The Neuroprotective Properties of Shogaol-Enriched Ginger Extract (SEGE) Mitigate Synaptic, Cholinergic, and Metabolic Brain Dysfunction in a Mouse Model of Metals and High-Fat-Diet-Induced Neuropathology

Background/Objective: Co-exposure to heavy metals from environment and a high-fat diet (HFD) represents a growing health concern, contributing to various diseases, but their combined effects on brain health remain less explored. This study aimed to evaluate the neuroprotective potential of Shogaol-enriched ginger extract (SEGE) against heavy metals- and HFD-induced neuropathology. Plant-derived isolated pure compounds can be costly and less accessible; SEGE may offer a translatable, multi-target dietary intervention. Methods: Male Balb/c mice (8–11 weeks old) were exposed to a metal mixture of arsenic (As), lead (Pb), and aluminum (Al; 25 mg/kg/day each) in drinking water and 40% HFD in feed for 60 days. SEGE was administered via feed at two different doses (2 mg/kg/day and 12 mg/kg/day). Assessments including gene expression analyses (using Quantitative Reverse Transcription Real Time Polymerase Chain Reaction (qRT-PCR)) of synaptic and cholinergic markers, spectrophotometric measurement of acetylcholine (ACh) levels, neuronal counting in the cortex and hippocampus via histology, and Gas chromatography mass spectrometric (GC/MS) analysis for brain metabolic quantification were performed. Results: The combined toxic exposure significantly downregulated the expression of synaptic plasticity markers (Synaptophysin, Polysynaptic Density Protein 95 (PSD95), and Calcium/Calmodulin-Dependent Protein Kinase-IV (CAMK-4)) and α and β Nicotinic Acetylcholine Receptors (α7nAChR, α4nAChR, and β2nAChR) in the hippocampus and cortex. ACh levels were also reduced along with significant neuronal loss in the cortical layers and the hippocampal regions. Met + HFD disrupted the brain’s metabolic profile. SEGE treatment significantly restored these markers and attenuated the cholinergic deficits. SEGE treatment, specifically at a higher dose, demonstrated a rescuing effect on the brain’s metabolic profile when compared to the metals and HFD. SEGE further preserved the neuronal count at a higher dose (12 mg/kg/day), exhibiting superior protective effects. Conclusions: These findings suggest that SEGE mitigates neurotoxicity induced by the interaction of toxic metals and dietary factors, likely by preserving synaptic plasticity, metabolic profile, and cholinergic functions, particularly at a higher dose.