Cerebral collateral therapeutics in acute ischemic stroke: A randomized preclinical trial of four modulation strategies

Abstract

Cerebral collaterals are dynamically recruited after arterial occlusion and highly affect tissue outcome in acute ischemic stroke. We investigated the efficacy and safety of four pathophysiologically distinct strategies for acute modulation of collateral flow (collateral therapeutics) in the rat stroke model of transient middle cerebral artery (MCA) occlusion. A composed randomization design was used to assign rats (n = 118) to receive phenylephrine (induced hypertension), polygeline (intravascular volume load), acetazolamide (cerebral arteriolar vasodilation), head down tilt (HDT) 15° (cerebral blood flow diversion), or no treatment, starting 30 min after MCA occlusion. Compared to untreated animals, treatment with collateral therapeutics was associated with lower infarct volumes (62% relative mean difference; 51.57 mm3 absolute mean difference; p < 0.001) and higher chance of good functional outcome (OR 4.58, p < 0.001). Collateral therapeutics acutely increased cerebral perfusion in the medial (+40.8%; p < 0.001) and lateral (+19.2%; p = 0.016) MCA territory compared to pretreatment during MCA occlusion. Safety indicators were treatment-related mortality and cardiorespiratory effects. The highest efficacy and safety profile was observed for HDT. Our findings suggest that acute modulation of cerebral collaterals is feasible and provides a tissue-saving effect in the hyperacute phase of ischemic stroke prior to recanalization therapy.

Paradigm Change? Cardiac Output Better Associates with Cerebral Perfusion than Blood Pressure in Ischemic Stroke

“…A preclinical trial with rats supports the implication as change of MAP by administration of phenylephrine showed no effect on infarction size or final functional outcome ( 14 ). Furthermore, other studies have shown a CO-dependent increase of CP in patients with subarachnoid hemorrhage ( 15 ).…”

“…Furthermore, other studies have shown a CO-dependent increase of CP in patients with subarachnoid hemorrhage ( 15 ). Various experimental interventions intending a shift of blood volume lead to a significant higher perfusion in rats with MCA-occlusion ( 14 ) and humans ( 5 ). Also, volume substitution lead to CO changes leaving MAP levels constant and secondary increased CP ( 15 , 16 ).…”

Temporal remodeling of pial collaterals and functional deficits in a murine model of ischemic stroke

“…This steep pressure gradient causes fluid shear stress to activate the endothelium, invoking a cascade of events (Buschmann et al, 2003; Heil et al, 2006; Toriumi et al, 2009) that leads to the production of cytokines, growth factors and proteases which mediate the enlargement of the collateral vessels (Heil et al, 2002; Schaper and Scholz, 2003; Cai and Schaper, 2008; Li et al, 2016). Enhancement of retrograde cerebral blood flow through remodeled collateral vessels into the territory of the occluded artery mitigates cellular damage and helps maintain tissue preservation (Crisostomo et al, 1993; Beretta et al, 2015; Liu et al, 2015; Winship, 2015; Cuccione et al, 2016; van Seeters et al, 2016; Beretta et al, 2017). Thus, enhancing collateral growth and remodeling has become an attractive target for therapeutic intervention in patients suffering from an ischemic attack (Schierling et al, 2011; Chen et al, 2014; Nishijima et al, 2015).…”

Prostaglandin E1-Mediated Collateral Recruitment Is Delayed in a Neonatal Rat Stroke Model

“…The present study shows that a supply in PgE1 improved blood-flow redistribution during reflow after ischemia in the neonatal P7, and reduced the size of the lesion. Increased collateral recruitment can be obtained by the administration of drugs to increase vasodilation [ 3 , 10 ] or by facilitating the synthesis of vasodilators [ 7 ] leading to the rerouting of BF through the numerous native anastomoses in the cerebral vascular network. We had also previously demonstrated that an increase in collateral supply induced by exogenous NO-donors is beneficial during ischemia but deleterious during reflow due to an elevation in oxidative stress and nitrogen species synthesis [ 3 ].…”