Antiallodynic and anti-inflammatory effects of intrathecal R-PIA in a rat model of vincristine-induced peripheral neuropathy

Abstract

Background: Studies investigating the correlation between spinal adenosine A1 receptors and vincristine-induced peripheral neuropathy (VIPN) are limited. This study explored the role of intrathecal N6-(2-phenylisopropyl)-adenosine R-(-)isomer (R-PIA) in the rat model of VIPN. Methods: Vincristine (100 μg/kg) was intraperitoneally administered for 10 days (two 5-day cycles with a 2-day pause) and VIPN was induced in rats. Pain was assessed by evaluating mechanical hyperalgesia, mechanical dynamic allodynia, thermal hyperalgesia, cold allodynia, and mechanical static allodynia. Biochemically, tumor necrosis factor-alpha (TNF-α) level and myeloperoxidase (MPO) activity were measured in the tissue from beneath the sciatic nerve.Results: Vincristine administration resulted in the development of cold allodynia, mechanical hyperalgesia, thermal hyperalgesia, mechanical dynamic allodynia, and mechanical static allodynia. Intrathecally administered R-PIA (1.0 and 3.0 μg/10 μl) reversed vincristine-induced neuropathic pain (cold and mechanical static allodynia). The attenuating effect peaked 15 min after intrathecal administration of R-PIA after which it decreased until 180 min. However, pretreatment with 1,3-dipropyl-8-cyclopentylxanthine (DPCPX, 10 μg/10 μl) 15 min before intrathecal R-PIA administration significantly attenuated the antiallodynic effect of R-PIA. This antiallodynic effect of intrathecal R-PIA may be mediated through adenosine A1 receptors in the spinal cord. Intrathecally administered R-PIA also attenuated vincristine-induced increases in TNF-α level and MPO activity. However, pretreatment with intrathecal DPCPX significantly reversed this attenuation.Conclusions: These results suggest that intrathecally administered R-PIA attenuates cold and mechanical static allodynia in a rat model of VIPN, partially due to its anti-inflammatory actions.

Through Its Powerful Antioxidative Properties, L-Theanine Ameliorates Vincristine-Induced Neuropathy in Rats

“…Following the VCR injection, the levels of TNF-α, IL-1, IL-6, and MPO were found to be significantly elevated in the nerve tissue of rats, while the IL-10 levels were lower, which is consistent with prior research [ 42 , 43 ]. This suggests that the inflammatory response in rats played a role in the formation of VCR-induced neuropathy.…”

“…MPO catalyzes the reaction between H 2 O 2 and chloride ions, resulting in hypochlorite, which interacts with polyunsaturated fatty acids and induces lipid peroxidation [ 37 ]. Neutrophils also contribute to oxidative stress by producing reactive oxygen species that oxidize lipids, proteins, and nucleic acids in injured sciatic nerve tissue [ 43 ]. Inflammatory mediators, such as TNF-α, IL-1, and IL-6, were shown in clinical and experimental research to contribute to neuropathy progression and maintenance [ 44 ].…”

5,7-Dimethoxycoumarin ameliorates vincristine induced neuropathic pain: potential role of 5HT3 receptors and monoamines

“…Daily VCR administration caused a decrease in the paw withdrawal threshold on protocol days 10 and 14, and this has been described earlier in mice ( Nawaz et al, 2018 ; Khan et al, 2021 ; Sahranavard et al, 2022 ) and rats ( Singh et al, 2019 ; Kim et al, 2020 ). In relation to this, VINP is associated with an increased expression of cyclooxygenase-2 (Cox-2), TNF-α, interlukin-1β and NF-κB (nuclear factor-kappa B) ( Ali et al, 2022 ) involving Aβ- and C-fibers ( Nagi et al, 2011 ; Ameyaw et al, 2014 ).…”

“…In relation to this, VINP is associated with an increased expression of cyclooxygenase-2 (Cox-2), TNF-α, interlukin-1β and NF-κB (nuclear factor-kappa B) ( Ali et al, 2022 ) involving Aβ- and C-fibers ( Nagi et al, 2011 ; Ameyaw et al, 2014 ). Administration of 5,7-DMC reversed the VCR decrease in paw withdrawal threshold, and this action has also been observed in other studies on cisplatin or VCR, co-administered along with other test agents ( Akbar et al, 2020 ; Kim et al, 2020 ; Lee et al, 2020 ), suggesting that 5,7-DMC has anti-allodynic effects which may be useful in VINP. Gabapentin as the positive control, caused significant effects on paw withdrawal threshold, which is supported by several studies in rats and mice at different doses ( Akbar et al, 2020 ; Khan et al, 2021 ; Ali et al, 2022 ; Basit et al, 2022 ; Jain et al, 2022 ).…”

Chemotherapy-induced peripheral neuropathy: bench to clinical practice

“…Numerous pre-clinical studies have shown efficacy in the treatment of established CIPN or the prevention of CIPN. Modulation of ion channels, including the sodium [6,7], potassium [8,9], and calcium channel [10], have shown promising efficacy in pre-clinical studies. However, the clinical efficacy of these targeting drugs is still limited [11].…”