Suppressing Inflammatory Activity of Supporting Cells in the Brain as a Treatment for ALS
Constant, unresolved inflammatory behavior in the supporting cells of the brain is implicated in the pathology of diverse neurodegenerative conditions. Here, researchers find that dampening this inflammation can help restore function in animal models of amyotrophic lateral sclerosis (ALS). This joins many other conceptually similar demonstrations conducted in the laboratory for a range of different neurodegenerative diseases. It remains to be seen as to how well these anti-inflammatory strategies will perform in human clinical trials.
ALS is caused by the loss of upper motor neurons, located in the brain, and lower motor neurons, which extend from the spinal cord to the muscles. Using a genetically modified mouse model, researchers found that structural changes in the upper neurons occurred prior to disease symptoms. The study suggests that these morphological changes send a signal to microglia and astrocytes, the immune cells of the central nervous system. When they arrive, their effect is protective, but if they stay too long, they become toxic to neurons. This leads to a reduction in synaptic connections between motor neurons in the brain and spinal cord, which in turn results in a reduction in synaptic connections with muscles. These changes lead to atrophy and loss of motor function.
Given this correlation between symptoms and immune response, the research team wondered whether it might be possible to restore synaptic connections by blocking inflammation. They tested a semi-synthetic drug based on Withaferin A, an extract of the Ashwagandha plant. The drug blocks inflammation and allows motor neurons to return to a more normal state. Neurons regenerate in the absence of activated immune cells. The dendrites of motor neurons start to grow and make connections again, increasing the number of synapses between motor neurons and muscles. This seems a promising way of improving ALS symptoms, whether the disease is familial or sporadic, since both types are associated with inflammation.