Adjunctive Therapy Approaches for Ischemic Stroke: Innovations to Expand Time Window of Treatment

Abstract

Tissue plasminogen activator (tPA) thrombolysis remains the gold standard treatment for ischemic stroke. A time-constrained therapeutic window, with the drug to be given within 4.5 h after stroke onset, and lethal side effects associated with delayed treatment, most notably hemorrhagic transformation (HT), limit the clinical use of tPA. Co-administering tPA with other agents, including drug or non-drug interventions, has been proposed as a practical strategy to address the limitations of tPA. Here, we discuss the pharmacological and non-drug approaches that were examined to mitigate the complications-especially HT-associated with delayed tPA treatment. The pharmacological treatments include those that preserve the blood-brain barrier (e.g., atovarstatin, batimastat, candesartan, cilostazol, fasudil, minocycline, etc.), enhance vascularization and protect the cerebrovasculature (e.g., coumarin derivate IMM-H004 and granulocyte-colony stimulating factor (G-CSF)), and exert their effects through other modes of action (e.g., oxygen transporters, ascorbic acid, etc.). The non-drug approaches include stem cell treatments and gas therapy with multi-pronged biological effects. Co-administering tPA with the abovementioned therapies showed promise in attenuating delayed tPA-induced side effects and stroke-induced neurological and behavioral deficits. Thus, adjunctive treatment approach is an innovative therapeutic modality that can address the limitations of tPA treatment and potentially expand the time window for ischemic stroke therapy.

Keywords: blood-brain barrier; hemorrhage; matrix metalloproteinase (MMP); stem cell; tissue plasminogen activator.

Figure 1

Proposed molecular targets of adjunctive treatments to enhance therapeutic window of tissue plasminogen activator (tPA) treatment. Acute stroke may cause injury to endothelial cells causing release of free radicals and pro-inflammatory cytokines. The signaling actions of tPA on the neurovascular unit may also increase blood-brain barrier (BBB) leakage, neurovascular cell death, and hemorrhagic transformation (HT). Moreover, the HT that ensues after delayed tPA treatment has been attributed to increased reperfusion and the effect of tPA on metalloproteinase (MMP) activity and other signaling pathways, including lipoprotein receptor-related protein (LRP), protease-activated receptor (PAR1), and PDGRF-α signaling. Ascorbic acid, normobaric oxygen (NBO) attenuates delayed tPA-induced complications in preclinical stroke models via inhibition of ROS production and BBB protection. Atovarstatin, minocycline, cilostazol, GM6001, fasudil, candesartan, bryostatin, and IMM-H004 reduces the HT by preserving the BBB through their actions on various MMPs and tight junction proteins. Granulocyte-colony stimulating factor (G-CSF) and IMM-H004 may reduce the HT by enhancing neurovascularization in addition to restoring BBB integrity. Imatinib reduces HT through the PDGRF-α receptor, while atovarstatin exerts its therapeutic benefits via inhibition of PAR1. Stem cells may also exert multi-pronged effects including BBB protection via its actions on various matrix metalloproteinases (MMPs). Abbreviations: EPC, endothelial progenitor cell; G-CSF, granulocyte-colony stimulating factor; HMGB1, high-mobility-group-box-1; ROS, reactive oxygen species; LRP, lipoprotein receptor-related protein; PAR1, protease-activated receptor; PDGFR-α, platelet-derived growth factor α-receptor (PDGFR-α); NBO, normobaric oxygen.