TY - JOUR
T1 - MRI-guided intracerebral convectionenhanced injection of gliotoxins to induce focal demyelination in swine
AU - Kalkowski, Lukasz
AU - Malysz-Cymborska, Izabela
AU - Golubczyk, Dominika
AU - Janowski, Miroslaw
AU - Holak, Piotr
AU - Milewska, Kamila
AU - Kedziorek, Dorota
AU - Adamiak, Zbigniew
AU - Maksymowicz, Wojciech
AU - Walczak, Piotr
N1 - Funding Information:
This work was supported by National Institutes of Health- R01 NS091100; Piotr Walczak is reciever, National Institutes of Health- R01 NS091110; Piotr Walczak is reciever, National Institutes of Health- R01 NS076573; Piotr Walczak is reciever, Narodowe Centrum Badan i Rozwoju- Strategmed 1/233209/12/NCBIR/2015; Piotr Walczak is reciever, National Institutes of Health - 2017-MSCRFD-3942, National Center for Research and Development - Strategmed 1/2352773/19/ NCBR/2016, National Center for Research and Development - Strategmed 12-/EuroNanoMed/ 2016. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.
Publisher Copyright:
© 2018 Kalkowski et al.
PY - 2018/10
Y1 - 2018/10
N2 - Demyelinating disorders such as multiple sclerosis (MS) or transverse myelitis are devastating neurological conditions with no effective cure. Prevention of myelin loss or restoration of myelin are key for successful therapy. To investigate the disease and develop cures animal models with good clinical relevance are essential. The goal of the current study was to establish a model of focal demyelination in the brain of domestic pig using MRI-guided gliotoxin delivery. The rationale for developing a new myelin disease model in the domestic pig was based on the fact that the brain in pigs is anatomically and histologically much more similar to that of humans compared to the rodent brain. For MRI-assisted gliotoxin injection, eight 30 kg pigs were subjected to treatment with lysolecithin (20, 30 mg/ml); or with ethidium bromide (0.0125, 0.05, 0.2 mg/ml). Animals were placed in an MRI scanner for intraparenchymal targeting of gliotoxin into the corona radiata (250 μl over 1h), with real-time monitoring of toxin distribution on T1 scans and monitoring of lesion evolution over seven days using both T1 and T2 scans. After the last MRI, animals were transcardially perfused and brains were processed for histological and immunofluorescent analysis. Gadoliniumenhanced T1 MRI during injection demonstrated biodistribution of the contrast (as a surrogate marker for toxin distribution) and its diffusion through the brain parenchyma. Lesion induction was confirmed on T2-weighted MRI and histopathology, thus enabling the establishment of optimal doses of gliotoxins. To conclude, MRI-guided focal demyelination in swine is accurate and provides real-time confirmation of gliotoxin, thus facilitating placement of focal lesions with high precision. This new model of focal demyelination can be used for further investigation and development of novel therapeutic approaches.
AB - Demyelinating disorders such as multiple sclerosis (MS) or transverse myelitis are devastating neurological conditions with no effective cure. Prevention of myelin loss or restoration of myelin are key for successful therapy. To investigate the disease and develop cures animal models with good clinical relevance are essential. The goal of the current study was to establish a model of focal demyelination in the brain of domestic pig using MRI-guided gliotoxin delivery. The rationale for developing a new myelin disease model in the domestic pig was based on the fact that the brain in pigs is anatomically and histologically much more similar to that of humans compared to the rodent brain. For MRI-assisted gliotoxin injection, eight 30 kg pigs were subjected to treatment with lysolecithin (20, 30 mg/ml); or with ethidium bromide (0.0125, 0.05, 0.2 mg/ml). Animals were placed in an MRI scanner for intraparenchymal targeting of gliotoxin into the corona radiata (250 μl over 1h), with real-time monitoring of toxin distribution on T1 scans and monitoring of lesion evolution over seven days using both T1 and T2 scans. After the last MRI, animals were transcardially perfused and brains were processed for histological and immunofluorescent analysis. Gadoliniumenhanced T1 MRI during injection demonstrated biodistribution of the contrast (as a surrogate marker for toxin distribution) and its diffusion through the brain parenchyma. Lesion induction was confirmed on T2-weighted MRI and histopathology, thus enabling the establishment of optimal doses of gliotoxins. To conclude, MRI-guided focal demyelination in swine is accurate and provides real-time confirmation of gliotoxin, thus facilitating placement of focal lesions with high precision. This new model of focal demyelination can be used for further investigation and development of novel therapeutic approaches.
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U2 - 10.1371/journal.pone.0204650
DO - 10.1371/journal.pone.0204650
M3 - Article
C2 - 30273376
AN - SCOPUS:85054098568
SN - 1932-6203
VL - 13
JO - PloS one
JF - PloS one
IS - 10
M1 - e0204650
ER -