Danegaptide Enhances Astrocyte Gap Junctional Coupling and Reduces Ischemic Reperfusion Brain Injury in Mice

Abstract

Ischemic stroke is a complex and devastating event characterized by cell death resulting from a transient or permanent arterial occlusion. Astrocytic connexin43 (Cx43) gap junction (GJ) proteins have been reported to impact neuronal survival in ischemic conditions. Consequently, Cx43 could be a potential target for therapeutic approaches to stroke. We examined the effect of danegaptide (ZP1609), an antiarrhythmic dipeptide that specifically enhances GJ conductance, in two different rodent stroke models. In this study, danegaptide increased astrocytic Cx43 coupling with no significant effects on Cx43 hemichannel activity, in vitro. Using matrix-assisted laser desorption ionization imaging mass spectrometry (MALDI IMS) the presence of danegaptide within brain tissue sections were detected one hour after reperfusion indicating successful transport of the dipeptide across the blood brain barrier. Furthermore, administration of danegaptide in a novel mouse brain ischemia/reperfusion model showed significant decrease in infarct volume. Taken together, this study provides evidence for the therapeutic potential of danegaptide in ischemia/reperfusion stroke.

Astrocytic Connexin43 Channels as Candidate Targets in Epilepsy Treatment

“…Zealand Pharma, Denmark, possesses several libraries of GJ modulating compounds, including a library of Cx43 CT interacting compounds and peptides (e.g., danegaptide, a GJ enhancer with oral bioavailability [ 222 ]); and focus on accelerated dermal wound healing. Noteworthy, danegaptide increases astrocytic Cx43 coupling with no significant effects on Cx43 HC activity in vitro and decreases infarct volume in a mouse brain ischemia/reperfusion model [ 223 ]. Interestingly, CoDa Therapeutics Inc., USA and New Zealand, has Cx channel modulators in clinical development (chronic skin wounds, ocular disease), e.g., an antisense oligodeoxynucleotide (Nexagon ® ) that transiently downregulates Cx43 protein expression (e.g., thermoreversible gel for eye injuries [ 224 ]), an extracellular acting Cx43 peptidomimetic that can be delivered locally or systemically (Peptagon™ [ 225 ]) (Peptide5) and a small molecule for systemic or oral delivery (HCB1019).…”

Structural and Functional Remodeling of the Brain Vasculature Following Stroke

“…In brief, perivascular astrocytes increase the tightness of TJs (Lee et al, 2003), promote the expression and localization of endothelial transporters (McAllister et al, 2001) and induce the expression of enzymes associated with the metabolic endothelial barrier (Abbott et al, 2006). Astrocytes are critical to neuronal survival and repair, a large part of this function being mediated through gap junction proteins that connect astrocyte networks into a cooperative functional syncytium (De Bock et al, 2017;Laird et al, 2017;Freitas-Andrade et al, 2019;Freitas-Andrade et al, 2020).…”

Astrocyte Networks as Therapeutic Targets in Glaucomatous Neurodegeneration

“…Astrocyte swelling can decouple Cx43 gap junctions and disrupt cell to cell communication [81]. Pharmacologic enhancement of Cx43 gap junctional coupling between astrocytes is protective in stroke models, decreasing the overall volume of the infarcted region [82]. These studies suggest that Cx43 gap junctions are neuroprotective in stroke.…”

“…The Cx43 overexpression leading to death of neighboring glioma cells may have been a cell-type specific effect, however. In studies involving a variety of animal models of neurologic diseases, increasing gap junctional coupling is associated with decreased neuronal death and improved histologic measures [82,109].…”