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 mmol/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 mmol/kg) and pregabalin (63-377 mmol/kg) also inhibited mechanical allodynia with virtually complete reversal at the highest doses tested. The minimum effective dose of MIV-247 (100 mmol/kg) in combination with the minimum effective dose of pregabalin (75 mmol/kg) or gabapentin (146 mmol/kg) resulted in enhanced antiallodynic efficacy without augmenting side effects. A subeffective dose of MIV-247 (50 mmol/kg) in combination with a subeffective dose of pregabalin (38 mmol/kg) or gabapentin (73 mmol/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.

The Role of Spinal Cord CX3CL1/CX3CR1 Signalling in Chronic Pain

“…In this case however, the elevation of CatS in the spinal cord is not a result of microglial activation and thus CatS release but is attributed to infiltrating monocytes from the periphery [37••]. Furthermore, despite systemic CatS inhibition showing limited efficacy in reversing established pain in surgical models, in a recent study using the partial sciatic nerve ligation preclinical model, treatment with an orally active CatS inhibitor, MIV-247, significantly reversed surgery-induced allodynia within 3 h of administration [43]. This suggests that the specific antagonist used could also determine the effectiveness of CatS disruption in different locations, i.e.…”

Microglia-Mediated Regulation of Neuropathic Pain: Molecular and Cellular Mechanisms

“…116) While mechanical hypersensitivity in a collagen-induced arthritis model is attenuated by intrathecal P2X7R antagonists, 117) clinical trials of P2X7 antagonists in rheumatoid arthritis have failed. 118) The role of P2X7R is thus still controversial. A selective inhibitor for CatS was also reported to attenuate neuropathic allodynia and to potentiate an anti-allodynic efficacy of pregabalin without influencing its side effects.…”

Inhibition of cathepsin S attenuates myocardial ischemia/reperfusion injury by suppressing inflammation and apoptosis

“…**p < .01 versus the sham group; ## p < 0.01 for the comparisons shown. DAPI, 4′,6-diamidino-2-phenylindole; IL-1β, interleukin-1β; IL-6, interleukin-6; I/R, ischemia/reperfusion; TNF-α, tumor necrosis factor-α; TUNEL, TdT-mediated dUTP nick-end labeling (Hewitt et al, 2016). In lupus nephritis, cathepsin S blockade suppressed systemic and peripheral autoimmune tissue injury (Tato et al, 2017).…”

“…Then, mice were randomly assigned to one of six groups: SH, SH + LY3000328, SH + MIV‐247, I/R, I/R + LY3000328, and I/R + MIV‐247. One of three solutions, LY3000328 (5 mg/kg; Jadhav et al, 2014; Steimle et al, 2016), MIV‐247 (200 µmol/kg; Hewitt et al, 2016), or the same volume of vehicle (20% hydroxypropyl‐β‐cyclodextrin in water), was administered by oral gavage for 3 days, twice daily, starting from 3 days before ischemia. The protein expression of cleaved caspase‐8, cleaved caspase‐3, and cleaved poly ADP‐ribose polymerase (PARP) was determined by western blot.…”