Title:Thymoquinone Lipid Nanoparticles Cut the Gordian Knots of Depression via Neuroprotective
BDNF and Downregulation of Neuro-inflammatory NF-κB, IL-6, and
TNF-α in LPS Treated Rats
Volume: 22
Issue: 12
Author(s): Mahtab Alam, Md. Noushad Javed, Abul Kalam Najmi, Farhan Jalees Ahmad, Syed Sarim Imam and Mohd Akhtar*
Affiliation:
- Department of Pharmacology, School of Pharmaceutical Education and Research, Jamia Hamdard, New Delhi, 110062, India
Keywords:
Depression, neuroinflammation, nanoparticles, herbal drugs, neuronal disorders, drug delivery, docking, histopathology, thymoquinone.
Abstract:
Background: In over 300 million clinical cases, antidepressant drugs seem to provide only symptomatic
relief and limited protection in life-threatening depressive events.
Objectives: To compare neuronal-signaling mechanism and neuroprotective roles of Thymoquinone (TQ) suspension
and its SLN (TQSLN) against standard antidepressant drug fluoxetine.
Methods: This research investigated in-silico docking at NF-KB p50 active site, CLSM based gut permeation,
screening of antidepressant activities and neurosignaling pathways involved.
Results: As compared to fluoxetine, TQ reporteda significantly better docking score (-6.83 v/s -6.22) and a better
lower free binding energy of (-34.715 Kcal/mol v/s -28.537 Kcal/mol). While poorly oral bioavailable and P-gp
substrate TQ reported approximately 250% higher gut permeation if delivered as TQSLN formulation. In locomotor
studies, as compared to TQS, TQSLN favored more prominent (p< 0.010) elevation in average time, horizontalactivity,
average-velocity, and total-movement with reduced rest time LPS treated groups. However, in the tail suspension
test, TQSLN significantly reduced immobility time (p<0.010). Similarly, In the modified force swimming
test, TQSLN also significantly reduced immobility time (p<0.010), but swimming time (p<0.010) and climbing time
(p<0.050) were significantly elevated. Subsequently, TQSLN reported significantly elevated neuroprotective BDNF
(p<0.010) as well as hippocampal 5HT/TRP; accompanied with reduced levels of hippocampal inflammatory markers
TNF-α (p<0.001) and IL-6 (p<0.010) as well as lower kynurenine and tryptophan ratio (KYN/TRP). Similarly,
the hippocampal CA1 region further revealed TQSL more predominantly attenuated NF-kB nuclear translocation in
the brain.
Conclusion: Despite the poor bioavailability of TQ, TQSLN potentially attenuates neuroinflammatory transmitters
and favors BDNF to modulate depressive neurobehavioral states.