Modified peptide that reduces pain in peripheral neuropathy

Abstract

Chemokine signaling is important in neuropathic pain, with microglial cells expressing CCR2 playing a well established key role. DAPTA, a gp120-derived CCR5 entry-inhibitor has been shown to inhibit CCR5-mediated monocyte migration and to attenuate neuroinflammation. We disclose here that as a stabilized analog of DAPTA, the short peptide All D TTNYT (SEQ ID NO:1) exhibits potent antagonism for both CCR2 (IC4.2 pM) and CCR5 (IC0.18 pM) in monocyte chemotaxis. Oral administration of All D TTNYT (SEQ ID NO:1) (0.05-1 mg/kg) for 7 days fully prevents mechanical allodynia and inhibits the development of thermal hyperalgesia following partial ligation of the sciatic nerve in rats. Administered from day 8 to day 12, All D TTNYT (SEQ ID NO:1) (0.2-1 mg/kg) reverses already established hypersensitivity. All D TTNYT (SEQ ID NO:1) relieves pain hypersensitivity probably through either or both CCR2 and CCR5, since by using genetically deficient animals, we demonstrated that in addition to CCR2, CCR5 is also required for the development of neuropathic pain. Moreover, All D TTNYT (SEQ ID NO:1) is able to reduce spinal microglial activation, monocyte infiltration, and to inhibit inflammatory responses evoked by peripheral nerve injury that cause chronic pain. Our findings suggests that the targeting CCR2/CCR5 should provide greater efficacy than targeting CCR2 or CCR5 alone and dual CCR2/CCR5 antagonist All D TTNYT (SEQ ID NO:1) has the potential for broad clinical use in neuropathic pain treatment.