Ilaria Saltarella
Proof of concept for drug repurposing of fenamates in myotonia congenita
Autori
- ILARIA SALTARELLA (SECTION OF PHARMACOLOGY, DEPARTMENT OF PRECISION AND REGENERATIVE MEDICINE AND IONIAN AREA, SCHOOL OF MEDICINE, UNIVERSITY OF BARI ALDO MORO, 70124 BARI, ITALY – FIXED-TERM TYPE A RESEARCHER)
- PAOLA LAGHETTI (SECTION OF PHARMACOLOGY, DEPARTMENT OF PRECISION AND REGENERATIVE MEDICINE AND IONIAN AREA, SCHOOL OF MEDICINE, UNIVERSITY OF BARI ALDO MORO, 70124 BARI, ITALY – )
- CARMEN CAMPANALE (SECTION OF PHARMACOLOGY, DEPARTMENT OF PRECISION AND REGENERATIVE MEDICINE AND IONIAN AREA, SCHOOL OF MEDICINE, UNIVERSITY OF BARI ALDO MORO, 70124 BARI, ITALY – )
- ILARIA NINNI (SECTION OF PHARMACOLOGY, DEPARTMENT OF PRECISION AND REGENERATIVE MEDICINE AND IONIAN AREA, SCHOOL OF MEDICINE, UNIVERSITY OF BARI ALDO MORO, 70124 BARI, ITALY – )
- CONCETTA ALTAMURA (SECTION OF PHARMACOLOGY, DEPARTMENT OF PRECISION AND REGENERATIVE MEDICINE AND IONIAN AREA, SCHOOL OF MEDICINE, UNIVERSITY OF BARI ALDO MORO, 70124 BARI, ITALY – )
- JEAN-FRANCOIS DESAPHY (SECTION OF PHARMACOLOGY, DEPARTMENT OF PRECISION AND REGENERATIVE MEDICINE AND IONIAN AREA, SCHOOL OF MEDICINE, UNIVERSITY OF BARI ALDO MORO, 70124 BARI, ITALY -)
Presentatore
ILARIA SALTARELLA (SECTION OF PHARMACOLOGY, DEPARTMENT OF PRECISION AND REGENERATIVE MEDICINE AND IONIAN AREA, SCHOOL OF MEDICINE, UNIVERSITY OF BARI ALDO MORO, 70124 BARI, ITALY)
Modalità
Oral Communication
Abstract
“Loss-of-function mutations of the skeletal muscle chloride channel, hClC-1, are responsible for Myotonia Congenita (MC). Nevertheless, to date there are no drugs able to target ClC-1 mutations in myotonic patients. Previously, we demonstrated that the non-steroidal anti-inflammatory drug niflumic acid, a reversible ClC-1 inhibitor belonging to fenamates, acts as a pharmacological chaperone able to rescue chloride currents in trafficking-defective ClC-1 mutants [Altamura C. et al, Front Pharmacol. 2022]. Here, we investigated the effect of fenamates mefenamic (MFA), meclofenamic (MCFA), tolfenamic (TFA), flufenamic (FFA) acids on ClC-1 activity.
HEK293 cells were transfected with the pRc/CMV plasmid containing the wild-type hClC-1 or the defective-trafficking isoform, p.A531V. The acute effect of fenamates was evaluated on the wild-type channel by whole-cell patch-clamp technique. The chaperone effect was tested on the p.A531V mutant after incubation with FFA for 24 hours followed by patch clamp analysis.
Dose-response relationships of fenamates (10, 30, 100 and 300 µM) demonstrated that TFA and FFA were the most potent fully reversible inhibitors of hClC-1 able to reduce the steady-state chloride currents at -90 mV. The use of chelerythrine, a protein kinase C (PKC) inhibitor, suggested that inhibition of ClC-1 induced by fenamates was not mediated by the Ca2+-dependent PKC pathway. Incubation of HEK293 cells expressing the p.A531V mutant with FFA induced an increase of the steady-state and instantaneous chloride currents.
Fenamates may act as pharmacological chaperones of trafficking-defective hClC-1 mutants, supporting a potential repurposing for the treatment of MC patients.
Supported by University of Bari “Horizon Europe Seeds – Medineuropa””