Vasorelaxing cell permeant phosphopeptide mimetics for subarachnoid hemorrhage.
Eur J Pharmacol
; 900: 174038, 2021 Jun 05.
Article
in En
| MEDLINE
| ID: mdl-33737008
ABSTRACT
Subarachnoid hemorrhage (SAH) due to rupture of an intracranial aneurysm leads to vasospasm resulting in delayed cerebral ischemia. Therapeutic options are currently limited to hemodynamic optimization and nimodipine, which have marginal clinical efficacy. Nitric oxide (NO) modulates cerebral blood flow through activation of the cGMP-Protein Kinase G (PKG) pathway. Our hypothesis is that SAH results in downregulation of signaling components in the NO-PKG pathway which could explain why treatments for vasospasm targeting this pathway lack efficacy and that treatment with a cell permeant phosphopeptide mimetic of downstream effector prevents delayed vasospasm after SAH. Using a rat endovascular perforation model, reduced levels of NO-PKG pathway molecules were confirmed. Additionally, it was determined that expression and phosphorylation of a PKG substrate Vasodilator-stimulated phosphoprotein (VASP) was downregulated. A family of cell permeant phosphomimetic of VASP (VP) was wasdesigned and shown to have vasorelaxing property that is synergistic with nimodipine in intact vascular tissuesex vivo. Hence, treatment targeting the downstream effector of the NO signaling pathway, VASP, may bypass receptors and signaling elements leading to vasorelaxation and that treatment with VP can be explored as a therapeutic strategy for SAH induced vasospasm and ameliorate neurological deficits.
Key words
Full text:
1
Database:
MEDLINE
Therapeutic Methods and Therapies TCIM:
Terapias_biologicas
/
Aromoterapia
Main subject:
Phosphopeptides
/
Subarachnoid Hemorrhage
/
Vasodilator Agents
/
Vasospasm, Intracranial
Language:
En
Journal:
Eur J Pharmacol
Year:
2021
Type:
Article
Affiliation country:
United States