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Neuroprotective potential of trimetazidine against tramadol-induced neurotoxicity: role of PI3K/Akt/mTOR signaling pathways.
- Source :
-
Toxicology mechanisms and methods [Toxicol Mech Methods] 2023 Sep; Vol. 33 (7), pp. 607-623. Date of Electronic Publication: 2023 Apr 26. - Publication Year :
- 2023
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Abstract
- Tramadol (TRA) causes neurotoxicity whereas trimetazidine (TMZ) is neuroprotective. The potential involvement of the PI3K/Akt/mTOR signaling pathway in the neuroprotection of TMZ against TRA-induced neurotoxicity was evaluated. Seventy male Wistar rats were divided into groups. Groups 1 and 2 received saline or TRA (50 mg/kg). Groups 3, 4, and 5 received TRA (50 mg/kg) and TMZ (40, 80, or 160 mg/kg) for 14 days. Group 6 received TMZ (160 mg/kg). Hippocampal neurodegenerative, mitochondrial quadruple complex enzymes, phosphatidylinositol-3-kinases (PI3Ks)/protein kinase B levels, oxidative stress, inflammatory, apoptosis, autophagy, and histopathology were evaluated. TMZ decreased anxiety and depressive-like behavior induced by TRA. TMZ in tramadol-treated animals inhibited lipid peroxidation, GSSG, TNF-α, and IL-1β while increasing GSH, SOD, GPx, GR, and mitochondrial quadruple complex enzymes in the hippocampus. TRA inhibited Glial fibrillary acidic protein expression and increased pyruvate dehydrogenase levels. TMZ reduced these changes. TRA decreased the level of JNK and increased Beclin-1 and Bax. TMZ decreased phosphorylated Bcl-2 while increasing the unphosphorylated form in tramadol-treated rats. TMZ activated phosphorylated PI3Ks, Akt, and mTOR proteins. TMZ inhibited tramadol-induced neurotoxicity by modulating the PI3K/Akt/mTOR signaling pathways and its downstream inflammatory, apoptosis, and autophagy-related cascades.
- Subjects :
- Male
Rats
Animals
Proto-Oncogene Proteins c-akt metabolism
Phosphatidylinositol 3-Kinases metabolism
Phosphatidylinositol 3-Kinases pharmacology
Neuroprotection
Rats, Wistar
Signal Transduction
TOR Serine-Threonine Kinases metabolism
TOR Serine-Threonine Kinases pharmacology
Apoptosis
Autophagy
Trimetazidine pharmacology
Tramadol toxicity
Neurotoxicity Syndromes etiology
Neurotoxicity Syndromes prevention & control
Neuroprotective Agents pharmacology
Neuroprotective Agents therapeutic use
Subjects
Details
- Language :
- English
- ISSN :
- 1537-6524
- Volume :
- 33
- Issue :
- 7
- Database :
- MEDLINE
- Journal :
- Toxicology mechanisms and methods
- Publication Type :
- Academic Journal
- Accession number :
- 37051630
- Full Text :
- https://doi.org/10.1080/15376516.2023.2202785