Therapeutic Potential of a Rhein-Loaded Self-Nano Emulsifying Drug Delivery System in Ameliorating LPS-Induced Depression: Mechanistic Insights and Behavioral Outcomes

Sachin More¹Md Abdur Rashid²Prashant Kumar Tiwari³Rohini Kharwade¹Yahya Alhamhoom²Turky Omar Asar⁴Mohammed Kaleem¹Nilesh Mahajan¹Ajay Pise¹Kishor Danao¹Sanjay Kumar^3*

• ¹Babasaheb Balpande College of Pharmacy, Nagpur, Maharashtra, India
• ²College of Pharmacy, King Khalid University, Abha, Saudi Arabia
• ³Sharda University, Greater Noida, India
• ⁴Jeddah University, Jeddah, Makkah, Saudi Arabia

Depression is a multifaceted disorder, caused by neuroinflammation, which is mainly demarcated by a significant increase in in pro-inflammatory cytokines, including interleukin-1ꞵ (IL-1ꞵ), interleukin-6 (IL-6) and tumor necrosis factor-α (TNF-α). Conventional treatments for depression typically focus on neurotransmitter theories and may lead to several undesirable side effects. Therefore, it is essential to identify innovative active compounds of herbal origin that can target pro-inflammatory cytokines to reduce neuroinflammation while minimizing side effects.Rhein has demonstrated considerable therapeutic efficacy in various neurological conditions; however, its mechanistic insights regarding antidepressant effects remain unclear. In-silico study of rhein against the putative target enzyme of depression showed prominent binding with neuroinflammatory proteins 1ALU, 2AZ5, and 5R88, with achieving docking scores -5.84 Kcal/mol, -5.23 Kcal/mol, and -5.243 kcal/mol, respectively. However, the poor absorption of rhein limited its therapeutic efficacy. To address this issue, a rhein-loaded self-nano-emulsifying drug delivery system (R-SNEDDSS) was developed and evaluated for its therapeutic effects in preventing a lipopolysaccharide-induced depression model in rats. The study found that intraperitoneal administration of R-SNEDDS (at doses of 50 mg/kg and 100 mg/kg rhein, i.p.) and duloxetine (as a positive control at 20 mg/kg) over three consecutive days reversed unusual depressive behaviors.Notably, the R-SNEDDS (100 mg/kg rhein, i.p.) significantly reduced levels of the pro-inflammatory cytokines IL-1β (30.91±0.906), IL-6 (133.9±2.232), and TNF-α (26.93±1.807) as compared to the lipopolysaccharide-induced group. These findings demonstrate that R-SNEDDS possesses anti-neuroinflammatory properties and could be promising for depression therapy.