Neuroprotective Effects of Trimetazidine against Cisplatin-Induced Peripheral Neuropathy: Involvement of AMPK-Mediated PI3K/mTOR, Nrf2, and NF- κ B Signaling Axes

Abstract

Cisplatin-induced peripheral neuropathy (CIPN) is a common and debilitating side effect of cisplatin chemotherapy used in cancer treatment. This study explored the neuroprotective effects of Trimetazidine (TRI) against CIPN by preserving nerve integrity, reducing neuro-oxidative stress, and alleviating neuroinflammation. Using a rat model of CIPN, we evaluated TRI's impact on motor coordination, pain sensitivity, and peripheral nerve histopathology. Also, its effects on neuro-oxidative stress and neuroinflammatory markers were assessed. The findings showed that rats with CIPN had worse motor coordination and increased sensitivity to pain but that these symptoms were alleviated by TRI therapy in a dose-dependent way. Nerve conduction velocities were normalized, and expression of genes involved in neuropathy signaling was suppressed after TRI therapy. Antioxidant benefits were also shown in TRI, with oxidative damage being reduced and the cellular energy balance being restored. By inhibiting the production of inflammatory markers, it also demonstrated anti-inflammatory properties. Histopathological examination revealed that TRI, especially when administered at a higher dose, inhibited the degeneration and demyelination of nerve fibers. The anti-inflammatory properties of TRI in the sciatic nerves were further shown by the fact that its administration reduced iNOS expression. In conclusion, AMPK-mediated PI3K/mTOR, Nrf2, and NF-κB signaling pathways may all be involved in the therapeutic benefits of TRI for CIPN. These results indicate that TRI may be useful for reducing the side effects of CIPN and enhancing patient outcomes during cisplatin chemotherapy.

Figure 1

Effect of trimetazidine on motor coordination: (a) rotarod and nociceptive thresholds, (b) mechanical pressure, (c) hind paw cold allodynia, (d) hot plate, and (e) adhesive tape in Cis-induced peripheral neuropathic rats. Each bar represents the mean ± SE of six rats. The values above the pairwise comparison represent the exact P-value. TRI, trimetazidine; Cis, cisplatin.

Figure 2

Effect of trimetazidine on sciatic (a) sensory nerve conduction velocity and (b) motor nerve conduction velocity in Cis-induced peripheral neuropathic rats. Each bar represents the mean ± SE of six rats. The values above the pairwise comparison represent the exact P-value. TRI, trimetazidine; Cis, cisplatin; SNVC, sensory-motor nerve conduction velocity; MNCV, motor nerve conduction velocity.

Figure 3

Effect of trimetazidine on sciatic nerve gene expression level of (a) AMPK, (b) mTOR, and (c) PI3K in Cis-induced peripheral neuropathic rats. Each bar represents the mean ± SE of six rats. The values above the pairwise comparison represent the exact P-value. TRI, trimetazidine; Cis, cisplatin; AMPK, AMP-activated protein kinase; mTOR, Mammalian target of rapamycin; PI3K, phosphoinositide 3-kinases.

Figure 4

Effect of trimetazidine on sciatic nerve oxidative stress parameters (a) MDA, (b) NO, and (c) Nrf2 in Cis-induced peripheral neuropathic rats. Each bar represents the mean ± SE of six rats. The values above the pairwise comparison represent the exact P-value. TRI, trimetazidine; Cis, cisplatin; MDA, malondialdehyde; NO, nitric oxide; Nrf2, nuclear factor erythroid 2–related factor 2.

Figure 5

Effect of trimetazidine on sciatic nerve cellular energy parameters (a) ATP, (b) ADP, and (c) NADPH in Cis-induced peripheral neuropathic rats. Each bar represents the mean ± SE of six rats. The values above the pairwise comparison represent the exact P-value. TRI, trimetazidine; Cis, cisplatin; ATP, adenosine triphosphate; ADP, adenosine diphosphate; NADPH, nicotinamide adenine dinucleotide phosphate.

Figure 6

Effect of trimetazidine on sciatic nerve inflammatory markers (a) p-NF-κB, (b) NF-κB, and (c) p-NF-κB/-NF-κB in Cis-induced peripheral neuropathic rats. Each bar represents the mean ± SE of six rats. The values above the pairwise comparison represent the exact P-value. TRI, trimetazidine; Cis, cisplatin; p-NF-κB, phosphate nuclear factor kappa B, NF-κB, nuclear factor kappa B.

Figure 7

Photomicrograph of H&E-stained sciatic nerve sections of various experimental groups eliciting the effect of trimetazidine on histopathological alterations in Cis-induced peripheral neuropathic rats. (a) The control rat shows normal endoneurium, axons (arrow), and nuclei of Schwann cells (dotted arrow). (b and c) Cisplatin-administered rats showed disorganization of the nerve fibers, segmental demyelination (arrow), swollen axons (arrowhead), and scattered digestion chamber (arrow in c). (d, and e) Tri-administered rats showed dose-related restorative effects with mild axonal degeneration (arrow) and mild demyelination. (f–i) scoring of various histopathological alterations in different experimental groups (Each bar represents the median (interquartile range) of six fields. The values above the pairwise comparison represent the exact P-value.

Figure 8

Photomicrographs of immunohistochemical stained sciatic nerve sections for iNOS expression: (a) control group; (b) cisplatin group; (c) Tri 20 group; (d) Tri 40 group; (e) The values above the pairwise comparison represent the exact P-value.

Figure 9

Illustration of trimetazidine associated pathway in suppression Cis-induced peripheral neuropathic rats. SNVC, sensory motor nerve conduction velocity; MNCV, motor nerve conduction velocity, AMPK, AMP-activated protein kinase; mTOR, Mammalian target of rapamycin; PI3K, phosphoinositide 3-kinases; MDA, malondialdehyde; NO, nitric oxide; Nrf2, nuclear factor erythroid 2–related factor 2, ATP, adenosine triphosphate; ADP, adenosine diphosphate; NADPH, nicotinamide adenine dinucleotide phosphate; p-NF-κB, phosphate nuclear factor kappa B; NF-κB, nuclear factor kappa B.