Re-evaluating the neuroprotective landscape of Nigella sativa: Molecular mechanisms, nanomedicine, and clinical translation.

Nigella Sativa (NS) L., commonly known as black seed, and its major bioactive compound, thymoquinone (TQ), have long been used in traditional medicine and have recently gained increasing attention as potential neuroprotective agents. TQ exerts pleiotropic effects within the central nervous system through several interconnected mechanisms, including activation of the Nrf2/HO-1 antioxidant pathway, inhibition of NF-κB-mediated neuroinflammation and NLRP3 inflammasome signaling, and regulation of the mitochondrial Bax/Bcl-2/caspase-3 apoptotic pathway. These effects have been reported in diverse preclinical models of neurodegeneration and neurotoxicity, including amyloid-β-, 6-hydroxydopamine-,1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP), and rotenone-induced neuronal injury, global and focal cerebral ischemia-reperfusion, pentylenetetrazole- and status epilepticus-associated seizures, and toxicant- or trauma-related brain injury. However, the clinical translation of native TQ is limited by its poor aqueous solubility, rapid systemic metabolism, and restricted penetration of the blood-brain barrier. These challenges have stimulated the development of nanomedicine-based delivery systems, including solid lipid nanoparticles, PLGA/chitosan nanoparticles, and mesoporous silica nanocarriers, which are designed to improve TQ stability, brain availability, and therapeutic performance. A limited number of controlled human studies have reported potential benefits of NS seed or oil preparations on memory, attention, mood, and pediatric seizure frequency, with generally acceptable tolerability at conventional doses. Nevertheless, substantial variability in reported rodent oral median lethal dose (LD50) values, together with carrier-specific organ toxicity reported for some nanoformulations (renal and hepatic changes with silica-based carriers), underscores the need for formulation- and exposure-specific safety assessment. Overall, current evidence positions NS and thymoquinone as promising but predominantly preclinical neuroprotective candidates. Their potential applications in Alzheimer's disease, Parkinson's disease, ischemic stroke, and epilepsy remain hypothesis-generating and will require validation through pharmacokinetically optimized formulations and adequately powered clinical trials.