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.

Keywords: IENF; axon degeneration; chemotherapy; intravenous immunoglobulin (IVIg); neuropathic pain; paclitaxel.

Figure 1

Flow chart and serum concentration of human intravenous immunoglobulin (IVIg). (a) Flow chart of the experimental plan. (b) At baseline, mid treatment and at the end of treatment blood samples were collected 1 h after IVIg infusion. At follow up, blood samples were collected two weeks after the last IVIg infusion. ** infusion with IVIg not performed as per the protocol.

Figure 2

Effects of PTX and IVIg co-treatment on mechanical allodynia. IVIg alleviates mechanical allodynia in a rat model of PIPN at the end of FU. * p < 0.01, ** p < 0.001 vs. VEH (n = 12 rats/group). The statistical analysis was performed using the Kruskal-Wallis test.

Figure 3

Effects of the IVIg on sensory nerve conduction velocity (NCV) and sensory nerve action potential (SNAP) amplitudes. (a) Proximal caudal nerve NCV and SNAP amplitude. (b) Distal caudal nerve NCV and SNAP amplitude. (c) Digital nerve NCV and SNAP amplitude. ◦ p < 0.05, * p < 0.01, ** p < 0.001 vs. VEH (n = 12 rats/group). All data were analyzed with the Kruskal-Wallis test.

Figure 4

Effects of PTX and IVIg co-treatment on IENF density. IVIg reduces the loss of unmyelinated fibers observed in paclitaxel-treated rats at the end of follow up period. ◦ p < 0.05, ** p < 0.001 vs. VEH (n = 12 rats/group). Data were analyzed using the non-parametric Kruskal-Wallis test.

Figure 5

Morphological analysis of distal caudal nerves. IVIg co-treatment starting from the first PTX administration (PTX + IVIg4 group) reduced PTX-induced distal axonal degeneration.

Figure 6

Immunolocalization of CD68⁺ macrophages in distal caudal nerves. IVIg + PTX co-treatment starting from the first day of PTX chemotherapy regimen induced a partial reduction in CD68⁺ infiltrating macrophages at both the end of treatment and after the follow-up period.