Neuroprotective potential of fortunellin against titanium dioxide nanoparticles induced neurotoxicity via regulating NLRP3, HMGB1/RAGE, and NF-κB pathway: A biochemical, histological and in-silico experimentation.

Titanium dioxide nanoparticles (TiO-NPs) are used in the production of various industrial and commercial products and reported to cause neurotoxicity in Sprague Dawley rats. Fortunellin (FRN) is a potent flavonoid with diverse biological properties. This research experiment was performed to explore the protective role FRN against TiO-NPs induced brain damage. Thirty-six male Sprague Dawley rats were categorized into control, TiO-NPs (120 mgkg), TiO-NPs (120 mgkg) + FRN (20 mgkg), and FRN (20 mgkg) treated groups. TiO-NPs significantly (p < 0.001) provoked the expressions of High-Mobility Group Box 1 (HMGB1) (4.1-fold), NLRP3 inflammasome (3.7-fold), nuclear factor-kappa B (NF-κB) (4.4-fold), interleukin-6 (IL-6) (4.0-fold), Receptor for Advanced Glycation End products (RAGE) (3.9-fold), Cyclooxygenase-2 (COX-2) (3.5-fold), interleukin-1 beta (IL-1β) (4.1-fold), and tumor necrosis-factor-alpha (TNF-α) (4.6-fold) in brain tissues. The enzymatic activities of HO-1 (52%), GPx (43%), SOD (49%), GST (46%), GSH (57%), CAT (41%), and GSR (45%) were suppressed (p < 0.001) while the concentrations of ROS (2.8-fold) & MDA (3.2-fold) were promoted substantially (p < 0.001) after TiO-NPs intoxication. Moreover, brain health was compromised after TiO-NPs exposure which is evident by reduced concentrations of nerve growth factor (NGF) (58%), Synaptophysin (63%), glial cell line derived neurotrophic factor (GDNF) (54%), postsynaptic density 95 (PSD-95) (49%), and brain-derived neurotrophic factor (BDNF) (61%). Besides, TiO-NPs administration significantly (p < 0.001) exacerbated Caspase-9 (3.2-fold), Bax (2.9-fold), and Caspase-3 (3.5%) while reducing Bcl-2 (55%). Histological scoring revealed TiO-NPs caused severe cortical and hippocampal degeneration (Injury score: 2.7 ± 0.2 vs 0.3 ± 0.14 in control; p < 0.001). However, FRN concurrent supplementation remarkably alleviated aforementioned alterations, restoring antioxidant enzyme's levels by 35-62%, reducing inflammatory gene's expression by up to 72%, improving neurotropic factors level by 45-58% and reducing apoptotic indices by 61-69% (p < 0.01). FRN shows promise result as a neuroprotective agent in rats, warranting further research.