Timing is critical. Recent work from the Michele Basso lab at Ohio State shows that spinal cord injured mice improve function after being trained on a treadmill – but not if the training starts too soon, and not if there is significant inflammation in the spinal cord.
Basso’s paper, appearing this week in the Journal of Neuroscence, is titled “Elevated mmp-9 in the lumbar cord early after thoracic spinal cord injury impedes motor relearning in mice
Key finding: motor recovery is improved if inflammation is controlled in the lumbar area of the cord that houses the key microcircuits for locomotion. In Basso’s model, this area was 10 spinal segments below the area of the spinal cord lesion in her experimental animals. This is news that a thoracic injury can have such profound effects on the motor system so many segments away.
Said Basso, “We got positive and negative effects with the same intervention, and it’s all influenced by inflammation. There’s so much happening so far away from the injury, and it’s all in the heart of where the neural circuits are for locomotion.”
Basso and her group found that an enzyme called MMP-9 may be the trigger for lumbar inflammation – it is part of biochemical chain of signaling molecules and questions remain about how it works, but it is elevated in the lumbar cord after injury. She notes that neuroinflammation is a known impediment to spinal learning and plasticity.
From the paper:
Matrix metalloproteinases (MMPs) regulate diverse functions, including tissue remodeling, inflammation, and learning. In particular, the gelatinase MMP-9 amplifies proinflammatory cytokine production, increases blood spinal cord barrier (BSCB) permeability, and regulates synaptic long-term potentiation.
If MMP-9 is produced in remote lumbar regions after SCI, it may contribute to an inhibitory microenvironment and interfere with plasticity and recovery of function even when treadmill training is delivered.
Here’s what the OSU group did to test the hypothesis that MMP-9 inhibits recovery. They spinal cord injured two kinds of mice, wild type or normal mice, and others that were specially bred to disable the MMP-9 response. The trained both animal types on treadmills. Only mice lacking MMP-9 showed significant improvements in walking after seven days of training. These improvements lasted for four weeks. They also started treadmill training at least 35 days after the injury; this failed to produce significant walking improvements in any of the animals.
Basso: “This was the exact same type of training, and in one group of mice the inflammation was controlled, but even in those mice the late training had no effect,” Basso said. “We still don’t know exactly when the window is for treadmill training, but this suggests early, and with controlled inflammation. ”
Said Basso et al, in the text:
Our work suggests that by attenuating remote mechanisms of inflammation, acute treadmill training can harness endogenous spinal plasticity to promote robust recovery.
...Deletion of MMP-9 reduces the inflammatory signature in the lumbar cord and allows robust locomotor plasticity and improved recovery that is otherwise refractory to early intervention. For the first time, we identify the blunting effect of remote inflammation on activity-dependent plasticity within locomotor interneuron networks. Our work demonstrates a negative, time-dependent interaction between lumbar MMP-9 production and motor relearning.
Timing, again, is the trick. Treadmill too soon is worse than none. From the paper:
An important finding of the present study was that intervening with treadmill training early after SCI during a period of marked neuroinflammation exacerbated deficits more than when no exercise was applied.
Moving this on to people? Could be. Previous research has linked MMM-9 to cancer; experimental drugs that block its effect are already being developed. Also, spinal cord inflammation might be attenuated with regular antibiotics.