Agomelatine improves memory and learning impairments in a rat model of LPS‑induced neurotoxicity by modulating the ERK/SorLA/ BDNF/TrkB pathway
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Date
2023-09
Authors
Abdelaziz, Mahmoud
Mohamed, Ahmed F
Zaki, Hala F
Gad, Sameh S
Journal Title
Journal ISSN
Volume Title
Type
Article
Publisher
Springer Verlag
Series Info
Naunyn-Schmiedeberg's Archives of Pharmacology;
Scientific Journal Rankings
Abstract
The mutual interplay between neuroinfammation, synaptic plasticity, and autophagy has piqued researchers’ interest, par-
ticularly when it comes to linking their impact and relationship to cognitive defcits. Being able to reduce infammation and
apoptosis, melatonin has shown to have positive neuroprotective efects; that is why we thought to check the possible role
of agomelatine (AGO) as a promising candidate that could have a positive impact on cognitive defcits. In the current study,
AGO (40 mg/kg/day, p.o., 7 days) successfully ameliorated the cognitive and learning disabilities caused by lipopolysac-
charide (LPS) in rats (250 μg/kg/day, i.p., 7 days). This positive impact was supported by improved histopathological fnd-
ings and improved spatial memory as assessed using Morris water maze. AGO showed a strong ability to control BACE1
activity and to rein in the hippocampal amyloid beta (Aβ) deposition. Also, it improved neuronal survival, neuroplasticity,
and neurogenesis by boosting BDNF levels and promoting its advantageous efects and by reinforcing the pTrkB expression.
In addition, it upregulated the pre- and postsynaptic neuroplasticity biomarkers resembled in synapsin I, synaptophysin, and
PSD-95. Furthermore, AGO showed a modulatory action on Sortilin-related receptor with A-type repeats (SorLA) pathway
and adjusted autophagy. It is noteworthy that all of these actions were abolished by administering PD98059 a MEK/ERK
pathway inhibitor (0.3 mg/kg/day, i.p., 7 days). In conclusion, AGO administration signifcantly improves memory and learn-
ing disabilities associated with LPS administration by modulating the ERK/SorLA/BDNF/TrkB signaling pathway parallel
to its capacity to adjust the autophagic process.
Description
Keywords
Agomelatine · ERK ½ · SorLA · BDNF · Neuroplasticity · Autophagy