Human Intravenous Immunoglobulin Alleviates Neuropathic Symptoms in a Rat Model of Paclitaxel-Induced Peripheral Neurotoxicity

Abstract

The onset of chemotherapy-induced peripheral neurotoxicity (CIPN) is a leading cause of the dose reduction or discontinuation of cancer treatment due to sensory symptoms. Paclitaxel (PTX) can cause painful peripheral neuropathy, with a negative impact on cancer survivors’ quality of life. While recent studies have shown that neuroinflammation is involved in PTX-induced peripheral neurotoxicity (PIPN), the pathophysiology of this disabling side effect remains largely unclear and no effective therapies are available. Therefore, here we investigated the effects of human intravenous immunoglobulin (IVIg) on a PIPN rat model. PTX-treated rats showed mechanical allodynia and neurophysiological alterations consistent with a severe sensory axonal polyneuropathy. In addition, morphological evaluation showed a reduction of intra-epidermal nerve fiber (IENF) density and evidenced axonopathy with macrophage infiltration, which was more prominent in the distal segment of caudal nerves. Three weeks after the last PTX injection, mechanical allodynia was still present in PTX-treated rats, while the full recovery in the group of animals co-treated with IVIg was observed. At the pathological level, this behavioral result was paralleled by prevention of the reduction in IENF density induced by PTX in IVIg co-treated rats. These results suggest that the immunomodulating effect of IVIg co-treatment can alleviate PIPN neurotoxic manifestations, probably through a partial reduction of neuroinflammation.

Discovery of Potential Neuroprotective Agents against Paclitaxel-Induced Peripheral Neuropathy

“…Neuroinflammation is regarded as a mechanism participating in the development of chemotherapy-induced peripheral neuropathy (CIPN). 30 , 31 Previous studies showed that paclitaxel could drive M1 macrophage activation and infiltration into DRG, and subsequent inflammatory responses occurred. Thus, inhibiting this inflammatory cascade might ameliorate paclitaxel-induced neuropathy.…”

Reversal of Bortezomib-Induced Neurotoxicity by Suvecaltamide, a Selective T-Type Ca-Channel Modulator, in Preclinical Models

“…In phase 1, rats were randomized into two groups, one that was untreated (CTRL, n = 8) and one that received BTZ 0.2 mg/kg (vehicle: 10% Tween ® 80, 10% ethanol 100, and saline) intravenously (IV) via the tail vein, thrice weekly, for 4 weeks (BTZ, n = 44). The dose of BTZ was based on previous experiments [ 30 ]; moreover, the control animals were untreated, as the toxicity of the BTZ vehicle was not evident in previously published data [ 31 ]. Body weight and animal observations were evaluated twice weekly during phase 1 from baseline (day 1) to day 28.…”

Neuroinflammation and сhemotherapy-induced peripheral neuropathy

“…Воздействие IL-20 приводит к высвобождению воспалительных цитокинов, таких как IL-6 и IL-1, IL-8, и способствует секреции хемокинов, включая MCP-1, в линии астроцитарных клеток человека [34]. Примечательно, что блокирование активации IL-20 с помощью моноклональных антител уменьшало тяжесть вызванной паклитакселом нейровоспалительной боли, снижало продукцию TNF-α, IL-6, IL-1β, указывая на способность IL-20 модулировать воспалительные заболевания [35,36].…”

“…Результаты некоторых исследований продемонстрировали эффективность применения человеческого внутривенного иммуноглобулина на фоне лечения паклитакселом у животных: его профилактическое назначение уменьшало степень проявления болевого поведения, связанного с механической стимуляцией, а также способствовало уменьшению повреждения периферических нервов и снижало потери плотности внутриэпидермальных нервных волокон [36].…”