Adenosine A2A Receptor Antagonism Affords Integrated Benefits for Neurological Symptoms of Neurofibromatosis Type I
Abstract
Why is neurofibromatosis type I (NF1) still without a cure? NF1 is a genetic disease causing skin alterations, tumors as well as problems in learning and memory, motor coordination and attention. Animal models were paramount to identify the gene affected and to grasp what goes wrong in NF1. Unfortunately, the alterations are not linear, since the product of the gene causes several parallel alterations in different cells and different neurons. These different alterations have a different impact in different individual and cause a different cluster of symptoms in each NF1 patient. This makes the disease particularly difficult to treat as illustrated by the global failure of the attempts so far made, which only attenuated particular symptoms in some patients. This hints at the need to find novel solutions that can simultaneously target the different alterations present in NF1 to maximize the likeliness of devising the first therapy to assist NF1 patients. A new possible target to manage NF1: We noted that there is a fine-tuning system of information processing in the brain that may fulfill these criteria, which is designated by adenosine A2A receptors (A2AR). A2AR are sensors in the membrane of neurons (and other cells), aimed at detecting the presence of adenosine (a danger signal): when things go wrong in neuron brain circuits, adenosine is produced; when sensed by A2AR, the system forces adaptive changes in neuronal connections to correct the abnormal function. This is efficient to resolve minor and episodic dysfunction; however, in disease conditions, the overfunctioning of A2AR actually the adaptive capacity of neurons, destroying their capacity to work. Accordingly, in different disease models, it was shown that drugs blocking A2AR are beneficial in ameliorating memory in Alzheimer’s disease, motor coordination in ataxia, attention in ADHD (attention deficit and hyperactivity disorder), mood and anxiety upon chronic stress. In spite of this promising profile, the therapeutic potential of drugs blocking A2AR has never been tested in the context of NF1. What we propose to do: We now propose to use a mouse model of NF1, which has been shown to display memory, attention, motor and mood deficits similar to these present in NF1 patients, to test if A2AR can be considered a new potential drug target to manage NF1 behavioral symptoms. This implies measuring if A2AR are functioning abnormally in different brain regions of NF1 mice and testing if a drug blocking A2AR can revert the different behavioral symptoms present in young adult NF1 mice of both genders. Possible impact of our project: If the present proof-of concept project is successful, we anticipate a rapid translation of this concept to clinical practice since drugs blocking A2AR have been tested as an anti-Parkinsonian drugs in over 3000 patients with a remarkable safety profile.
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Oct 29, 2018
- Source ID
- W81XWH1810532
Entities
People
- Rodrigo A. Cunha
Organizations
- Centre for Neuroscience and Cell Biology
- United States Army