Translocator protein 18 ligand Emapunil protects against neurodegeneration in the MPTP mouse model of Parkinsonism

Parkinson’s disease (PD) is the second most common neurodegenerative disorder in old age. The presence of akinesia, rigidity and rest tremor caused by dopaminergic neuronal loss in the substantia nigra are the major clinical hallmarks of PD. Although several treatments can temporarily improve motor symptoms and the quality of life in PD patients, it is still incurable until now. PD is neuropathologically characterized by aggregation of misfolded α-synuclein in dopaminergic neurons, neurodegeneration and neuroinflammation. Translocator protein 18 (TSPO) is a mitochondrial protein which is upregulated in microglia during neuroinflammation, and several TSPO ligands have been shown to exert neuroprotective effects in neurodegenerative diseases. In this study, we investigated the potential neuroprotective effects of Emapunil (also known as AC-5216 or XBD-173), a TSPO ligand, in female mice with subacute 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) treatment, and in 1-methyl-4-phenylpyridinium (MPP+) treated human dopaminergic cell line Lund Human Mesencephalic (LUHMES). We find, that application of Emapunil protects against dopaminergic neuron loss, preserves dopamine metabolism, and also improves motor performance. Furthermore, Emapunil treatment ameliorates MPP+ and rotenone toxicity in LUHMES cells. We identified that Emapunil inhibits endoplasmic reticulum (ER) stress-induced activation of the IRE1α/XBP1 (X-box binding protein 1) pathway, which can result in apoptosis. In addition, Emapunil induces the shift from pro-inflammatory M1 to anti-inflammatory M2 microglia activation state. Given that Emapunil has been found to be safe and well-tolerated in a phase II clinical trial, our results indicate that Emapunil could be a promising drug for PD patients