Effect of fluoxetine on neuromuscular function in acetylcholinesterase (AChE) knockout mice
Christelle Bertrand1, Beatrice Bonafos, Maud Tremblay
1Différenciation Cellulaire et Croissance UMR 866 INRA, Université Montpellier 1 & 2 Montpellier, 2 place Vila, Montpellier, France.
Abstract:
Congenital myasthenic syndromes (CMS) are a heterogeneous group of diseases caused by genetic defects affecting neuromuscular transmission. The causal mutations have been described in number of cases. The slow channel myasthenic syndrome (slow-channel-CMS) results in a marked prolongation of channel opening in stimulated receptors (nAChR) and the end plate acetylcholinesterase (AChE) deficiency congenital myasthenic syndrome (ColQ-CMS) results in an increased action of acetylcholine (ACh) at the synapse. Anticholinesterase medication is detrimental in these cases. The successful treatment of slow-channel-CMS patients with the antidepressant serotonin re-uptake inhibitor fluoxetine has been reported. At high concentration it has a non-depolarizing effect on nicotinic receptors. This led us to the idea that fluoxetine could protect AChR from a relative excess of ACh. We investigated the possible use of fluoxetine as treatment in the AChE KO mouse. Treatment at 6 mg/kg from 3 weeks to 2 months increased slightly the daily weight gain but not the final weight at 2 months in AChE-/- mice. Isometric force production of Tibialis anterior in response to electric nerve stimulation was measured in situ in AChE-/- and wild type mice treated or not by fluoxetine. The results show that the maximum twitch force in response to a single nerve stimulation, the maximal tetanic force (P0) in response to repetitive nerve stimulation and the tetanic fade are not changed in AChE-/- mice treated with fluoxetine versus control AChE-/- mice.
Insights
Fluoxetine, an antidepressant, was investigated for treating congenital myasthenic syndromes (CMS) involving acetylcholinesterase (AChE) deficiency. While it did not improve muscle function in AChE knockout mice, further research into fluoxetine for CMS is warranted.
Area of Science:
- Neurology
- Genetics
- Pharmacology
Background:
- Congenital myasthenic syndromes (CMS) are genetic disorders affecting neuromuscular transmission.
- Specific CMS types, like slow-channel CMS and ColQ-CMS, involve nicotinic receptor (nAChR) dysfunction or acetylcholinesterase (AChE) deficiency.
- Anticholinesterase drugs can worsen these conditions, necessitating alternative treatments.
Purpose of the Study:
- To investigate the therapeutic potential of fluoxetine in a mouse model of AChE deficiency congenital myasthenic syndrome.
- To determine if fluoxetine can mitigate the effects of excess acetylcholine at the neuromuscular junction.
Main Methods:
- Utilized acetylcholinesterase knockout (AChE-/-) mice as a model for ColQ-CMS.
- Administered fluoxetine (6 mg/kg) to AChE-/- mice from 3 weeks to 2 months of age.
- Assessed isometric muscle force production in the Tibialis anterior muscle via in situ electrophysiological nerve stimulation.
Main Results:
- Fluoxetine treatment showed a slight increase in daily weight gain but did not affect final body weight in AChE-/- mice.
- No significant differences were observed in maximum twitch force, maximal tetanic force (P0), or tetanic fade between fluoxetine-treated and untreated AChE-/- mice.
- Muscle function parameters in AChE-/- mice treated with fluoxetine were comparable to control AChE-/- mice.
Conclusions:
- Fluoxetine at the tested dosage and duration did not improve neuromuscular transmission or muscle function in a mouse model of AChE deficiency CMS.
- The proposed mechanism of fluoxetine protecting nAChRs from acetylcholine excess was not supported by these findings in this specific model.
- Further investigation is needed to explore alternative therapeutic strategies for AChE deficiency congenital myasthenic syndromes.
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