The Cannabidiol Analog PECS-101 Prevents Chemotherapy-Induced Neuropathic Pain via PPAR gamma Receptors

Author(s)

Silva, Nicole Rodrigues ^[1] ; Gomes, Francisco Isaac Fernandes ^[1] ; Lopes, Alexandre Hashimoto Pereira ^[1] ; Cortez, Isadora Lopes ^[1] ; dos Santos, Jessica Cristina ^[1] ; Silva, Conceicao Elidianne Anibal ^[2] ; Mechoulam, Raphael ^[3] ; Gomes, Felipe Villela ^[1] ; Cunha, Thiago Mattar ^{[1, 2]} ; Guimaraes, Francisco Silveira ^{[1, 4]}

Affiliation

^[1] Univ Sao Paulo, Ribeirao Preto Med Sch, Dept Pharmacol, Ribeirao Preto - Brazil

^[2] Univ Sao Paulo, Ribeirao Preto Med Sch, Dept Pharmacol, Ctr Res Inflammatory Dis CRID, Ribeirao Preto - Brazil

^[3] Hebrew Univ Jerusalem, Dept Med Chem & Nat Prod, Fac Med, Jerusalem - Israel

^[4] Univ Sao Paulo, Ribeirao Preto Med Sch, Natl Inst Sci & Translat Med, Dept Pharmacol, Ribeirao Preto - Brazil

• Document type: Journal article
• Source: NEUROTHERAPEUTICS; DEC 2021.
• Web of Science Citations: 0

Abstract

Chemotherapy-induced peripheral neuropathy (CIPN) is the main dose-limiting adverse effect of chemotherapy drugs such as paclitaxel (PTX). PTX causes marked molecular and cellular damage, mainly in the peripheral nervous system, including sensory neurons in the dorsal root ganglia (DRG). Several studies have shown the therapeutic potential of cannabinoids, including cannabidiol (CBD), the major non-psychotomimetic compound found in the Cannabis plant, to treat peripheral neuropathies. Here, we investigated the efficacy of PECS-101 (former HUF-101), a CBD fluorinated analog, on PTX-induced neuropathic pain in mice. PECS-101, administered after the end of treatment with PTX, did not reverse mechanical allodynia. However, PECS-101 (1 mg/kg) administered along with PTX treatment caused a long-lasting relief of the mechanical and cold allodynia. These effects were blocked by a PPAR gamma, but not CB1 and CB2 receptor antagonists. Notably, the effects of PECS-101 on the relief of PTX-induced mechanical and cold allodynia were not found in macrophage-specific PPAR gamma-deficient mice. PECS-101 also decreased PTX-induced increase in Tnf, Il6, and Aif1 (Iba-1) gene expression in the DRGs and the loss of intra-epidermal nerve fibers. PECS-101 did not alter motor coordination, produce tolerance, or show abuse potential. In addition, PECS-101 did not interfere with the chemotherapeutic effects of PTX. Thus, PECS-101, a new fluorinated CBD analog, could represent a novel therapeutic alternative to prevent mechanical and cold allodynia induced by PTX potentially through the activation of PPAR gamma in macrophages. (AU)

• FAPESP's process: 17/24304-0 - New perspectives in the use of drugs that modify atypical neurotransmitters in the treatment of neuropsychiatric disorders
• Grantee: Francisco Silveira Guimaraes
• Support Opportunities: Research Projects - Thematic Grants