Repositioning imatinib for spinal cord injury

Kjell, Jacob; Olson, Lar̀s

doi:10.4103/1673-5374.167751

Cited by 7 publications

(3 citation statements)

References 11 publications

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“…Imatinib inhibits signaling of platelet-derived growth factor receptor (PDGFR) by inducing receptor dimerization via binding to RTK phosphorylation sites [ 26 ]. Imatinib has been found to maintain BBB integrity [ 27 ].…”

Section: Methodsmentioning

confidence: 99%

Reduction in pericyte coverage leads to blood–brain barrier dysfunction via endothelial transcytosis following chronic cerebral hypoperfusion

Sun

Gao

et al. 2021

Fluids Barriers CNS

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Background Chronic cerebral hypoperfusion (CCH) is the leading cause of cerebral small vessel disease (CSVD). CCH is strongly associated with blood–brain barrier (BBB) dysfunction and white matter lesions (WMLs) in CSVD. However, the effects of CCH on BBB integrity and components and the cellular and molecular mechanisms underlying the effects of BBB dysfunction remain elusive. Whether maintaining BBB integrity can reverse CCH-induced brain damage has also not been explored. Methods In this study, we established a rat model of CSVD via permanent bilateral common carotid artery occlusion (2VO) to mimic the chronic hypoperfusive state of CSVD. The progression of BBB dysfunction and components of the BBB were assessed using immunostaining, Western blotting, transmission electron microscopy (TEM) and RNA sequencing. We also observed the protective role of imatinib, a tyrosine kinase inhibitor, on BBB integrity and neuroprotective function following CCH. The data were analyzed using one-way or two-way ANOVA. Results We noted transient yet severe breakdown of the BBB in the corpus callosum (CC) following CCH. The BBB was severely impaired as early as 1 day postoperation and most severely impaired 3 days postoperation. BBB breakdown preceded neuroinflammatory responses and the formation of WMLs. Moreover, pericyte loss was associated with BBB impairment, and the accumulation of serum protein was mediated by increased endothelial transcytosis in the CC. RNA sequencing also revealed increased transcytosis genes expression. BBB dysfunction led to brain damage through regulation of TGF-β/Smad2 signaling. Furthermore, imatinib treatment ameliorated serum protein leakage, oligodendrocyte progenitor cell (OPC) activation, endothelial transcytosis, microglial activation, and aberrant TGF-β/Smad2 signaling activation. Conclusions Our results indicate that reduced pericyte coverage leads to increased BBB permeability via endothelial transcytosis. Imatinib executes a protective role on the BBB integrity via inhibition of endothelial transcytosis. Maintenance of BBB integrity ameliorates brain damage through regulation of TGF-β/Smad2 signaling following CCH; therefore, reversal of BBB dysfunction may be a promising strategy for CSVD treatment.

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Section: Methodsmentioning

confidence: 99%

Reduction in pericyte coverage leads to blood–brain barrier dysfunction via endothelial transcytosis following chronic cerebral hypoperfusion

Sun

Gao

et al. 2021

Fluids Barriers CNS

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“…The studies by Su et al in a stroke model (Su et al, 2008) have prompted investigations into the therapeutic potential of imatinib, a PDGFR-α antagonist and cancer drug, in acute spinal cord injury (Kjell and Olson, 2015). A first proof-of-concept study for imatinib involved rats with weight-drop injury to the lower thoracic spinal cord (Abrams et al, 2012).…”

Section: To Rescue What Can Be Rescuedmentioning

confidence: 99%

Rat models of spinal cord injury: from pathology to potential therapies

Kjell

Olson

2016

Disease Models &Amp; Mechanisms

Self Cite

294

209

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A long-standing goal of spinal cord injury research is to develop effective spinal cord repair strategies for the clinic. Rat models of spinal cord injury provide an important mammalian model in which to evaluate treatment strategies and to understand the pathological basis of spinal cord injuries. These models have facilitated the development of robust tests for assessing the recovery of locomotor and sensory functions. Rat models have also allowed us to understand how neuronal circuitry changes following spinal cord injury and how recovery could be promoted by enhancing spontaneous regenerative mechanisms and by counteracting intrinsic inhibitory factors. Rat studies have also revealed possible routes to rescuing circuitry and cells in the acute stage of injury. Spatiotemporal and functional studies in these models highlight the therapeutic potential of manipulating inflammation, scarring and myelination. In addition, potential replacement therapies for spinal cord injury, including grafts and bridges, stem primarily from rat studies. Here, we discuss advantages and disadvantages of rat experimental spinal cord injury models and summarize knowledge gained from these models. We also discuss how an emerging understanding of different forms of injury, their pathology and degree of recovery has inspired numerous treatment strategies, some of which have led to clinical trials.

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“…Imatinib inhibits signaling of tyrosine kinase receptor PDGFR by inducing receptor dimerization via ligand binding of RTK phosphorylation sites [23]. Imatinib has been found to protect BBB integrity [24].…”

Section: Bbb Protectionmentioning

confidence: 99%

Reduction of Pericyte Coverage Leads to Blood-Brain Barrier Dysfunction Via Endothelial Transcytosis Following Chronic Cerebral Hypoperfusion

Sun

Gao

et al. 2021

Preprint

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Background: Chronic cerebral hypoperfusion (CCH) is the leading cause for cerebral small vessel disease (CSVD). CCH is strongly associated with blood–brain barrier (BBB) dysfunction and white matter lesions (WML) in CSVD. But the effects of CCH on BBB integrity and constituents as well as the cellular and molecular mechanisms about the consequences of BBB dysfunction remain elusive. Whether maintaining BBB integrity can reverse CCH induced brain damage has also not been explored. Methods: In this study, we used a rat model of CSVD, established via permanent bilateral common carotid artery occlusion (2VO) to mimic the chronic hypoperfusive state of CSVD. The progression of BBB dysfunction and components of the BBB was assessed using immunostaining, western blotting and transmission electron microscopy. Data were analyzed using the one-way ANOVA test or two-tailed unpaired Student’s t tests.Results: We noted a transient yet severe breakdown of the BBB in the CC following CCH. The BBB was severely impaired as early as 1 day post operation and most severely impaired 3 days post operation. BBB breakdown preceded WML and neuroinflammatory responses. Moreover, pericyte loss was associated with BBB impairment and accumulation of serum proteins was mediated by increased endothelial transcytosis in the CC. BBB dysfunction led to brain damage by regulating TGF-β/Smad2 signaling. Further, protection of the BBB via inhibition of endothelial transcytosis ameliorated serum proteins leakage, microglial activation, oligodendrocyte progenitor cells (OPCs) activation and inappropriate TGF-β/Smad2 signaling activation. Conclusions: Our results indicate that reduced pericyte coverage leads to increased BBB permeability via endothelial transcytosis and protection of the BBB integrity ameliorates brain damage by regulating TGF-β/Smad2 signaling following CCH, therefore reversal of BBB dysfunction may be a promising strategy to treat CSVD.

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Repositioning imatinib for spinal cord injury

Cited by 7 publications

References 11 publications

Reduction in pericyte coverage leads to blood–brain barrier dysfunction via endothelial transcytosis following chronic cerebral hypoperfusion

Reduction in pericyte coverage leads to blood–brain barrier dysfunction via endothelial transcytosis following chronic cerebral hypoperfusion

Rat models of spinal cord injury: from pathology to potential therapies

Reduction of Pericyte Coverage Leads to Blood-Brain Barrier Dysfunction Via Endothelial Transcytosis Following Chronic Cerebral Hypoperfusion

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