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Fluoxetine is neuroprotective in slow-channel congenital myasthenic syndrome.

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.
AuthorsHaipeng Zhu, Gary E Grajales-Reyes, Vivianette Alicea-Vázquez, Jose G Grajales-Reyes, KaReisha Robinson, Peter Pytel, Carlos A Báez-Pagán, Jose A Lasalde-Dominicci, Christopher M Gomez
JournalExperimental neurology (Exp Neurol) Vol. 270 Pg. 88-94 (Aug 2015) ISSN: 1090-2430 [Electronic] United States
PMID25448156 (Publication Type: Journal Article, Research Support, N.I.H., Extramural)
CopyrightCopyright © 2014 Elsevier Inc. All rights reserved.
Chemical References
  • Neuroprotective Agents
  • Fluoxetine
Topics
  • Animals
  • Disease Models, Animal
  • Fluoxetine (pharmacology)
  • Male
  • Mice
  • Mice, Transgenic
  • Motor Activity (drug effects)
  • Myasthenic Syndromes, Congenital (physiopathology)
  • Neuromuscular Junction (drug effects)
  • Neuroprotective Agents (pharmacology)
  • Patch-Clamp Techniques
  • Recovery of Function (drug effects)

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