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Int. J. Mol. Sci. 2017, 18(12), 2756; https://doi.org/10.3390/ijms18122756

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

1
Department of Pharmaceutical and Administrative Sciences, Loma Linda University School of Pharmacy, Loma Linda, CA 92350, USA
2
Department of Psychology, University of California, San Diego, CA 92093, USA
3
Department of Neuroscience, University of California, Riverside, CA 92521, USA
4
Department of Neurosurgery and Brain Repair, Center of Excellence for Aging and Brain Repair, University of South Florida College of Medicine, Tampa, FL 33612, USA
These authors contributed equally to this work.
*
Author to whom correspondence should be addressed.
Received: 7 December 2017 / Revised: 12 December 2017 / Accepted: 16 December 2017 / Published: 19 December 2017
(This article belongs to the Special Issue Molecular Research on Neurodegenerative Diseases)
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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. View Full-Text
Keywords: tissue plasminogen activator; hemorrhage; blood-brain barrier; stem cell; matrix metalloproteinase (MMP) tissue plasminogen activator; hemorrhage; blood-brain barrier; stem cell; matrix metalloproteinase (MMP)
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Knecht, T.; Story, J.; Liu, J.; Davis, W.; Borlongan, C.V.; dela Peña, I.C. Adjunctive Therapy Approaches for Ischemic Stroke: Innovations to Expand Time Window of Treatment. Int. J. Mol. Sci. 2017, 18, 2756.

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