Modulation of chemotherapy-induced peripheral neuropathy by JZL195 through glia and the endocannabinoid system

Biomed Pharmacother. 2024 Nov:180:117515. doi: 10.1016/j.biopha.2024.117515. Epub 2024 Oct 2.

Abstract

Chemotherapy-induced peripheral neuropathy (CIPN) used to treat cancer, is a significant side effect with a complex pathophysiology, and its mechanisms remain unclear. Recent research highlights neuroinflammation, which is modulated by the endocannabinoid system (ECS) and associated with glial activation, and the role of toll-like receptor 4 (TLR4) in CIPN. This study aimed to investigate the effects of JZL195, an inhibitor of fatty acid amide hydrolase (FAAH) and monoacylglycerol lipase (MAGL), and explore the connection between cannabinoid receptors and TLR4 in glial cells. A CIPN animal model was developed using cisplatin-injected male C57BL/6 mice. Mechanical and cold allodynia were assessed through von Frey and acetone tests. Western blot analysis was used to examine the expression of catabolic enzymes, cannabinoid receptors, glial cells, and neuroinflammatory factors in the dorsal root ganglia (DRGs) and spinal cord. Immunohistochemistry was used to investigate the colocalization of cannabinoid receptors and TLR4 in glial cells. JZL195 alleviated pain by inhibiting FAAH/MAGL, modulating the ECS and neuroinflammatory factors, and suppressing glial cell activity. Additionally, cannabinoid receptors and TLR4 colocalized with astrocytes and microglia in the spinal cord. This study highlights the therapeutic potential of JZL195 in modulating the ECS and suggests a correlation between cannabinoid receptors and TLR4 in spinal glial cells, providing insight into alleviating pain and neuroinflammation in CIPN.

Keywords: Chemotherapy-induced peripheral neuropathy; Endocannabinoid system; Glia; Neuroinflammation; Toll-like receptor 4.

MeSH terms

  • Amidohydrolases / antagonists & inhibitors
  • Amidohydrolases / metabolism
  • Animals
  • Antineoplastic Agents / adverse effects
  • Antineoplastic Agents / pharmacology
  • Carbamates
  • Cisplatin / adverse effects
  • Cisplatin / pharmacology
  • Disease Models, Animal
  • Endocannabinoids* / metabolism
  • Ganglia, Spinal* / drug effects
  • Ganglia, Spinal* / metabolism
  • Hyperalgesia / chemically induced
  • Hyperalgesia / drug therapy
  • Hyperalgesia / metabolism
  • Male
  • Mice
  • Mice, Inbred C57BL*
  • Monoacylglycerol Lipases / antagonists & inhibitors
  • Monoacylglycerol Lipases / metabolism
  • Neuroglia* / drug effects
  • Neuroglia* / metabolism
  • Neuroglia* / pathology
  • Peripheral Nervous System Diseases* / chemically induced
  • Peripheral Nervous System Diseases* / drug therapy
  • Peripheral Nervous System Diseases* / metabolism
  • Peripheral Nervous System Diseases* / pathology
  • Piperazines
  • Piperidines / pharmacology
  • Receptors, Cannabinoid / metabolism
  • Spinal Cord / drug effects
  • Spinal Cord / metabolism
  • Spinal Cord / pathology
  • Toll-Like Receptor 4* / metabolism

Substances

  • Endocannabinoids
  • Toll-Like Receptor 4
  • fatty-acid amide hydrolase
  • JZL195
  • Monoacylglycerol Lipases
  • Amidohydrolases
  • Piperidines
  • Cisplatin
  • Antineoplastic Agents
  • Receptors, Cannabinoid
  • Tlr4 protein, mouse
  • Carbamates
  • Piperazines