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
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DOI：
10.1124/jpet.116.232926
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发表时间：
2016-09-01
影响因子：
3.5
通讯作者：
Lindstrom, Erik
中科院分区：
文献类型：
--
作者：
Hewitt, Ellen;Pitcher, Thomas;Lindstrom, Erik
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 mu mol/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 mu mol/kg) and pregabalin (63-377 mu mol/kg) also inhibited mechanical allodynia with virtually complete reversal at the highest doses tested. The minimum effective dose of MIV-247 (100 mu mol/kg) in combination with the minimum effective dose of pregabalin (75 mu mol/kg) or gabapentin (146 mu mol/kg) resulted in enhanced antiallodynic efficacy without augmenting side effects. A sub-effective dose of MIV-247 (50 mu mol/kg) in combination with a sub-effective dose of pregabalin (38 mu mol/kg) or gabapentin (73 mu mol/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 pharma-cokinetic interactions.
