Adenosine Tonus is Impaired in Toxin Induced Myasthenia Gravis
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1
Universidade do Porto, Laboratorio de Farmacologia e Neurobiologia, UMIB, Instituto de Ciencias Biomedicas de Abel Salazar (ICBAS), Portugal
At the rat motor endplate, adenosine acts as a neuromodulator either inhibiting (A1 receptors) or facilitating (A2A receptors) ACh release [1]. The A1/A2A receptors activation balance is dependent on extracellular adenosine levels, which is a function of adenosine formation from the catabolism of released adenine nucleotides (e.g. ATP), adenosine uptake and extracellular deamination [1,2]. The fine-tuning between adenosine receptors activity and the mechanisms involved in extracellular adenosine accumulation can assume an important role when neuromuscular transmission is impaired, like in Myasthenia Gravis. This prompted us to evaluate the effect of the adenosine precursor, AMP, as well as of adenosine, on evoked (5 Hz, 50 pulses) [3H]-ACh release using a rat model of Myasthenia gravis induced by alpha-bungarotoxin (TIMG) [3].
Application of adenosine (3-500 μM) caused a biphasic effect on evoked [3H]-ACh release in control rats [2]. The bell-shape inhibitory effect of adenosine was shifted to the right in TIMG animals, but the nucleoside failed to facilitate ACh release. Preliminary results in TIMG animals suggest that synaptic adenosine deaminase activity is increased as compared to controls. While we observed reduced levels of the nucleoside coming from contracting skeletal muscle fibres of myasthenic animals (see Trigo, 2007, Biochem. Thesis), adenosine formation from the catabolism of adenine nucleotides (e.g. ATP, AMP) was virtually unchanged. Interestingly, adenosine A1-receptor-mediated inhibition recovered to control levels after pretreatment with the nucleoside transport inhibitor, S-(p-nitrobenzyl)-6-(thioinosine) (NBTI, 10 μM), whereas reestablishment of the A2A-mediatd facilitation of ACh release required incubation with higher amounts of the adenosine precursor, AMP (100 μM), in TIMG animals.
Overall, the results suggest that reinforcement of transmitter release mediated by adenosine that is required to improve neuromuscular transmission in Myasthenia gravis can be obtained upon increasing the amount of the nucleoside formed from the extracellular catabolism of adenine nucleotides (e.g. using AMP as a precursor), which preferentially activates facilitatory A2A receptors [see e.g. 4].
Work supported by FCT
References
1. Correia-de-Sá et al. (1996) J. Neurophysiol., 76, 3910-19;
2. Correia-de-Sá & Ribeiro (1996) Neuroscience, 73, 85-92;
3. Plomp et al. (1992) J. Physiol., 458, 487-99;
4. Cunha et al. (1996) Br. J. Pharmacol., 119, 253-60.
Conference:
11th Meeting of the Portuguese Society for Neuroscience, Braga, Portugal, 4 Jun - 6 Jun, 2009.
Presentation Type:
Poster Presentation
Topic:
Neuronal Communication
Citation:
Costa
C,
Morais
T,
Trigo
D,
Noronha-Matos
JB,
Timoteo
MA,
Magalhaes-Cardoso
MT,
Oliveira
L and
Correia-de-Sa
P
(2009). Adenosine Tonus is Impaired in Toxin Induced Myasthenia Gravis.
Front. Neurosci.
Conference Abstract:
11th Meeting of the Portuguese Society for Neuroscience.
doi: 10.3389/conf.neuro.01.2009.11.147
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Received:
12 Aug 2009;
Published Online:
12 Aug 2009.
*
Correspondence:
Cristina Costa, Universidade do Porto, Laboratorio de Farmacologia e Neurobiologia, UMIB, Instituto de Ciencias Biomedicas de Abel Salazar (ICBAS), Porto, Portugal, cristina.marques.costa@gmail.com