Astrocyte activation blocked by antidiabetic drugs – evidence for neuroprotective effects
A key mechanism driving the neuroprotective effects of the GLP1 receptor agonist NLY01, which is in the same drug class as exenatide, may be occuring by blocking the toxic activation of non-neuronal cells: microglia and astrocytes.
Why is it important?
Uncovering the entire range of effects for these promising drugs is essential because it brings glia into the spotlight – these critical but often understudied cells in the brain may represent an important means of promoting neuronal survival, and thus potential drug targets.
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This research involved a number of sequential experiments in animal models of Parkinson’s.
The build-up of aggregates of the protein alpha synuclein is a hallmark of Parkinson’s, and injecting it in the form of toxic, preformed fibrils into brain regions central to movement, such as the striatum, was shown to cause problems with movement 3-6 months later in an animal model.
Having established a valid animal model, the researchers sought to understand what effect the antidiabetic GLP1 receptor agonist NLY01 has on neuronal survival. A month after injecting the harmful alpha synuclein fibrils, NLY01 was administered twice weekly for 5 months.
NLY01 treatment significantly reduced alpha synuclein build up, promoted dopamine neuron survival and improved movement in the animals that had been treated with the drug compared to those who were not.
The researchers then went on to a more naturalistic experiment where they treated genetically engineered mice which carry one of the most prominent genetic mutations seen in Parkinson’s, in the SNCA gene which provides the instruction for the production of alpha synuclein protein. Again, NLY01 showed neuroprotective effects and reduced abnormal alpha synuclein build up.
But how did NLY01 confer these effects? NLY01 did not promote dopamine neuron survival when applied to a cell culture of dopamine neurons alone. Moreover, injecting alpha synuclein fibrils into brain tissue containing both neurons and non-neuronal cells which include microglia and astrocytes, increased levels of the GLP1 receptor in these non-neuronal cells. These findings shift the focus directly onto microglia and astrocytes.
What are microglia and astrocytes? Both are glial cells, which are as abundant in the brain as neurons. Microglia are the first line of immune defense for the brain, clearing noxious substances and through inflammatory substances they secrete (called cytokines) also trigger astrocytes into a reactive state so that they too can effectively fight off infection. This process however can also kill neurons.
The researchers found that alpha synuclein fibrils activated microglia, but what effect did NLY01 have on them? Normally, activated microglia begin to pump out cytokines aimed at activating astrocytes. The researchers collected the solution in which the microglia were grown and applied it to astrocytes. They found that the solution that came from the NLY01 treated microglia did not trigger astrocyte reactivity, which in turn promoted dopamine neuron survival.
Given that NLY01 does not lead to weight loss and crosses the blood brain barrier (BBB), could it be added to the growing list of GLP1 receptor agonists (such as exenatide) for consideration in trials in humans? This research is also relevant to a possible mechanism of action of exenatide (Bydureon) and gives ideas for how its target engagement in Parkinson’s might be assessed.