Impact of poly-arginine peptides R18D and R18 on alteplase and tenecteplase thrombolysis in vitro, and neuroprotective stability to proteolysis

Abstract

The poly-arginine peptides R18D and R18 represent novel potential neuroprotective treatments for acute ischaemic stroke. Here we examined whether R18D and R18 had any significant effects on the thrombolytic activity of alteplase (tPA) and tenecteplase (TNK) on clots formed from whole blood in an in vitro thrombolysis plate assay. R18D and R18 were examined at concentrations of 0.25, 0.5, 1, 2, 4, 8 and 16 µM during the 1-h thrombolytic assay. We also included the well-characterised neuroprotective NA-1 peptide as a control. R18D, R18 and NA-1 all reduced tPA or TNK percentage clot lysis by 0–9.35%, 0–3.44% and 0–4.8%, respectively. R18D, R18 and NA-1 had a modest and variable effect on the lag time, increasing the time to the commencement of thrombolysis by 0–9.9 min, 0–5.53 min and 0–7.16 min, respectively. Lastly, R18 and NA-1 appeared to increase the maximal activity of the thrombolysis reaction. In addition, the in vitro anti-excitotoxic neuroprotective efficacy of R18D and R18 was not affected by pre-incubation for 1–2 h or overnight with tPA or TNK, whereas only R18D retained high anti-excitotoxic neuroprotective efficacy when pre-incubated in a synthetic trypsin (TrypLE Express). The present in vitro findings suggest that neither R18D or R18 when co-administered with the thrombolytic inducing agents tPA or TNK are likely to have a significant impact when used clinically during clot thrombolysis and confirm the superior proteolytic stability of the R18D peptide.

Intracalvariosseous injection bypasses the blood-brain barrier as a novel drug delivery approach for pre-clinical and clinical trials in stroke

“…NA-1(a polypeptide, C 105 H 188 N 42 O 30 , molecular weight: 2518.88) and Y-3 (a chemical compound, C 24 H 27 Cl 2 NO 4 , molecular weight: 463.13) are two different types PSD95 inhibitors. Preclinical studies have demonstrated that administering NA1/Y-3 during the acute stage of stroke can minimize temporary and permanent damage 21-24 . After 24 hours of administration, the brain tissue was stained with TTC to label the area of brain infarction.…”

“…Preclinical studies have demonstrated that administering NA1/Y-3 during the acute stage of stroke can minimize temporary and permanent damage [21][22][23][24] . After 24 hours of administration, the brain tissue was stained with TTC to label the area of brain infarction.…”

Effect of co-administered dalteparin sodium and alteplase on clinical and biochemical parameters in postpartum patients with lower extremity deep venous thrombosis

“…Compared with general heparin, dalteparin sodium injection is more effective in antithrombotic activity and in inhibiting coagulation factor Xa [12]. Its benefits are mainly due to its antithrombotic effect which results from the application of the fibrinolytic system or the function of vessel wall [13]. Hence, this study was aimed to further evaluate the efficacy of combining the above two drugs for the management of lower extremity deep venous thrombosis.…”

Neuroprotective Peptides and New Strategies for Ischemic Stroke Drug Discoveries

“…Meloni et al are actively studying peptides of this class in vitro for the activity of the thrombolytic agents alteplase (tPA) and tenecteplase (TNK). In one of the latest studies by the Meloni team, it was shown that arginine-rich peptides R18D (polyarginine-18, D-isomer) and R18 (polyarginine-18, L-isomer) (Table 1), when co-administered with thrombolytic agents, increase the maximum activity of the thrombolysis reaction while maintaining these neuroprotective properties [58]. Thus, the polyarginine peptides R18D and R18 represent new potential neuroprotective agents for the treatment of acute IS, the administration of which can have a significant effect in clinical use during clot thrombolysis.…”