A preclinical murine model for the early detection of radiation-induced brain injury using magnetic resonance imaging and behavioral tests for learning and memory: with applications for the evaluation of possible stem cell imaging agents and therapies

Abstract

Stem cell therapies are being developed for radiotherapy-induced brain injuries (RIBI). Magnetic resonance imaging (MRI) offers advantages for imaging transplanted stem cells. However, most MRI cell-tracking techniques employ superparamagnetic iron oxide particles (SPIOs), which are difficult to distinguish from hemorrhage. In current preclinical RIBI models, hemorrhage occurs concurrently with other injury markers. This makes the evaluation of the recruitment of transplanted SPIO-labeled stem cells to injury sites difficult. Here, we developed a RIBI model, with early injury markers reflective of hippocampal dysfunction, which can be detected noninvasively with MRI and behavioral tests. Lesions were generated by sub-hemispheric irradiation of mouse hippocampi with single X-ray beams of 80 Gy. Lesion formation was monitored with anatomical and contrast-enhanced MRI and changes in memory and learning were assessed with fear-conditioning tests. Early injury markers were detected 2 weeks after irradiation. These included an increase in the permeability of the blood-brain barrier, demonstrated by a 92 ± 20 % contrast enhancement of the irradiated versus the non-irradiated brain hemispheres, within 15 min of the administration of an MRI contrast agent. A change in short-term memory was also detected, as demonstrated by a 40.88 ± 5.03 % decrease in the freezing time measured during the short-term memory context test at this time point, compared to that before irradiation. SPIO-labeled stem cells transplanted contralateral to the lesion migrated toward the lesion at this time point. No hemorrhage was detected up to 10 weeks after irradiation. This model can be used to evaluate SPIO-based stem cell-tracking agents, short-term.

Blood-brain barrier permeability following conventional photon radiotherapy – A systematic review and meta-analysis of clinical and preclinical studies

“…, 27 (55%), investigate BBB disruption in rats [51] , [52] , [53] , [54] , [55] , [56] , [57] , [58] , [59] , [60] , [61] , [62] , [63] , [64] , [65] , [66] , [67] , [68] , [69] , [70] , [71] , [72] , [73] , [74] , [75] , [76] , [77] . In addition, eleven (22%) studies use mice [12] , [78] , [79] , [80] , [81] , [82] , [83] , [84] , [85] , [86] , [87] , five involve rabbits [88] , [89] , [90] , [91] , [92] , two include dogs [93] , [94] , two describe monkeys [95] , [96] , one article studied the effects of RT on the BBB in sharks [97] and one in pigs [98] .…”

Evaluation of acute esophageal radiation-induced damage using magnetic resonance imaging: a feasibility study in mice

“…Preclinical studies exist that reported on the use of OCT to detect ARIED in mice [15]. Moreover, other studies used MRI to detect and monitor radiation-induced degenerative changes in articular cartilage and bone in rats [40], progression of radiation-induced necrosis and dose escalation limitations in mouse and rat brains respectively [41, 42], radiation-induced damage in mouse brains [43–46] in xenografts in mice [47, 48], and radiation-induced lung damage in rabbits [49]. However, no studies have reported use of MRI to detect ARIED.…”

In Vivo Imaging With Confirmation by Histopathology for Increased Rigor and Reproducibility in Translational Research: A Review of Examples, Options, and Resources

“…Cardiac MRI is used to evaluate cardiac function in preclinical models of heart disease. 87,88 MRI is particularly advantageous in studying the soft tissue anatomy: resolutions of 25 to 100 μm are achievable in preclinical animal studies of cancer, 89 brain injury, 90 and stem cells. 91 Advantages MRI is a powerful, noninvasive method for phenotypical characterization and therapeutic efficacy evaluation in animal models of disease used in preclinical research and drug discovery and development.…”