Neuroprotective Potential of Sesamum indicum in a Multifactorial In Vitro Neuron–Astrocyte System Exposed to Chronic Stress Mediators

Chronic stress is increasingly recognized as a major contributor to Alzheimer’s disease (AD)-related neurodegeneration through mechanisms involving neuroinflammation, oxidative stress, mitochondrial dysfunction, excitotoxicity, and amyloidogenic processing. Here, we investigated the neuroprotective effects of Sesamum indicum whole paste extract (SIPE) using 2D neuron–astrocyte-like cell (ALC) co-cultures and 3D neuron–ALC spheroids exposed to a TNF-α/glutamate/cortisol (TGC) chronic stress paradigm. TGC exposure induced mitochondrial dysfunction, mitochondrial superoxide generation, astrocytic reactivity, NF-κB activation, reduced pro-BDNF expression, intracellular and extracellular Aβ42 accumulation, Tau phosphorylation, and caspase-3 activation, reproducing key hallmarks associated with chronic stress-related neurodegeneration. Among sesame-derived preparations evaluated, SIPE exhibited the strongest neuroprotective effects, preserving mitochondrial membrane potential, reducing oxidative stress, preventing neuronal loss, attenuating gliosis, and suppressing inflammatory, amyloidogenic, and apoptotic signaling. These effects were consistently reproduced in 3D spheroids. Phytochemical analysis revealed that SIPE contained the highest enrichment of sesamin, representing approximately 25% of the detected relative composition. Molecular docking analyses demonstrated favorable sesamin binding affinity toward TNF-α, DJ-1, Aβ42, and caspase-3. Collectively, these findings identify SIPE as a promising multitarget neuroprotective strategy against chronic stress-associated AD-related pathology.