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Papers of the Week

Papers: 11 Mar 2023 - 17 Mar 2023

Basic Science

Animal Studies, Molecular/Cellular, Pharmacology/Drug Development

Cancer Pain, Neuropathic Pain

2023 Mar 08

Chem Biol Interact


Trimetazidine alleviates paclitaxel-induced peripheral neuropathy through modulation of TLR4/p38/NFκB and klotho protein expression.


Hammad ASA, Sayed-Ahmed MM, Abdel Hafez SMN, Ibrahim ARN, Khalifa MMA, El-Daly M


Chemotherapy-induced peripheral neuropathy is a common adverse effect associated with a number of chemotherapeutic agents including paclitaxel (PTX) which is commonly used in a wide range of solid tumors. Development of PTX-induced peripheral neuropathy (PIPN) during cancer treatment requires dose reduction which limits its clinical benefits. This study is conducted to investigate the role of toll like receptor-4 (TLR4) and p38 signaling and Klotho protein expression in PIPN and the role of Trimetazidine (TMZ) in this pathway. Sixty-four male Swiss albino mice were divided into 4 groups (n = 16); Group (1) injected intraperitoneally (IP) with ethanol/tween 80/saline for 8 successive days. Group (2) received TMZ (5 mg/kg, IP, day) for 8 successive days. Group (3) treated with 4 doses of PTX (4.5 mg/kg, IP) every other day over a period of 8 days. Group (4) received a combination of TMZ as group 2 and PTX as group 3. The Effect of TMZ on the antitumor activity of PTX was studied in another set of mice-bearing Solid Ehrlich Carcinoma (SEC) that was similarly divided as the above-mentioned set. TMZ mitigated tactile allodynia, thermal hypoalgesia, numbness and fine motor dyscoordination associated with PTX in Swiss mice. The results of the current study show that the neuroprotective effect of TMZ can be attributed to inhibition of TLR4/p38 signaling which also includes a reduction in matrix metalloproteinase-9 (MMP9) protein levels as well as the proinflammatory interleukin-1β (IL-1β) and preserving the levels of the anti-inflammatory IL-10. Moreover, the current study is the first to demonstrate that PTX reduces the neuronal levels of klotho protein and showed its modulation via cotreatment with TMZ. In addition, this study showed that TMZ neither alter the growth of SEC nor the antitumor activity of PTX. In conclusion, we suggest that (1) Inhibition of Klotho protein and upregulation of TLR4/p38 signals in nerve tissues may contribute to PIPN. (2) TMZ attenuates PIPN by modulating TLR4/p38 and Klotho protein expression in without interfering with its antitumor activity.