Chemotherapy can induce painful peripheral neuropathy (PNIC), a chronic condition and a common side effect in cancer patients on treatment. Researchers at the University of California San Diego School of Medicine, along with colleagues elsewhere, used a mouse model to demonstrate the central role of cholesterol in CIPN and proposed a new therapeutic approach to reverse it.
The results are published in the May 10, 2021 online issue of Journal of Experimental Medicine.
The study was a lab collaboration between study lead author Yury Miller, MD, PhD, professor of medicine, and Tony Yaksh, PhD, professor of anesthesiology and pharmacology, both at UC San Diego School of Medicine. Miller studies cholesterol metabolism and cardiovascular and neuro inflammation. Yaksh specializes in neuropathic pain.
“It was truly rewarding to work at the intersection of two disciplines and identify the role of cholesterol in activating microglia – the immune cells in the spinal cord – and regulating chronic pain,” said first author Juliana Navia-Pelaez, PhD, a postdoctoral fellow in Miller’s lab.
“Cellular cholesterol metabolism was already linked to neurological disorders, such as Alzheimer’s disease, but we were the first to show its role and its underlying mechanisms in chronic pain.
Cholesterol is essential for the functioning of the brain, both during development and in adulthood. It is a major component of cell membranes, a precursor of certain hormones and serves as a cellular messenger. However, an excess of cholesterol is detrimental to human health; the build-up of cholesterol plaques in the large arteries often causes heart attacks and strokes.
The UC San Diego team found that changes in cholesterol metabolism helped reprogram microglia in a way that perpetuated chronic inflammation in the spinal cord. Genetically engineered mice lacking cholesterol transporters in the microglia were unable to remove excessive amounts of cholesterol, and therefore experienced pain – even without chemotherapy intervention.
The outer membrane of these cells, which is normally fluid, has become rigid with the cholesterol accumulated in the form of solid floating platforms called lipid rafts. The environment of the lipid raft, the authors said, promotes the assembly and activation of cellular proteins that mediate the inflammatory response, such as the Toll-4 receptor (TLR4).
“We were surprised to find that in the NHIC, the enlarged lipid rafts and TLR4 assemblies persisted for days and weeks,” Miller said. “We even started calling them ‘inflammarafts’ to emphasize the importance of these membrane domains in neuroinflammation and pain states.”
To reverse the harmful effects of excessive cholesterol in the microglia, the researchers used a modified version of the apoA-I binding protein (AIBP), which accelerates the elimination of cholesterol and disrupts inflammarafts, but does not damage rafts. physiological lipids. A single injection of AIBP into the spinal canal of mice reversed CIPN pain, and the therapeutic effect lasted for several weeks with no adverse effects.
“The lasting effect that we have observed with the delivery of AIBP indicates a reprogramming of these immune cells which implies that cholesterol plays a fundamental role in the expression of the genes,” said Navia-Pelaez. “It might even act as a driver of epigenetic alterations in microglia and ultimately in pain behavior.”
The authors said the findings were part of a series of promising investigations conducted by UC San Diego and Raft Pharmaceuticals.
“Considerable work remains to be done in terms of safety and kinetics to advance this new biologic for clinical trials,” said Yaksh, “but the current results are extremely promising as they provide a hitherto unappreciated target – the inflammarafts in immune cells – for drug development in the management of chronic neuropathic pain. “