This research is relevant to a possible mechanism of action of exenatide and gives ideas for how target engagement with exenatide in PD might be assessed.

In this study, when researchers injected preformed fibrils of alpha synuclein into animal models of Parkinson's, they started to observe alpha synuclein protein build-up in the brain approximately one month later, and motor problems were exhibited 3-6 months later.

In the NLY01 study, the researchers injected the preformed fibrils and waited one month before initiating treatment with either NLY01 or a placebo treatment. The treatment went on twice weekly for 5 months.

The results found that NLY01 treatment significantly reduced the amount of alpha synuclein aggregating and also reduced the loss of dopamine neurons. The drug also rescued the motor deficits across a range of behaviour tests.

Next, models of Parkinson's with the genetic SNCA mutation were treated with the NLY01 molecule and they survived longer and exhibited less alpha-synuclein aggregation.

Also of interest, the study reported that treating cultured neuron cells with preformed fibrils of alpha synuclein decreased GLP-1 levels in the neurons themselves and increased GLP-1 levels almost two fold in the surrounding microglia.

Microglia are some of the helper cells in the brain. They act as the resident immune cells. When infection or damage occurs, the microglia become ‘activated’ and start cleaning up the area. Previously the study had demonstrated that activation of microglia can cause them to release inflammatory chemicals alerting other microglia to potential problems. And these chemicals can also cause astrocytes (other support cells to neurons) to shift to a highly reactive state which is bad news for any neurons nearby.

Given this scenario, the researchers of the study began to wonder whether the interactions between microglial cells and astrocytes could be involved in the neuroprotective effects of NLY01.

They decided to test this idea by firstly treating microglia with preformed fibrils of alpha synuclein. This resulted in the microglia becoming activated. The researchers then split the microglia into two groups: one group was treated with NLY01 and the other group was not. Next the investigators collected the solutions from these two groups of microglia cultures, and they applied those solutions to two groups of astrocytes in cell culture. Astrocytes given the NLY01-treated microglial solution did not become reactive in an inflammatory way.

Subsequent experiments demonstrated that this reduction in reactive astrocytes was neuroprotective for dopamine neurons when they were grown in culture solution from the NLY01-treated activated microglia and reactive astrocytes.

These highly original findings lend further support and therapeutic promise for Parkinson's disease modification in an upcoming large trial of the GLP1 agonist Exenatide, as prioritised by our international Linked Clinical Trials programme.

Dr Richard Wyse - Director, Research and Development, CPT.

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Abstract

'Activation of microglia by classical inflammatory mediators can convert astrocytes into a neurotoxic A1 phenotype in a variety of neurological diseases. Development of agents that could inhibit the formation of A1 reactive astrocytes could be used to treat these diseases for which there are no disease-modifying therapies. Glucagon-like peptide-1 receptor (GLP1R) agonists have been indicated as potential neuroprotective agents for neurologic disorders such as Parkinson’s. The mechanisms by which GLP1R agonists are neuroprotective are not known. Here we show that a potent, brain-penetrant long-acting GLP1R agonist, NLY01, protects against the loss of dopaminergic neurons and behavioral deficits in the α-synuclein preformed fibril (α-syn PFF) mouse model of sporadic Parkinson’s. NLY01 also prolongs the life and reduces the behavioral deficits and neuropathological abnormalities in the human A53T α-synuclein (hA53T) transgenic mouse model of α-synucleinopathy-induced neurodegeneration. We found that NLY01 is a potent GLP1R agonist with favorable properties that is neuroprotective through the direct prevention of microglial-mediated conversion of astrocytes to an A1 neurotoxic phenotype. In light of its favorable properties, NLY01 should be evaluated in the treatment of Parkinson’s disease and related neurologic disorders characterised by microglial activation.'