Terpenoid-rich Elettaria cardamomum extract prevents Alzheimer-like alterations induced in diabetic rats via inhibition of GSK3β activity, oxidative stress and pro-inflammatory cytokines

[Display omitted] •Cardamom extract inhibits the accumulation of β amyloid and p-tau in diabetic rats.•It decreases AChE and caspase-3 activity in brain of T2D rats.•It reduces hippocampal elevated cytokines and oxidative stress in T2D.•It enhances sensitivity of insulin receptors and suppressed expression of glutamate receptors. Recent studies suggested that the non-familiar form of Alzheimer's disease (AD) could be consequence of metabolic syndrome and neuroinflammation. Elettaria cardamomum extract (EC) has exhibited antidiabetic, antioxidant and anti-inflammatory properties. This research was conducted to evaluate the effects of EC on AD-like alterations in rats induced by high fructose and high fat diet coupled with a single small dose of STZ (25 mg/kg) (T2DM rats). Phytochemical analysis was carried out. Behavioral tests, immunohistochemical examination, biochemical analysis and gene expression determination were performed in treated and controls rats. The majority of EC compounds were terpenoids. EC extract administration for 8 weeks attenuated AD-like alterations. It reversed a T2DM-induced decline in cognitive functions in passive avoidance task and Morris water maze test. It significantly lowered the elevated hippocampal level of AChE activity and caspase-3 activity, an indicator of degeneration in T2DM rats Also, it reduced the accumulation of Aβ and p-tau in the brain of T2DM rats. Furthermore, it elevated the suppressed glutamate receptor expression (AMPA GluR1 subunit and NMDA receptor subunits NR1, NR2A, NR2B). EC treatment reduced hippocampal lipid peroxidation marker malondialdehyde (MDA) and augmented antioxidant defensive system, including superoxide dismutase (SOD) and reduced glutathione (GSH). Meanwhile, it lowered hippocampal TNFα, IL β1but not IL6 and reduced GSK-3β in brainT2D rats. EC treatment could ameliorate AD-like alterations in T2DM rats through activation of blunted insulin signal transduction in the brain, attenuation of associated oxidative stress and neuroinflammation.