Nimodipine Reduces Dysfunction and Demyelination in Models of Multiple Sclerosis.

OBJECTIVE: Treatment of relapses in multiple sclerosis (MS) has not advanced beyond steroid use, which reduces acute loss of function, but has little effect on residual disability. Acute loss of function in an MS model (experimental autoimmune encephalomyelitis [EAE]) is partly due to central nervous system (CNS) hypoxia, and function can promptly improve upon breathing oxygen. Here, we investigate the cause of the hypoxia and whether it is due to a deficit in oxygen supply arising from impaired vascular perfusion. We also explore whether the CNS-selective vasodilating agent, nimodipine, may provide a therapy to restore function, and protect from demyelination in 2 MS models. METHODS: A variety of methods have been used to measure basic cardiovascular physiology, spinal oxygenation, mitochondrial function, and tissue perfusion in EAE. RESULTS: We report that the tissue hypoxia in EAE is associated with a profound hypoperfusion of the inflamed spinal cord. Treatment with nimodipine restores spinal oxygenation and can rapidly improve function. Nimodipine therapy also reduces demyelination in both EAE and a model of the early MS lesion. INTERPRETATION: Loss of function in EAE, and demyelination in EAE, and the model of the early MS lesion, seem to be due, at least in part, to tissue hypoxia due to local spinal hypoperfusion. Therapy to improve blood flow not only protects neurological function but also reduces demyelination. We conclude that nimodipine could be repurposed to offer substantial clinical benefit in MS. ANN NEUROL 2020 ANN NEUROL 2020;88:123-136.

Multispectral oximetry of murine tendon microvasculature with inflammation.

We report a novel multispectral imaging technique for localised measurement of vascular oxygen saturation (SO2) in vivo. Annular back-illumination is generated using a Schwarzchild-design reflective objective. Analysis of multispectral data is performed using a calibration-free oximetry algorithm. This technique is applied to oximetry in mice to measure SO2 in microvasculature supplying inflamed tendon tissue in the hind leg. Average SO2 for controls was 94.8 ± 7.0 % (N = 6), and 84.0 ± 13.5 % for mice with inflamed tendon tissue (N = 6). We believe this to be the first localised measurement of hypoxia in tendon microvasculature due to inflammation. Quantification of localised SO2 is important for the study of inflammatory diseases such as rheumatoid arthritis, where hypoxia is thought to play a role in pathogenesis.

A multispectral microscope for in vivo oximetry of rat dorsal spinal cord vasculature.

Quantification of blood oxygen saturation (SO2) in vivo is essential for understanding the pathogenesis of diseases in which hypoxia is thought to play a role, including inflammatory disorders such as multiple sclerosis (MS) and rheumatoid arthritis (RA). We describe a low-cost multispectral microscope and oximetry technique for calibration-free absolute oximetry of surgically exposed blood vessels in vivo. We imaged the vasculature of the dorsal spinal cord in healthy rats, and varied inspired oxygen (FiO2) in order to evaluate the sensitivity of the imaging system to changes in SO2. The venous SO2 was calculated as 67.8 ± 10.4% (average ± standard deviation), increasing to 83.1 ± 11.6% under hyperoxic conditions (100% FiO2) and returning to 67.4 ± 10.9% for a second normoxic period; the venous SO2 was 50.9 ± 15.5% and 29.2 ± 24.6% during subsequent hypoxic states (18% and 15% FiO2 respectively). We discuss the design and performance of our multispectral imaging system, and the future scope for extending this oximetry technique to quantification of hypoxia in inflamed tissue.