title: Selective Cathepsin S Inhibition with MIV-247 Attenuates Mechanical Allodynia and Enhances the Antiallodynic Effects of Gabapentin and Pregabalin in a Mouse Model of Neuropathic Pain.
abstract: Cathepsin S inhibitors attenuate mechanical allodynia in preclinical neuropathic pain models. The current study evaluated the effects when combining the selective cathepsin S inhibitor MIV-247 with gabapentin or pregabalin in a mouse model of neuropathic pain. Mice were rendered neuropathic by partial sciatic nerve ligation. MIV-247, gabapentin, or pregabalin were administered alone or in combination via oral gavage. Mechanical allodynia was assessed using von Frey hairs. Neurobehavioral side effects were evaluated by assessing beam walking. MIV-247, gabapentin, and pregabalin concentrations in various tissues were measured. Oral administration of MIV-247 (100-200 µmol/kg) dose-dependently attenuated mechanical allodynia by up to approximately 50% reversal when given as a single dose or when given twice daily for 5 days. No behavioral deficits were observed at any dose of MIV-247 tested. Gabapentin (58-350 µmol/kg) and pregabalin (63-377 µmol/kg) also inhibited mechanical allodynia with virtually complete reversal at the highest doses tested. The minimum effective dose of MIV-247 (100 µmol/kg) in combination with the minimum effective dose of pregabalin (75 µmol/kg) or gabapentin (146 µmol/kg) resulted in enhanced antiallodynic efficacy without augmenting side effects. A subeffective dose of MIV-247 (50 µmol/kg) in combination with a subeffective dose of pregabalin (38 µmol/kg) or gabapentin (73 µmol/kg) also resulted in substantial efficacy. Plasma levels of MIV-247, gabapentin, and pregabalin were similar when given in combination as to when given alone. Cathepsin S inhibition with MIV-247 exerts significant antiallodynic efficacy alone, and also enhances the effect of gabapentin and pregabalin without increasing side effects or inducing pharmacokinetic interactions.
authors.affiliation: Medivir AB, Huddinge, Sweden (E.H., B.R., K.T., I.H., B.-L.S., U.G., B.C., C.E., E.L.); King´s College London, London, United Kingdom (T.P., M.M.).
authors.forename: Ellen
authors.initials: E
authors.lastname: Hewitt
authors.affiliation: Medivir AB, Huddinge, Sweden (E.H., B.R., K.T., I.H., B.-L.S., U.G., B.C., C.E., E.L.); King´s College London, London, United Kingdom (T.P., M.M.).
authors.forename: Thomas
authors.initials: T
authors.lastname: Pitcher
authors.affiliation: Medivir AB, Huddinge, Sweden (E.H., B.R., K.T., I.H., B.-L.S., U.G., B.C., C.E., E.L.); King´s College London, London, United Kingdom (T.P., M.M.).
authors.forename: Biljana
authors.initials: B
authors.lastname: Rizoska
authors.affiliation: Medivir AB, Huddinge, Sweden (E.H., B.R., K.T., I.H., B.-L.S., U.G., B.C., C.E., E.L.); King´s College London, London, United Kingdom (T.P., M.M.).
authors.forename: Karin
authors.initials: K
authors.lastname: Tunblad
authors.affiliation: Medivir AB, Huddinge, Sweden (E.H., B.R., K.T., I.H., B.-L.S., U.G., B.C., C.E., E.L.); King´s College London, London, United Kingdom (T.P., M.M.).
authors.forename: Ian
authors.initials: I
authors.lastname: Henderson
authors.affiliation: Medivir AB, Huddinge, Sweden (E.H., B.R., K.T., I.H., B.-L.S., U.G., B.C., C.E., E.L.); King´s College London, London, United Kingdom (T.P., M.M.).
authors.forename: Britt-Louise
authors.initials: BL
authors.lastname: Sahlberg
authors.affiliation: Medivir AB, Huddinge, Sweden (E.H., B.R., K.T., I.H., B.-L.S., U.G., B.C., C.E., E.L.); King´s College London, London, United Kingdom (T.P., M.M.).
authors.forename: Urszula
authors.initials: U
authors.lastname: Grabowska
authors.affiliation: Medivir AB, Huddinge, Sweden (E.H., B.R., K.T., I.H., B.-L.S., U.G., B.C., C.E., E.L.); King´s College London, London, United Kingdom (T.P., M.M.).
authors.forename: Björn
authors.initials: B
authors.lastname: Classon
authors.affiliation: Medivir AB, Huddinge, Sweden (E.H., B.R., K.T., I.H., B.-L.S., U.G., B.C., C.E., E.L.); King´s College London, London, United Kingdom (T.P., M.M.).
authors.forename: Charlotte
authors.initials: C
authors.lastname: Edenius
authors.affiliation: Medivir AB, Huddinge, Sweden (E.H., B.R., K.T., I.H., B.-L.S., U.G., B.C., C.E., E.L.); King´s College London, London, United Kingdom (T.P., M.M.).
authors.forename: Marzia
authors.initials: M
authors.lastname: Malcangio
authors.affiliation: Medivir AB, Huddinge, Sweden (E.H., B.R., K.T., I.H., B.-L.S., U.G., B.C., C.E., E.L.); King´s College London, London, United Kingdom (T.P., M.M.) Erik.Lindstrom@albireopharma.com.
authors.forename: Erik
authors.initials: E
authors.lastname: Lindström
mesh_terms: D000588:Amines / Q000494:pharmacology*; D000818:Animals; D001522:Behavior, Animal / Q000187:drug effects; D002403:Cathepsins / Q000037:antagonists & inhibitors*; D003509:Cyclohexanecarboxylic Acids / Q000494:pharmacology*; D004151:Dipeptides / Q000494:pharmacology* / Q000627:therapeutic use; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D004357:Drug Synergism; D000077206:Gabapentin; D006801:Humans; D006930:Hyperalgesia / Q000188:drug therapy* / Q000201:enzymology; D008297:Male; D051379:Mice; D009437:Neuralgia / Q000188:drug therapy* / Q000201:enzymology; D000069583:Pregabalin / Q000494:pharmacology*; D011480:Protease Inhibitors / Q000494:pharmacology* / Q000627:therapeutic use; D005680:gamma-Aminobutyric Acid / Q000494:pharmacology*
chemical_list: D000588:Amines; D003509:Cyclohexanecarboxylic Acids; D004151:Dipeptides; C000619416:MIV-247; D011480:Protease Inhibitors; D000069583:Pregabalin; D005680:gamma-Aminobutyric Acid; D000077206:Gabapentin; D002403:Cathepsins; C028217:cathepsin S