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Exp Neurol. 2015 Aug;270:88-94. doi: 10.1016/j.expneurol.2014.10.008. Epub 2014 Oct 23.

Fluoxetine is neuroprotective in slow-channel congenital myasthenic syndrome.

Author information

1
Department of Neurology, The University of Chicago, Chicago, IL, USA.
2
School of Medicine, Washington University, St. Louis, St. Louis, MO, USA.
3
Department of Biology, The University of Puerto Rico, San Juan, Puerto Rico, USA.
4
Department of Pathology, The University of Chicago, Chicago, IL, USA.
5
Department of Neurology, The University of Chicago, Chicago, IL, USA. Electronic address: gomez001@uchicago.edu.

Abstract

The slow-channel congenital myasthenic syndrome (SCS) is an inherited neurodegenerative disease that caused mutations in the acetylcholine receptor (AChR) affecting neuromuscular transmission. Leaky AChRs lead to Ca(2+) overload and degeneration of the neuromuscular junction (NMJ) attributed to activation of cysteine proteases and apoptotic changes of synaptic nuclei. Here we use transgenic mouse models expressing two different mutations found in SCS to demonstrate that inhibition of prolonged opening of mutant AChRs using fluoxetine not only improves motor performance and neuromuscular transmission but also prevents Ca(2+) overload, the activation of cysteine proteases, calpain, caspase-3 and 9 at endplates, and as a consequence, reduces subsynaptic DNA damage at endplates, suggesting a long term benefit to therapy. These studies suggest that prolonged treatment of SCS patients with open ion channel blockers that preferentially block mutant AChRs is neuroprotective.

KEYWORDS:

Acetylcholine receptor; Ca2+ overload; Fluoxetine; Ion channel blockers; Mutation; Neurodegenerative disease; Neuromuscular junction; Neuromuscular transmission; Neuroprotective; Slow-channel congenital myasthenic syndrome; Subsynaptic DNA damage

PMID:
25448156
PMCID:
PMC4430442
DOI:
10.1016/j.expneurol.2014.10.008
[Indexed for MEDLINE]
Free PMC Article

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