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 disorders 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 Alzheimer’s disease and Parkinson’s disease, but the mechanisms by which these agonists are neuroprotective are not known. Here Yun and colleagues show that a potent, brain-penetrant long-acting GLP1R agonist, NLY01, protects against the loss of dopaminergic neurons and behavioral deficits in a mouse model of sporadic Parkinson’s disease.
NLY01 is a potent GLP1R agonist and is neuroprotective through the direct prevention of microglial-mediated conversion of astrocytes to an A1 neurotoxic phenotype. In light of its favorable properties, the study concluded that NLY01 should be evaluated in the treatment of Parkinson’s disease and related neurologic disorders characterized by microglial activation.
Yun SP, Kam TI, Panicker N, Kim S, Oh Y, et al: Block of A1 astrocyte conversion by microglia is neuroprotective in models of Parkinson’s disease. Nature Medicine 2018 Jun 11. doi: 10.1038/s41591-018-0051-5. [Epub ahead of print].