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

Asmaa S A Hammad; Mohamed M Sayed-Ahmed; Sara Mohamed Naguib Abdel Hafez; Ahmed R N Ibrahim; Mohamed M A Khalifa; Mahmoud El-Daly

doi:10.1016/j.cbi.2023.110446

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

Chem Biol Interact. 2023 May 1:376:110446. doi: 10.1016/j.cbi.2023.110446. Epub 2023 Mar 9.

Authors

Asmaa S A Hammad¹, Mohamed M Sayed-Ahmed², Sara Mohamed Naguib Abdel Hafez³, Ahmed R N Ibrahim⁴, Mohamed M A Khalifa⁵, Mahmoud El-Daly⁵

Affiliations

¹ Department of Pharmacology and Toxicology, Faculty of Pharmacy, Minia University, Minia, 61511, Egypt. Electronic address: assmaaslyman@minia.edu.eg.
² Pharmacology and Experimental Oncology Unit, National Cancer Institute, Cairo University, Cairo, 11796, Egypt.
³ Department of Histology and Cell Biology, Faculty of Medicine, Minia University, Minia, 61511, Egypt.
⁴ Clinical Pharmacy Department, College of Pharmacy, King Khalid University, Abha, 61441, Saudi Arabia; Department of Biochemistry, Faculty of Pharmacy, Minia University, Minia, 61511, Egypt.
⁵ Department of Pharmacology and Toxicology, Faculty of Pharmacy, Minia University, Minia, 61511, Egypt.

PMID: 36898573
DOI: 10.1016/j.cbi.2023.110446

Abstract

Chemotherapy-induced peripheral neuropathy is a common adverse effect associated with a number of chemotherapeutic agents including paclitaxel (PTX) which is 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) /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 7 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 solid Ehrlich carcinoma (SEC)-bearing mice that was similarly divided as the above-mentioned set. TMZ mitigated tactile allodynia, thermal hypoalgesia, numbness and fine motor discoordination 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 without interfering with its antitumor activity.

Keywords: Hyperalgesia priming; Klotho; NFκB; Nesting; Trimetazidine; p38.

MeSH terms

Animals
Male
Mice
NF-kappa B
Paclitaxel / pharmacology
Peripheral Nervous System Diseases* / chemically induced
Peripheral Nervous System Diseases* / drug therapy
Toll-Like Receptor 4 / metabolism
Trimetazidine* / adverse effects

Substances

Paclitaxel
NF-kappa B
Trimetazidine
Toll-Like Receptor 4
Tlr4 protein, mouse