Cannabinoids: an Effective Treatment for Chemotherapy-Induced Peripheral Neurotoxicity?

Abstract

Chemotherapy-induced peripheral neurotoxicity (CIPN) is one of the most frequent side effects of antineoplastic treatment, particularly of lung, breast, prostate, gastrointestinal, and germinal cancers, as well as of different forms of leukemia, lymphoma, and multiple myeloma. Currently, no effective therapies are available for CIPN prevention, and symptomatic treatment is frequently ineffective; thus, several clinical trials are addressing this unmet clinical need. Among possible pharmacological treatments of CIPN, modulation of the endocannabinoid system might be particularly promising, especially in those CIPN types where analgesia and neuroinflammation modulation might be beneficial. In fact, several clinical trials are ongoing with the specific aim to better investigate the changes in endocannabinoid levels induced by systemic chemotherapy and the possible role of endocannabinoid system modulation to provide relief from CIPN symptoms, a hypothesis supported by preclinical evidence but never consistently demonstrated in patients. Interestingly, endocannabinoid system modulation might be one of the mechanisms at the basis of the reported efficacy of exercise and physical therapy in CIPN patients. This possible virtuous interplay will be discussed in this review.

Keywords: Cannabinoid receptors; Chemotherapy; Endocannabinoid system; Neuropathy; Treatment.

Fig. 1

Representative images of macrophage infiltration in caudal nerves of a control and a bortezomib- (BTZ) treated rats taken from a previously published experiment [49] To investigate the macrophage infiltration immunohistochemistry was performed using anti-CD68 antibody to detect macrophage infiltrating cells (b) compared with control animals (a). In addition, anti-iNOS (inducible Nitric Oxide Synthase) antibody (c), and anti-ARG1 (Arginase-1) antibody (d) was used to discriminate M1 (proinflammatory) from M2 (anti-inflammatory) macrophages, respectively. While no infiltrating macrophages were observed in controls, marked M1 macrophage infiltration was present in the caudal nerves of BTZ-treated rats [49]

Fig. 2

Animal model’s nocifensive behavior and current perception threshold (CPT) after bortezomib (BTZ) administration Withdrawal latency to an infrared heat stimulus was determined using a Plantar Test apparatus that showed thermal allodynia in BTZ-treated rats (a, left panel); mechanical threshold was assessed with the Dynamic Aesthesiometer Test device that showed mechanical allodynia in BTZ-treated rats (a, right panel), b) the Neurometer device was used to evaluate the CPT as a quantitative measure of nerve function by selectively depolarizing different subpopulations of afferent fibers. BTZ treatment significantly increased the sensitivity of the A-delta and C fibers function, which resulted in a behavioral response to a lower current stimulus than the control group, while BTZ had no effect on large myelinated fibers (b). °P<0.05 vs control 250Hz; *P<0.05 vs control 5 Hz; **P<0.01 vs control; ***P<0.001 vs control. For more details about Materials and Methods, see Supplementary material

Fig. 3

Extracellular electrophysiological recording in the SCDH of bortezomib (BTZ)-treated rats BTZ-treated animals showed significant wide dynamic range neurons (WDRN) hyperexcitability during all evoked response by light tactile (sable-hair brush, light Von Frey (VF) hairs), moderate noxious tactile (press) and painful stimuli (pinching). Control, bortezomib (BTZ) ****P<0.0001 vs control. For more details about Materials and Methods, see Supplementary material

Fig. 4

Effects of bortezomib (BTZ) treatment on CB1R and CBR2 expression in DRG and SCDH Localization of CB1R-like immunoreactivity (LI) in the DRG of a control (a, upper panel) and a BTZ-treated rat (a, lower panel); localization of CB2R-LI in the DRG of a control (b, upper panel) and a BTZ-treated rat (b, lower panel); western blot and results quantification comparing control vs BTZ-treated animals (c). Localization of CB1R-L5 in the SCDH of a control (d, upper panel) and a BTZ-treated rat (d, intermediate panel) with optical density quantification (d, lower panel); localization of CB2R-LI in the SCDH of a control (e, upper panel) and a BTZ-treated rat (e, intermediate panel), with optical density quantification (e, lower panel); western blot and results quantification of the whole spinal cord comparing control vs BTZ-treated animals (f). *P<0.05 vs control; ***P<0.001 vs control. For more details about Materials and Methods, see Supplementary material