Lack of dystrophin results in abnormal cerebral diffusion and perfusion in vivo

Abstract

Dystrophin, the main component of the dystrophin–glycoprotein complex, plays an important role in maintaining the structural integrity of cells. It is also involved in the formation of the blood–brain barrier (BBB). To elucidate the impact of dystrophin disruption in vivo, we characterized changes in cerebral perfusion and diffusion in dystrophin-deficient mice (mdx) by magnetic resonance imaging (MRI). Arterial spin labeling (ASL) and diffusion-weighted MRI (DWI) studies were performed on 2-month-old and 10-month-old mdx mice and their age-matched wild-type controls (WT). The imaging results were correlated with Evan's blue extravasation and vascular density studies. The results show that dystrophin disruption significantly decreased the mean cerebral diffusivity in both 2-month-old (7.38± 0.30 × 10−4mm2/s) and 10-month-old (6.93 ± 0.53 × 10−4 mm2/s) mdx mice as compared to WT (8.49±0.24×10−4, 8.24±0.25× 10−4mm2/s, respectively). There was also an 18% decrease in cerebral perfusion in 10-month-old mdx mice as compared to WT, which was associated with enhanced arteriogenesis. The reduction in water diffusivity in mdx mice is likely due to an increase in cerebral edema or the existence of large molecules in the extracellular space from a leaky BBB. The observation of decreased perfusion in the setting of enhanced arteriogenesis may be caused by an increase of intracranial pressure from cerebral edema. This study demonstrates the defects in water handling at the BBB and consequently, abnormal perfusion associated with the absence of dystrophin.

Abnormalities in brain structure and biochemistry associated with mdx mice measured by in vivo MRI and high resolution localized 1H MRS

“…In muscle, the uniform distribution of dystrophin beneath the plasma membrane is thought to provide structural support to the membrane. In the mdx mouse brain, the blood-brain barrier (BBB) is markedly altered due to disruption of tight junctions, leading to increased permeability in the BBB [50;51]. Although its role in the brain is still being defined, the absence of dystrophin may enable water in the cell to diffuse more easily and less anisotropically, as indicated by DTI results of the current study (i.e.…”

Development and Application of an Ultrasensitive Hybridization-Based ELISA Method for the Determination of Peptide-Conjugated Phosphorodiamidate Morpholino Oligonucleotides

“…If there is accumulation of P-PMO in the brain, then it would strongly suggest that P-PMOs are able to penetrate the BBB. Comparison with wild-type mice will also confirm whether there are differences in uptake between healthy and dystrophic mice due to a compromised BBB [38].…”

Neurodevelopmental, emotional, and behavioural problems in Duchenne muscular dystrophy in relation to underlying dystrophin gene mutations

“…36 In an animal model, disrupted cerebral diffusivity was demonstrated to be associated with lack of dystrophin. 37 Finally, novel pharmaco-gene therapies aiming at restoring dystrophin expression and delaying the course of the disease progression are currently in different phases of experimentation. Some of these compounds, such as the tricyclo-DNA antisense molecules, are also capable of crossing the blood-brain barrier and restoring dystrophin expression through exon skipping in the CNS.…”