In the current research, a thymoquinone-enriched naringenin (NGN)-loaded nanostructured lipid carrier (NLC) was developed and delivered via the nasal route for depression. Thymoquinone (TQ) oil was used as the liquid lipid and provided synergistic effects. A TQ- and NGN-enriched NLC was developed via the ultrasonication technique and optimized using a central composite rotatable design (CCRD). The optimized NLC exhibited the following properties: droplet size, 84.17 to 86.71 nm; PDI, 0.258 to 0.271; zeta potential, −8.15 to −8.21 mV; and % EE, 87.58 to 88.21%. The in vitro drug release profile showed the supremacy of the TQ-NGN-NLC in comparison to the NGN suspension, with a cumulative drug release of 82.42 ± 1.88% from the NLC and 38.20 ± 0.82% from the drug suspension. Ex vivo permeation study displayed a 2.21-fold increase in nasal permeation of NGN from the NLC compared to the NGN suspension. DPPH study showed the better antioxidant potential of the TQ-NGN-NLC in comparison to NGN alone due to the synergistic effect of NGN and TQ oil. CLSM images revealed deeper permeation of the NGN-NLC (39.9 µm) through the nasal mucosa in comparison to the NGN suspension (20 µm). Pharmacodynamic studies, such as the forced swim test and the locomotor activity test, were assessed in the depressed rat model, which revealed the remarkable antidepressant effect of the TQ-NGN-NLC in comparison to the NGN suspension and the marketed formulation. The results signify the potential of the TQ-enriched NGN-NLC in enhancing brain delivery and the therapeutic effect of NGN for depression treatment.

Background: Human brain is amongst the most complex organs in human body, and delivery of therapeutic agents across the brain is a tedious task. Existence of blood brain barrier (BBB) protects the brain from invasion of undesirable substances; therefore it hinders the transport of various drugs used for the treatment of different neurological diseases including glioma, Parkinson's disease, Alzheimer's disease, etc. To surmount this barrier, various approaches have been used such as the use of carrier mediated drug delivery; use of intranasal route, to avoid first pass metabolism; and use of ligands (lactoferrin, apolipoprotein) to transport the drug across the BBB. Ligands bind with proteins present on the cell and facilitate the transport of drug across the cell membrane via. receptor mediated, transporter mediated or adsorptive mediated transcytosis.Objective: The main focus of this review article is to illustrate various studies performed using ligands for delivering drug across BBB; it also describes the procedure used by various researchers for conjugating the ligands to the formulation to achieve targeted action.Methods: Research articles that focused on the used of ligand conjugation for brain delivery and compared the outcome with unconjugated formulation were collected from various search engines like PubMed, Science Direct and Google Scholar, using keywords like ligands, neurological disorders, conjugation, etc.Results and Conclusion: Ligands have shown great potential in delivering drug across BBB for treatment of various diseases, yet extensive research is required so that the ligands can be used clinically for treating neurological diseases.