory genes known to participate in the genesis and progression of CVD (OXR1, NRF2, NQO1, SOD1, SOD2, CAT, GSR, GPX1, GPX4, GCH1, HMOX1, BiP, EIF2α, ATF4, PERK, XBP1, ATF6, CHOP, GSK3β, NFkB, TXNIP, PIN1, BECN1, TLR2, TLR4, TLR10, MAPK8, NLRP3, CCR2, GCR, L-selectin, VCAM1, ICAM1) and (ii) humoral measures of sympathetic tone (norepinephrine and normetanephrine), whole-body oxidative stress (nitrotyrosine, TBARS), and pro-inflammatory factors (IL-1β, IL-6, IL-18, MCP-1, prolactin, C-reactive protein [CRP]). Relative to pre-treatment status, 4 months of bromocriptine-QR therapy resulted in significant reductions of mRNA levels in PBMC endoplasmic reticulum stress-unfolded protein response effectors [GRP78/BiP (34%), EIF2α (32%), ATF4 (29%), XBP1 (25%), PIN1 (14%), BECN1 (23%)], oxidative stress response proteins [OXR1 (31%), NRF2 (32%), NQO1 (39%), SOD1 (52%), CAT (26%), GPX1 (33%), GPX4 (31%), GCH1 (30%), HMOX1 (40%)], mRNA levels of TLR pro-inflammatory pathway proteins [TLR2 (46%), TLR4 (20%), GSK3β (19%), NFkB (33%), TXNIP (18%), NLRP3 (32%), CCR2 (24%), GCR (28%)], mRNA levels of pro-inflammatory cellular receptor proteins CCR2 and GCR by 24% and 28%, and adhesion molecule proteins L-selectin (35%) and VCAM1 (24%). Relative to baseline, bromocriptine-QR therapy also significantly reduced plasma levels of norepinephrine and normetanephrine by 33% and 22%, respectively, plasma pro-oxidative markers nitrotyrosine and TBARS by 13% and 10%, respectively, and pro-inflammatory factors IL-18, MCP1, IL-1β, prolactin, and CRP by 21%,13%, 12%, 42%, and 45%, respectively. These findings suggest a unique role for circadian-timed bromocriptine-QR sympatholytic dopamine agonist therapy in reducing systemic low-grade sterile inflammation to thereby reduce cardiovascular disease risk.

Macrophage CREBZF Orchestrates Inflammatory Response to Potentiate Insulin Resistance and Type 2 Diabetes

“…[ 36 ] The precise mechanisms underlying the antidiabetic effects of bromocriptine remain unclear. In addition, bromocriptine treatment shows reduced low‐grade systemic inflammation in clinical trials or preclinical studies, [ 37 , 38 ] but the underlying mechanisms are largely unknown. Our findings support CREBZF acts as a new mechanism of bromocriptine treatment.…”

The molecular mechanisms of peptidyl-prolyl cis/trans isomerase Pin1 and its relevance to kidney disease

“…Francesco et al demonstrated that Pin1 exacerbates hyperglycemia-induced reactive oxygen species (ROS) production and mitochondrial oxidative stress in human aortic endothelial cells (HAECs) through the translocation of p66Shc, a prooxidant adaptor ( Pinton et al, 2007 ; Paneni et al, 2015 ). Suppression of Pin1, through gene silencing, Juglone treatment, Vitamin D receptor (VDR) agonists, or bromocriptine-QR, alleviates chronic oxidative stress and vascular dysfunction induced by diabetes ( Paneni et al, 2015 ; Costantino et al, 2016 ; Zhang et al, 2018 ; Cincotta et al, 2022 ). Similar effects of Pin1 on p66Shc translocation and ROS accumulation were observed in intestinal ischemia/reperfusion (I/R) injury and hippocampal neuronal oxidative stress ( Zhu et al, 2014 ; Feng et al, 2017 ).…”

The interplay between prolactin and cardiovascular disease

“…A bromocriptine quick-release formulation was designed as a glucose-lowering drug and approved for clinical use by the FDA in 2009 (commercialized as CYCLOSET ® ). Recent evidence indicates that circadian-timed bromocriptine quick-release treatment reduces the sympathetic tone and improves systemic low-grade inflammation in type 2 diabetes subjects ( 108 ). Thus, these findings help to explain how circadian-timed DA administration is able to improve the metabolic status of patients and reduce the risk of cardiovascular diseases, independently of their effects on prolactin secretion.…”