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Int J Mol Sci. 2019 Oct 29;20(21). pii: E5395. doi: 10.3390/ijms20215395.

In Vitro and In Vivo Pipeline for Validation of Disease-Modifying Effects of Systems Biology-Derived Network Treatments for Traumatic Brain Injury-Lessons Learned.

Author information

1
A. I. Virtanen Institute for Molecular Sciences, University of Eastern Finland, PO Box 1627, FIN-70211 Kuopio, Finland. anssi.lipponen@uef.fi.
2
Institute of Biomedicine, University of Eastern Finland, PO Box 1627, FIN-70211 Kuopio, Finland. teemu.natunen@uef.fi.
3
School of Computing, University of Eastern Finland, PO Box 1627, FIN-70211 Kuopio, Finland. mika.hujo@uef.fi.
4
A. I. Virtanen Institute for Molecular Sciences, University of Eastern Finland, PO Box 1627, FIN-70211 Kuopio, Finland. robert.ciszek@uef.fi.
5
A. I. Virtanen Institute for Molecular Sciences, University of Eastern Finland, PO Box 1627, FIN-70211 Kuopio, Finland. elina.hamalainen@uef.fi.
6
A. I. Virtanen Institute for Molecular Sciences, University of Eastern Finland, PO Box 1627, FIN-70211 Kuopio, Finland. jussi.tohka@uef.fi.
7
Institute of Biomedicine, University of Eastern Finland, PO Box 1627, FIN-70211 Kuopio, Finland. mikko.hiltunen@uef.fi.
8
Institute of Biomedicine, University of Eastern Finland, PO Box 1627, FIN-70211 Kuopio, Finland. jussi.paananen@uef.fi.
9
Bioinformatics Center, University of Eastern Finland, PO Box 1627, FIN-70211 Kuopio, Finland. jussi.paananen@uef.fi.
10
Jacobs School of Medicine and Biomedical Sciences, University of Buffalo, 875 Ellicott St, 6071 CTRC, Buffalo, NY 14203, USA. davidpou@buffalo.edu.
11
A. I. Virtanen Institute for Molecular Sciences, University of Eastern Finland, PO Box 1627, FIN-70211 Kuopio, Finland. emilia.kansanen@uef.fi.
12
A. I. Virtanen Institute for Molecular Sciences, University of Eastern Finland, PO Box 1627, FIN-70211 Kuopio, Finland. xavier.ekollendode-ekane@uef.fi.
13
A. I. Virtanen Institute for Molecular Sciences, University of Eastern Finland, PO Box 1627, FIN-70211 Kuopio, Finland. anna-liisa.levonen@uef.fi.
14
A. I. Virtanen Institute for Molecular Sciences, University of Eastern Finland, PO Box 1627, FIN-70211 Kuopio, Finland. asla.pitkanen@uef.fi.

Abstract

We developed a pipeline for the discovery of transcriptomics-derived disease-modifying therapies and used it to validate treatments in vitro and in vivo that could be repurposed for TBI treatment. Desmethylclomipramine, ionomycin, sirolimus and trimipramine, identified by in silico LINCS analysis as candidate treatments modulating the TBI-induced transcriptomics networks, were tested in neuron-BV2 microglial co-cultures, using tumour necrosis factor α as a monitoring biomarker for neuroinflammation, nitrite for nitric oxide-mediated neurotoxicity and microtubule associated protein 2-based immunostaining for neuronal survival. Based on (a) therapeutic time window in silico, (b) blood-brain barrier penetration and water solubility, (c) anti-inflammatory and neuroprotective effects in vitro (p < 0.05) and (d) target engagement of Nrf2 target genes (p < 0.05), desmethylclomipramine was validated in a lateral fluid-percussion model of TBI in rats. Despite the favourable in silico and in vitro outcomes, in vivo assessment of clomipramine, which metabolizes to desmethylclomipramine, failed to demonstrate favourable effects on motor and memory tests. In fact, clomipramine treatment worsened the composite neuroscore (p < 0.05). Weight loss (p < 0.05) and prolonged upregulation of plasma cytokines (p < 0.05) may have contributed to the worsened somatomotor outcome. Our pipeline provides a rational stepwise procedure for evaluating favourable and unfavourable effects of systems-biology discovered compounds that modulate post-TBI transcriptomics.

KEYWORDS:

LINCS analysis; adverse event; common data element; machine-learning; neuroinflammation; neuroprotection; traumatic brain injury

PMID:
31671916
DOI:
10.3390/ijms20215395
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