Endocannabinoid System Attenuates Oxaliplatin-Induced Peripheral Sensory Neuropathy Through the Activation of CB1 Receptors.

Oxaliplatin-induced neurotoxicity is expressed as a dose-limiting peripheral sensory neuropathy (PSN). Cannabinoid substances have been investigated for the analgesic effect. This study aimed to investigate the role of cannabinoid receptors in oxaliplatin-associated PSN. Swiss male mice received nine oxaliplatin injections (2 mg/kg, i.v.). Mechanical and thermal nociceptive tests were performed for 56 days. CB1, CB2, and c-Fos expression were assessed in dorsal root ganglia (DRG), spinal cord (SC), trigeminal ganglia (TG), spinal trigeminal nucleus caudalis (Sp5C), and periaqueductal gray (PAG). Iba-1 expression was assessed in DRG and ATF3 in TG. Cannabidiol (10 mg/kg, p.o.) or a CB1/CB2 non-selective agonist (WIN 55,212-2; 0.5 mg/kg, s.c.) or AM251 (CB1 antagonist) or AM630 (CB2 antagonist) (3 mg/kg, i.p.) were injected before oxaliplatin. Oxaliplatin increased CB1 in DRG, SC, TG, Sp5C, and ventrolateral PAG, with no interference in CB2 expression. Cannabidiol increased CB1 in DRG, reduced mechanical hyperalgesia and c-Fos expression in DRG and SC. Additionally, WIN 55,212-2 increased CB1 in DRG, reduced mechanical hyperalgesia, cold allodynia and c-Fos expression in DRG and SC. CB1 blockage hastened the cold allodynia response, but the CB2 antagonist failed to modulate the oxaliplatin-induced nociceptive behavior. Oxaliplatin also increased Iba-1 in DRG, suggesting immune response modulation which was reduced by cannabidiol and enhanced by AM630. The modulation of the endocannabinoid system, through the CB1 receptor, attenuates the oxaliplatin-associated PNS. The activation of the endocannabinoid system could be considered as a therapeutic target for controlling oxaliplatin-associated neuropathy.

Electroacupuncture Reduces Inflammation but Not Bone Loss on Periodontitis in Arthritic Rats.

Periodontitis and rheumatoid arthritis (RA) are inflammatory diseases characterized by chronic inflammation and bone erosion. Electroacupuncture (EA) shows anti-inflammatory and anti-resorptive effects in experimental periodontitis (EP) and in RA. It is important to investigate whether EA shows these effects in periodontal tissues in the presence of these two inflammatory diseases or not. For this, Wistar rats were divided into six groups: control (C); experimental rheumatoid arthritis (RA; bovine type II collagen-induced (CII)); experimental periodontitis (EP); RA/EP (RA + EP); EP/EA (EP treated with EA); RA/EP/EA (RA + EP treated with EA). EP was induced 21 days after RA induction and EA was performed previously and during the EP induction period, every 3 days until the 36th experimental day. The rats were euthanized on day 39. RA was evaluated by edema and the withdrawal threshold of hind paws. The maxillae were removed, and alveolar bone loss (ABL) and bone radiographic density (BRD) were evaluated. Immunohistochemical analyses for interleukins (IL)-6 and -17 and nuclear factor (NF)-κB were performed. Our results showed that EA reduced only the pain intensity in arthritic rats. Histomorphometric, macroscopic, and radiographic analyses did not show differences between the control and EP/EA groups. EA caused a reduction in ABL and BRD only in the presence of EP. EA caused a reduction in IL-6 and -17 in all groups, but NF-κB was only reduced in the arthritic rats with EP. In conclusion, EA reduced the inflammation related to periodontitis in arthritic rats but did not prevent ABL.

Metformin reduces c-Fos and ATF3 expression in the dorsal root ganglia and protects against oxaliplatin-induced peripheral sensory neuropathy in mice.

