A compound called emapunil prevented the characteristic loss of nerve cells associated with Parkinson’s disease, lowered levels of dopamine, brain inflammation, and motor deficits in a mouse model of the disease.
Researchers suggest that treatment with emapunil, already proven safe in humans as a therapy for anxiety disorders, may be effective for people with Parkinson’s.
The study, “Translocator protein ligand protects against neurodegeneration in the MPTP mouse model of Parkinsonism,” was published in the Journal of Neuroscience.
In Parkinson’s, the progressive loss of dopamine-producing neurons in the substantia nigra — a brain region implicated in motor control — is associated with brain inflammation.
Pro-inflammatory stimuli may activate microglia (key immune cells in the central nervous system that protect nerve cells against harmful agents and pathogens), which further contributes to oxidative stress, neurotoxicity, and disease progression. Several genes associated with familial forms of Parkinson’s have been linked with the immune response, while variations in genes encoding inflammatory molecules are linked with a higher risk for the sporadic form of the disease.
The levels of a specific protein, called translocator protein (TSPO), are elevated in microglia during inflammatory activation. TSPO ligands have been used to monitor neuroinflammation, including in patients with Parkinson’s, and have shown neuroprotective effects. However, the mechanisms through which TSPO ligands modulate inflammation are still unclear.
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Researchers at the German Center for Neurodegenerative Diseases (DZNE) and University Medical Center Goettingen, Germany, investigated the therapeutic potential of emapunil, a synthetic TSPO ligand, in a mouse model of Parkinson’s disease. Emapunil previously had shown anti-inflammatory properties, as well as the ability to cross the blood-brain barrier — a semipermeable membrane that protects the brain against the external environment, and is a major obstacle for the efficient delivery of certain therapeutics that need to reach the brain and central nervous system.
“This compound is able to penetrate into the microglia and flip a molecular switch that attenuates the inflammatory reaction,” Anja Schneider, the study’s senior author, said in a press release. Emapunil, added Schneider, “has already been tested in clinical studies on humans as a possible remedy for anxiety disorders. Therefore, data on this substance exists that proves its safety and tolerability in humans.”
The findings revealed that treatment with emapunil (every two days for up to 15 days) completely prevented loss of nerve cells in the substantia nigra, preserved dopamine metabolism in the striatum (a brain area that shows reduced levels of this neurotransmitter in Parkinson’s) lessened inflammation, and restored the animals’ motor function and postural control.
The team also found that emapunil lessened the unfolded protein response — a cellular stress reaction upon defects in protein folding that may lead to cell death — by reducing the RNA levels of the active form of a molecule known as XBP1 (XBP1s). Also, emapunil induced a shift from pro- to anti-inflammatory gene expression in microglia, which may underlie the compound’s protective effects, the team noted.
Mice given emapunil also showed normalized expression of genes linked to the innate immune response, production of inflammatory molecules, and nerve cell generation and differentiation, among other processes.
The investigators also confirmed that the effects of emapunil were mediated through TSPO, as genetic manipulation to lower TSPO levels impaired emapunil’s benefits.
“This drug acts on the microglia and dampens inflammatory reactions. Basically, this was already known. However, we now discovered that the compound also affects neurons directly,” said Tiago Outeiro, a co-author in the study.
“Our data suggest that Emapunil may be a promising approach in the treatment of Parkinson’s,” researchers wrote. “We thus propose to further validate Emapunil in other Parkinson’s disease mouse models and subsequently in clinical trials.”