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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 09; 358(3):387-96.JP

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+Show Affiliations

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.).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.).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.).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.).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.).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.).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.).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.).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.).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.).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.

Pub Type(s)

Journal Article

Language

eng

PubMed ID

27335437

Citation

Hewitt, Ellen, et al. "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." The Journal of Pharmacology and Experimental Therapeutics, vol. 358, no. 3, 2016, pp. 387-96.
Hewitt E, Pitcher T, Rizoska B, et al. 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;358(3):387-96.
Hewitt, E., Pitcher, T., Rizoska, B., Tunblad, K., Henderson, I., Sahlberg, B. L., Grabowska, U., Classon, B., Edenius, C., Malcangio, M., & Lindström, E. (2016). 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. The Journal of Pharmacology and Experimental Therapeutics, 358(3), 387-96. https://doi.org/10.1124/jpet.116.232926
Hewitt E, et al. 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;358(3):387-96. PubMed PMID: 27335437.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - 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. AU - Hewitt,Ellen, AU - Pitcher,Thomas, AU - Rizoska,Biljana, AU - Tunblad,Karin, AU - Henderson,Ian, AU - Sahlberg,Britt-Louise, AU - Grabowska,Urszula, AU - Classon,Björn, AU - Edenius,Charlotte, AU - Malcangio,Marzia, AU - Lindström,Erik, Y1 - 2016/06/22/ PY - 2016/02/19/received PY - 2016/06/20/accepted PY - 2016/6/24/entrez PY - 2016/6/24/pubmed PY - 2017/5/27/medline SP - 387 EP - 96 JF - The Journal of pharmacology and experimental therapeutics JO - J Pharmacol Exp Ther VL - 358 IS - 3 N2 - 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. SN - 1521-0103 UR - https://www.unboundmedicine.com/medline/citation/27335437/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_ L2 - https://jpet.aspetjournals.org/cgi/pmidlookup?view=long&pmid=27335437 DB - PRIME DP - Unbound Medicine ER -