Reestablishment of adenosine levels: a possible strategy for Rett Syndrome
Catarina
Miranda-Lourenço1, 2*,
Sofia
T.
Duarte1,
Cátia
Palminha1, 2,
Mariana
Colino-Oliveira1, 2,
Jéssica
Rosa1, 2,
Rui
Gomes1,
Tiago
M.
Rodrigues1, 2,
Sara
Xapelli1, 2,
Luísa
V.
Lopes1,
Ana
M.
Sebastião1, 2 and
Maria
J.
Diógenes1, 2*
-
1
Institute of Molecular Medicine João Lobo Antunes, Faculty of Medicine, University of Lisbon, Portugal
-
2
Institute of Pharmacology and Neurosciences, Faculty of Medicine, University of Lisbon, Portugal
Rett Syndrome (RTT) is a rare neurodevelopmental disorder primarily caused by mutations in the methyl-CpG binding protein 2 (MECP2) gene (1). MeCP2 is known to modulate the expression of brain-derived neurotrophic factor (BDNF), a neurotrophin with essential functions in cell differentiation, synaptic plasticity and survival. BDNF signalling is impaired in RTT (2). Thus, therapeutic strategies designed at delivering BDNF to the brain could be a breakthrough in RTT treatment. However, this strategy is challenged by the inability of BDNF to cross the blood-brain barrier. Adenosine (ADO) is a neuromodulator that acts mainly through A1 and A2A receptors (A1R, A2AR). The activation of A2AR potentiates BDNF synaptic actions (3), important to overcome cognitive deficits presented by RTT patients. On the other hand, A1R activation provides potent seizure control important to ameliorate epilepsy in RTT patients. Thus, activation of both ADO receptors could be a potential therapeutic strategy (4).
In the present work we set out to characterize the adenosinergic system and BDNF signalling in a well-established animal model of RTT, both in male homozygous mice (KO) and female heterozygous (HET) for Mecp2 gene (5).
The obtained results provided valuable information about alterations in BDNF signalling and changes in excitability. Importantly, for the first time, a highly deregulation on adenosinergic system was detected which supports the use of adenosine augmentation therapy in RTT.
Importantly, our data showed that the ex vivo activation of A2AR with a selective agonist recovers the lost effect of BDNF upon Long-term potentiation (LTP). Remarkably the effect of BDNF upon LTP in hippocampal slices taken from animals treated in vivo intraperitoneal with an inhibitor of adenosine kinase, an enzyme highly responsible for the regulation of adenosine levels through its degradation, was also increased.
Taken together, this data highlights the central role of adenosinergic system deregulation in RTT pathophysiology and it shed light into the relevance of the reestablishment of adenosinergic system in RTT.
Acknowledgements
Funding:
AdoRett - LISBOA-01-0145-FEDER-031929, Fundação para a Ciência e Tecnologia
Regulation of adenosine levels as a new therapeutic strategy for Rett Syndrome, Association française du syndrome de rett
SynaNet – Twinning Action (GA-692340), European Union’s H2020
GAPIC, Faculdade de Medicina da Universidade de Lisboa
References
1 - Chahrour, M. and Zoghbi, H.Y. Neuron. 2007;56(3): 422–437;
2 - Li, W. and Pozzo-Miller, L. Neuropharmacology. 2014;76: 737–746;
3 - Ribeiro FF et al. Neuropharmacology. 2015. S0028-3908(15): 30170-2;
4 - Boison, D. Epilepsy Res. 2009;85(503):131–141
5 - Guy, J. et al., 2001. Nat. Genet., 27(3), pp.322–326; 6 - Shi, Y. et al. Nat. Protoc. 2012; 7(10):1836–1846.
Keywords:
Rett Syndrome,
rare disorders,
BDNF,
Adenosine,
Adenosine augmentation therapy
Conference:
XVI Meeting of the Portuguese Society for Neuroscience (SPN2019), Lisboa, Portugal, 30 May - 1 Jun, 2019.
Presentation Type:
Oral presentation
Topic:
Rare Disorders
Citation:
Miranda-Lourenço
C,
Duarte
ST,
Palminha
C,
Colino-Oliveira
M,
Rosa
J,
Gomes
R,
Rodrigues
TM,
Xapelli
S,
Lopes
LV,
Sebastião
AM and
Diógenes
MJ
(2019). Reestablishment of adenosine levels: a possible strategy for Rett Syndrome.
Front. Cell. Neurosci.
Conference Abstract:
XVI Meeting of the Portuguese Society for Neuroscience (SPN2019).
doi: 10.3389/conf.fncel.2019.01.00046
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Received:
03 Mar 2019;
Published Online:
27 Sep 2019.
*
Correspondence:
Miss. Catarina Miranda-Lourenço, Institute of Molecular Medicine João Lobo Antunes, Faculty of Medicine, University of Lisbon, Lisboa, Portugal, catmlourenco@gmail.com
Prof. Maria J Diógenes, Institute of Pharmacology and Neurosciences, Faculty of Medicine, University of Lisbon, Lisbon, Portugal, diogenes@medicina.ulisboa.pt