Oxaliplatin is a third-generation platinum drug commonly used as the first line treatment of metastatic colorectal cancer. Oxaliplatin-based anticancer regimens course with dose-limiting neurotoxicity. The pharmacological strategies used to manage such side effect are not totally effective. Metformin is an anti-diabetic drug that is described to negatively modulate painful diabetic neuropathy. Then, this study aimed to assess the effect of metformin in the oxaliplatin-induced peripheral sensory neuropathy in mice. For that purpose, Swiss male mice were injected with oxaliplatin (1, 2 or 4 mg/kg, i.v., twice a week with a total of nine injections) alone or in combination with daily administration of metformin (250 mg/kg, p.o.). Thermal and mechanical nociceptive tests were performed once a week for five weeks. Then, the animals were euthanized on day 35 post-first injection of oxaliplatin and the dorsal root ganglia were harvested for the assessment of c-Fos and ATF3 expressions. Oxaliplatin caused a nociceptive response accompanied by the increased expression of c-Fos and ATF3 in the dorsal root ganglia and spinal cord. In addition, the oxaliplatin-associated nociception was significantly attenuated by metformin (P < 0.05), which also reduced the expression of c-Fos and ATF3 (P < 0.05). Therefore, metformin protected from the peripheral sensory neuropathy induced by oxaliplatin, which was confirmed by the reduction of c-Fos and ATF3 expression, two known neuronal activation and damage markers, respectively.

Involvement of Endothelin Receptors in Peripheral Sensory Neuropathy Induced by Oxaliplatin in Mice.

The aim of this study was to evaluate the participation of the endothelin ETA and ETB receptors and the effects of bosentan in oxaliplatin-induced peripheral sensory neuropathy (OIN) in mice. Adult male Swiss mice received 1 mg/kg of oxaliplatin intravenously, twice a week for 5 weeks. Dorsal root ganglia (DRG) and spinal cords were removed for evaluation of the endothelin ETA and ETB receptor expression. Afterwards, selective (BQ-123 and BQ-788; 10 nmol in 30 µL, intraplantarly) and non-selective (bosentan, 100 mg/kg, orally) antagonists were administered in order to evaluate the involvement of the endothelin receptors in OIN. Mechanical and thermal nociception tests were performed once a week for 56 days. Oxaliplatin induced mechanical and thermal hypersensitivity and increased the endothelin ETA receptor expression in both the DRG and spinal cord (P < 0.05). Endothelin ETB receptor expression was increased in the DRG (P < 0.05) but not in the spinal cord. Both endothelin ETA and ETB receptor selective antagonists partially prevented mechanical hyperalgesia in mice with OIN (P < 0.05). Moreover, bosentan prevented mechanical and thermal hypersensitivity in oxaliplatin-treated mice (P < 0.05). In conclusion, both endothelin ETA and ETB receptors seem to be involved in the OIN in mice and they should be considered possible targets for the management of this clinical feature.

Neurotoxic effect of oxaliplatin: Comparison with its oxalate-free analogue cis-[PtII(1R,2R-DACH)(3-acetoxy-1,1-cyclobutanedicarboxylato)] (LLC-1402) in mice.

Studies suggest that oxalate is involved in the development oxaliplatin-induced peripheral sensory neuropathy (OPSN). This study aimed to compare the neurotoxic effects of oxaliplatin with its oxalate-free cytotoxic analogue cis-[PtII(1R,2R-DACH)(3-acetoxy-1,1-cyclobutanedicarboxylato)] (LLC-1402) in mice. Oxaliplatin and LLC-1402 were intravenously injected in male Swiss mice with a total of nine injections. Oxalate was intraperitoneally injected in other animals. The development of OPSN was evaluated using mechanical and thermal sensitivity tests. Dorsal root ganglia of the mice were removed to evaluate c-Fos, ATF3 and iNOS expression and a sample of blood was collected for leukocyte count and hepatic and renal biochemical function tests. Oxaliplatin and LLC-1402 decreased the mechanical and thermal nociceptive threshold, whilst oxalate lead to a partial and later increase in the mechanical sensitivity (P<0.05). c-Fos, ATF3 and iNOS expressions were increased in neuronal cells during and after the end of the injections in animals treated with oxaliplatin and LLC-1402 (P<0.05), even though oxaliplatin lead to an earlier increase. Only c-Fos expression was elevated during the period of injections in the oxalate group (P<0.05), but this expression reduced after the end of the treatment. c-Fos expression was also shown in glial satellite cells only in the oxaliplatin-treated animals. Oxaliplatin and LLC-1402 reduced leukocyte count (P<0.05), but did not change renal and liver functions. In conclusion, oxalate may contribute to an earlier development of peripheral sensory neuropathy. However, the antitumor cytotoxic mechanism of oxaliplatin seems to be the main responsible by its neurotoxic effect.