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Gene & Protein in Disease In silico insights on fisetin’s antidepressant effects

environmental factors and is involved in the regulation of paving the way for future research into its role in treating
serotonin, noradrenaline, and dopamine. 39,40 In addition, MDD. In the CNS, MMPs play crucial roles in various
increased ACHE activity may decrease dopamine activity physiological processes, such as myelin formation, axonal
and therefore increase depressive symptoms. 41 growth, angiogenesis, and regeneration. However, the
43
The analysis also identified two other critical target overproduction or dysregulation of MMPs has been linked
proteins – MMP9 and MPO – as potential targets for to the pathogenesis of several neurological disorders,
44,45
FT’s therapeutic effects in the context of MDD. During including AD, PD, ischemia, and MDD. Interestingly,
inflammatory states, excessive levels of MMP-9 and MPO the bioactive compound FT has been shown to possess
are believed to be involved in the process of demyelination. the ability to suppress the expression of specific MMPs,
MMP-9 and MPO can disrupt the BBB through their including MMP-1, MMP-3, MMP-7, and MMP-9, in
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effects on tight junction proteins or by degrading the tumor cells. Furthermore, FT has been found to inhibit
basement membrane. This disruption of the BBB can lead the metastatic potential of PC-3 prostate cancer cells by
to increased neuroinflammation, which may contribute reducing the expression of MMP-2 and MMP-9, potentially
to the development and progression of MDD and other through the suppression of the c-Jun N-terminal kinase
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neuropsychiatric disorders like bipolar disorder, especially and phosphoinositide 3-kinase/Akt signaling pathways.
when accompanied by cognitive decline. 41,42 On the other In addition to its effects on MMPs, FT has also been
hand, a sustained reduction of MPO and MMP9 activity reported to inhibit the activity of the MAOA isoform in
reduces inflammation and increases cell protection. Thus, C6 glial cells. MAOA plays a crucial role in the regulation
42
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FT may alleviate the MPO and MMP9 function while of catecholamine and serotonin (5-HT) levels within the
improving the MDD condition. brain. Dysregulation of MAOA has been implicated in the
The docking analysis revealed that FT exhibited pathogenesis of various neuropsychiatric psychiatric and
promising interactions with five key proteins associated age-related disorders, such as MDD and PD. 49
with MDD: GSK3B, MAOA, ACHE, MMP9, and MPO. Furthermore, FT has been shown to exert anti-
Notably, the highest binding affinities were observed for inflammatory effects by inhibiting the production
MAOA and MPO, both with a Vina score of −10.2. These of proinflammatory mediators, including TNF, IL-1,
findings suggest that FT may have significant therapeutic IL-6, and IL-17, and the suppression of their signaling
potential in MDD treatment through its interactions with pathways in macrophages. 44,50 In addition, FT has been
these critical targets. In comparison, FLX, a well-established shown to decrease MPO activity and alleviate symptoms
antidepressant, displayed varying binding affinities across associated with neurocognitive impairments, such as AD.
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the same targets. The Vina scores for FLX were −7.7 for Interestingly, FT administration has also been observed to
GSK3B, −9.0 for MAOA, −10.0 for ACHE, −8.5 for MMP9, ameliorate alterations in the levels of neurotransmitters,
and −8.0 for MPO. While FLX demonstrated strong such as dopamine, GABA, and glutamate, as well as
interactions, FT’s superior binding affinities, particularly ACHE in the hippocampus and cortex of kindled mice.
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with MAOA and MPO, indicate that FT may be more Thus, FT counteracts the pathological processes involved
effective in targeting these proteins. This suggests that in MDD. On the other hand, FT has previously been
FT could potentially offer enhanced therapeutic effects reported to inhibit GSK3B, a regulator that suppresses
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compared to FLX, especially in modulating the pathways mitochondrial biogenesis. Moreover, it has been reported
associated with MDD. The implications of these results that GSK3B inhibition protects against dopaminergic
are significant. The strong binding of FT to MAOA, an neurodegeneration while increasing the brain’s energy
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enzyme involved in the metabolism of neurotransmitters metabolism. Therefore, by affecting the IL-17 signaling
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such as serotonin, norepinephrine, and dopamine, pathway, FT could reduce the expression of targets such
highlights its potential role in enhancing mood regulation. as GSK3B, MAOA, ACHE, MMP9, and MPO, potentially
Similarly, the interaction with MPO, which is implicated improving neurological disorders like MDD.
in inflammatory processes, suggests that FT may also exert
anti-inflammatory effects that could further benefit MDD 5. Conclusion
treatment. This comprehensive investigation utilized docking analyses
Overall, the comparative analysis of FT and FLX to explore a novel therapeutic approach for managing
underscores the potential of FT as a novel therapeutic MDD. The primary goal was to assess the potential of the
agent for MDD. The enhanced binding affinities observed bioactive compound FT and analyze its interactions with
in this study warrant further investigation into FT’s key molecular targets associated with MDD. Insights gained
mechanisms of action and its efficacy in clinical settings, from GO and KEGG pathway analyses illuminated the

Volume 4 Issue 1 (2025) 9 doi: 10.36922/gpd.4846