1. Academic Validation
  2. 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

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

  • J Pharmacol Exp Ther. 2016 Sep;358(3):387-96. doi: 10.1124/jpet.116.232926.
Ellen Hewitt 1 Thomas Pitcher 1 Biljana Rizoska 1 Karin Tunblad 1 Ian Henderson 1 Britt-Louise Sahlberg 1 Urszula Grabowska 1 Björn Classon 1 Charlotte Edenius 1 Marzia Malcangio 1 Erik Lindström 2
Affiliations

Affiliations

  • 1 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.).
  • 2 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.) [email protected].
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.

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