Astrocyte Conversion by Microglia is Neuroprotective in PD Models Following the recent exenatide trial results, further studies of the potentially important disease-modifying role of GLP-1's in Parkinson's are taking place. This recent study of a drug, NLY01, further examines neuroprotection. Similar drugs to NLY01 already approved for the treatment of type 2 diabetes include exenatide, lixisenatide, and liraglutide - all three of these drugs have been or are being trialled in Parkinson's through The Cure Parkinson's Trust Linked Clinical Trials 'repurposing' programme. NLY01 is a long-acting drug with improved brain penetration compared to the approved drugs for diabetes. Story Source: Johns Hopkins Medicine. Johns Hopkins researchers say the experimental drug NLY01, has been shown to slow the progression of Parkinson's disease itself - as well as its symptoms - in mice. In experiments performed with cultures of human brain cells and live mouse models, they report the drug blocked the degradation of brain cells that is the hallmark of Parkinson's. The drug is expected to move to clinical trials this year. "It is amazingly protective of target nerve cells," says Ted Dawson, M.D., Ph.D., director of the Institute for Cell Engineering and professor of neurology at the Johns Hopkins University School of Medicine. Dawson explains that if planned clinical trials for NLY01 are successful in humans, it could be one of the first treatments to directly target the progression of Parkinson's, and not just the symptomatic relief of the condition. A report of the study's results was published June 11 in Nature Medicine. According to the investigators, NLY01 works by binding to so-called glucagon-like peptide-1 (GLP-1) receptors on the surface of certain cells. Similar drugs are used widely in the treatment of type 2 diabetes to increase insulin levels in the blood. Though past studies in animals suggested the neuroprotective potential of this class of drugs, researchers had not shown directly how it operated in the brain. To find out, Dawson and his team tested NLY01 on three major cell types in the human brain: astrocytes, microglia and neurons. They found that microglia, a brain cell type that sends signals throughout the central nervous system in response to infection or injury, had the most sites for NLY01 to bind to - two times higher than the other cell types, and 10 times higher in humans with Parkinson's compared to those without the disease. Dawson and his team knew that microglia secreted chemical signals that converted astrocytes - the star shaped cells that help neurons communicate with their neighbors - into aggressive "activated" astrocytes, which eat away at the connections between cells in the brain, causing neurons to die off. They speculated that NLY01 might stop this conversion. "The activated astrocytes we focused on go into a revolt against the brain," says Dawson, "and this structural breakdown contributes to the dead zones of brain tissue found in those with Parkinson's disease. The ideas was that if we could find a way to calm those astrocytes, we might be able to slow the progression of Parkinson's disease." In a preliminary experiment in laboratory-grown human brain cells, Dawson's team treated human microglia with NLY01 and found that they were able to turn the activating signals off. When healthy astrocytes were combined with the treated microglia, they did not convert into destructive activated astrocytes and remained healthy neuroprotective cells. Dawson's team suspected that neurons throughout the body could be protected in the same way. They explored this hypothesis by testing the drug's effectiveness in mice engineered to have a rodent version of Parkinson's disease. In one experiment, Dawson's team injected the mice with alpha-synuclein, the toxic protein known to be the primary driver of Parkinson's, and treated mice with NLY01. Similar but untreated mice injected with alpha-synuclein showed pronounced motor impairment over the course of six months in behavioural tests such as the pole test, which allows researchers to measure motor impairment such as that caused by Parkinson's. However, Dawson's team found that the mice treated with NLY01 maintained normal physical function and had no loss of dopamine neurons, indicating that the drug protected against the development of Parkinson's. In a second experiment, Dawson's team used mice that were genetically engineered to naturally produce more human-type alpha-synuclein typically used to model human Parkinson's disease that runs in families. Under normal conditions, these so-called transgenic mice will succumb to the disease in 387 days. However, Dawson's team found that treatment with NLY01 extended the lives of the 20 mice treated with the drug by over 120 days. Upon further investigation, Dawson's team found that the brains of the mice treated with NLY01 showed few signs of the neurodegenerative characteristics of Parkinson's. Dawson cautions that the experimental drug must still be tested for safety as well as effectiveness in people, but based on the safety profile of other similar drugs, he does not anticipate any major roadblocks to its use in humans. Dawson says he and his team have reason to be hopeful that NLY01 could, in a relatively short period of time, make an impact on the lives of those with Parkinson's. “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. __________________________________________________________________________________ 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.'