Prioritizing Clinical Candidates for Motor Recovery in Multiple Sclerosis: Kinematic Gait Analysis of Mice Subjected to Experimental Autoimmune Encephalomyelitis

Finding drugs that improve the recovery of movement in multiple sclerosis (MS) by stimulating myelin repair: Multiple sclerosis is caused by destruction of the fatty insulation called myelin that surrounds the axons of nerve cells. Axons are slender processes that act like telephone cables, which join excitable nerve cells, called neurons, into circuits responsible for vision, sensation, reasoning, emotion, memory, and movement. Just like the rubber insulation around telephone cables in a saltwater ocean, myelin is required to increase the speed and efficiency by which axons conduct electrical signals in the brain and spinal cord. Myelin loss in the spinal cord disrupts communication between neurons that control movement, resulting in walking deficits or, in extreme cases, paralysis of the legs. Recovery of movement in MS is thought to require the regrowth of myelin-producing cells called oligodendrocytes. The lack of treatments that promote motor recovery in MS has fueled an intense search for drugs that stimulate remyelination. At least seven different types of drugs, used to treat conditions other than MS, promote remyelination and motor recovery in a mouse model of MS called experimental autoimmune encephalomyelitis (EAE) that mimics key pathological features of MS. However, it is unclear as to which of these compounds are most likely to be effective in MS patients. This is a considerable problem because the clinical trials required to establish the effectiveness of new drugs for MS are expensive, complex, long, and risky. It is therefore crucial that the most promising drugs be selected for human testing. We propose that this problem can be solved using kinematic gait analysis to identify drugs that increase the recovery of normal leg movements for EAE mice. These sophisticated behavioural techniques will be used to identify the most promising of several remyelinating agents for clinical testing in MS. Use of kinematic gait analysis to identify the most promising remyelinating drugs for MS: Neurologists use a clinical rating scale called the Expanded Disability Status Scale to assess the degree of disability in people with MS. A clinical scale is also used to measure paralysis and motor deficits in EAE mice. However, these clinical scales provide little information about the relative degree and nature of motor disabilities in MS and EAE. In MS, this problem has been addressed by using kinematic gait analysis to break down the complex leg movements that occur during walking into specific parts. These parts include how the hip, knee, ankle, and foot move back and forth during each step. Kinematic gait analysis has shown that MS patients suffer from impaired hip, knee, ankle, and foot movements that disrupt balance and increase the risk of injurious falls. We have recently used kinematic gait analysis to measure hip, knee, ankle, and foot movements in the video recordings of EAE mice walking on a treadmill. These studies have shown that EAE mice display impaired leg movements typical of MS. Moreover, increased variability in knee and ankle movements closely predicted elevated myelin loss in the spinal cords of EAE mice. Drugs that improve the knee and ankle movements of EAE mice by increasing myelin repair may thus have similar benefits for MS patients. We hypothesize that the degree to which the knee and ankle movements of EAE mice are normalized will predict the magnitude of spinal cord remyelination produced by each of the compounds that will be tested. If this prediction is correct, knee and ankle measurements used in our studies could also be accurate tests of myelin repair in MS. Pioglitazone improves MS disease severity, which has been linked to increased myelin repair. Pioglitazone is a drug used to treat type II diabetes that appears to improve the mobility of MS patients by increasing myelin repair. We have found that ingestion of pioglitazone improves the hip, knee, and ankle mov