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Assessment of recombinant tissue plasminogen activator (rtPA) toxicity in cultured neural cells and subsequent treatment with poly-arginine peptide R18D

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Abstract

Thrombolytic therapy with recombinant tissue plasminogen activator (rtPA) in ischaemic stroke has been associated with neurotoxicity, blood brain barrier (BBB) disruption and intra-cerebral hemorrhage. To examine rtPA cellular toxicity we investigated the effects of rtPA on cell viability in neuronal, astrocyte and brain endothelial cell (bEnd.3) cultures with and without prior exposure to oxygen–glucose deprivation (OGD). In addition, the neuroprotective peptide poly-arginine-18 (R18D; 18-mer of d-arginine) was examined for its ability to reduce rtPA toxicity. Studies demonstrated that a 4- or 24-h exposure of rtPA was toxic, affecting neuronal cell viability at ≥ 2 µM, and astrocyte and bEnd.3 cells viability at ≥ 5 μM. In addition, a 4-h exposure to rtPA after a period of OGD (OGD/rtPA) exacerbated toxicity, affecting neuronal, astrocyte and bEnd.3 cell viability at rtPA concentrations as low as 0.1 µM. Treatment of cells with low concentrations of R18D (0.5 and 1 µM) reduced the toxic effects of rtPA and OGD/rtPA, while on some occasions a higher 2 µM R18D concentrations exacerbated neuronal and bEnd.3 cell toxicity in OGD/rtPA exposed cultures. In exploratory studies we also demonstrated that OGD activates matrix metalloproteinase-9 (MMP-9) release into the supernatant of astrocyte and bEnd.3 cell cultures, but not neuronal cultures, and that OGD/rtPA increases MMP-9 activation. Furthermore, R18D decreased MMP-9 activation in OGD/rtPA treated astrocyte and bEnd.3 cell cultures. In summary, the findings show that rtPA can be toxic to neural cells and that OGD exacerbates toxicity, while R18D has the capacity to reduce rtPA neural cellular toxicity and reduce MMP-9 activation in astrocytes and bEnd.3. Poly-arginine-18 peptides, which are being developed as neuroprotective therapeutics for ischaemic stroke, therefore have the additional potential of reducing cytotoxic effects associated with rtPA thrombolysis in the treatment of ischaemic stroke.

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Funding

This research did not receive any specific grant from funding agencies in the public, commercial, or not-for-profit sectors. The study was funded by Research support from the Perron Institute for Neurological and Translational Science and The University of Western Australia.

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Authors and Affiliations

  1. Perron Institute for Neurological and Translational Science, RR Block, QEII Medical Centre, 8 Verdun St, Nedlands, WA, 6009, Australia

    Jade E. Kenna, Ryan S. Anderton, Neville W. Knuckey & Bruno P. Meloni

  2. Department of Neurosurgery, Sir Charles Gairdner Hospital, QEII Medical Centre, Nedlands, WA, 6009, Australia

    Neville W. Knuckey & Bruno P. Meloni

  3. Centre for Neuromuscular and Neurological Disorders, The University of Western Australia, Crawley, WA, 6009, Australia

    Jade E. Kenna, Ryan S. Anderton, Neville W. Knuckey & Bruno P. Meloni

  4. School of Heath Sciences, and Institute for Health Research, The University Notre Dame Australia, Fremantle, WA, 6160, Australia

    Ryan S. Anderton

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  1. Jade E. Kenna
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Correspondence to Jade E. Kenna.

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Bruno P. Meloni and Neville W. Knuckey are named inventors of several patent applications (Provisional Patents: 2013904197; 30/ 10/2013 and 2014902319; 17/6/2014 and PCT/ AU2014/050326; 30/10/2104) regarding the use of arginine-rich peptides as neuroprotective agents.

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Kenna, J.E., Anderton, R.S., Knuckey, N.W. et al. Assessment of recombinant tissue plasminogen activator (rtPA) toxicity in cultured neural cells and subsequent treatment with poly-arginine peptide R18D. Neurochem Res 45, 1215–1229 (2020). https://doi.org/10.1007/s11064-020-03004-3

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