Parkinson’s Therapy May Hold Promise for Fragile X
Treatment with istradefylline — an approved therapy for Parkinson’s disease — normalized several molecular and functional nerve cell features of fragile X syndrome and improved cognitive skills in a mouse model of the disease, a study shows.
The therapy, sold by Kyowa Hakko Kirin Pharma under the brand name Nourianz, works by suppressing the activity of adenosine A2A receptors (A2AARs), proteins known to tightly control the overly active activity of a nerve cell receptor in fragile X patients.
Together with the fact that A2AAR production was found to be normally regulated by FMRP — the protein lacking in fragile X — these findings highlight the disease-contributing role of such receptors and point out their suppression as a potential therapeutic approach for fragile X.
Future studies are needed to better understand A2AAR’s role in fragile X and further evaluate the therapeutic potential of istradefylline, researchers said.
The study, “Adenosine A2A receptor inhibition reduces synaptic and cognitive hippocampal alterations in Fmr1 KO mice,” was published in the journal Translational Psychiatry.
Fragile X is caused by low or no levels of FMRP, which controls the production of several proteins at synapses — the site of near contact between nerve cells that allows them to communicate.
FMRP deficiency leads to excessive protein production at synapses, resulting in synapse weakening and lack of synaptic plasticity (the ability to strengthen or weaken in response to information), which causes memory and learning impairments.
These damaging effects were previously shown to be associated with higher-than-normal activation of mGluR5, a specific receptor of the neurotransmitter glutamate, at synapses.
Neurotransmitters are key molecules in nerve cell communication, and glutamate is involved in several brain functions such as learning and memory.
The effects of a selective mGlu5R suppressor called AFQ056 (developed as mavoglurant by Novartis but was discontinued in 2014) were previously evaluated in clinical trials of fragile X patients, with disappointing results. A new Phase 2 trial (NCT02920892) is currently assessing whether the therapy can specifically improve language learning in young children with the disease.
Notably, blocking mGluR5 may cause serious adverse events, due to its major role in synaptic activity and plasticity, and result in treatment tolerance (waning of effectiveness), as observed in a mouse model.
Now, researchers in Italy have shown that selectively blocking the A2AAR, a nerve cell receptor known to tightly control mGluR5s in different brain regions, may be a new therapeutic approach for fragile X.
A previous study showed that A2AARs, involved in the regulation of synaptic activity, co-localized and interacted with mGluR5s in the hippocampus, a brain region involved in learning and memory that is strongly affected in fragile X. Notably, the data also highlighted that A2AARs needed to be activated to allow mGluR5s-induced effects to occur.
In the current study, the researchers first discovered that the interaction between the two types of receptors was altered in a mouse model of fragile X, when compared with healthy mice. Particularly, activation of A2AARs promoted greater mGlu5R-induced synapse weakening in affected mice than in healthy mice.
The team then evaluated whether blocking A2AAR activity with istradefylline — a specific A2AAR suppressor — could improve or normalize molecular signaling and synaptic function in the hippocampus, as well as behavior.
Results showed that treatment normalized the levels of several signaling molecules affected by fragile X, improved synaptic resistance to mGlu5R-induced weakening, and normalized the number of dendritic spines — tiny nerve cell structures involved in nerve cell communication.
Treated mice also showed reduced testes size (closer to normal) and fewer cognitive problems compared with no treatment. There were, however, no changes in the animal’s hyperactivity, repetitive behavior, and motor discoordination, compared with untreated mice.
These findings suggest that A2AAR suppressors, such as istradefylline, “could represent a possible novel therapeutic tool in FXS [fragile X],” the team wrote, adding that “given the complexity of the molecular abnormalities observed in FXS, targeting different pathways at the same time could represent a better therapeutic strategy.”
Notably, further analyses revealed that, in normal conditions, FMRP regulates the production of A2AARs in different brain areas, including the hippocampus, suggesting that A2AAR abnormalities and subsequent effects “might derive from the defective FMRP complex control” of A2AAR production at early stages of brain development, the researchers wrote.
Further studies are needed to clarify this and the nature of the interaction between A2AARs and mGlu5Rs, as well as to better understand the potential benefits of istradefylline in fragile X.