Polyphenols from Conyza dioscoridis (L.) ameliorate Alzheimer's disease- like alterations through multi-targeting activities in two animal models.

BACKGROUND: Recent investigations suggested that anticancer agents may inhibit the progression of Alzheimer's disease (AD) pathology. Conyza dioscoridis (L.) was demonstrated to have anticancer, antioxidant, anti-inflammatory and antidiabetic effects. This study was carried out to investigate the efficacy of polyphenols from Conyza dioscoridis (L.) extract (PCDE) on AD. METHODS: Impacts of 3 doses of PCDE and donepezil, a reference drug, on the features of Alzheimer's disease in two animal models were investigated. RESULTS: PCDE ameliorated the memory and learning impairment shown in rats following a single dose of scopolamine (scopolamine model) or 17 weeks of high-fat/high-fructose(HF/Hfr) diet coupled with a single dose of streptozotocin, (25 mg/kg) (T2D model). They reduced significantly the high hippocampal cholinesterase activity in the two models of rats. Administration of PCDE for 8 weeks in the T2D model showed a significant reduction in hippocampal GSK-3ß, caspase-3 activity and increase in the inhibited glutamate receptor expression (AMPA GluR1 subunit and NMDA receptor subunits NR1, NR2A, NR2B). A significant reduction of HOMA-insulin resistance and serum hypercholesterolemia was observed. The Tau hyperphosphorylation and Aß 1-42 generation in the hippocampal of T2D rats were significantly decreased by PCDE. Modulation of the oxidative stress markers, (rise in GH and SOD; decrease in MDA levels) and a significant reduction of TNF-α and IL-1ß in the hippocampus of T2D rats treated by PCDE extract were important findings in this study. The highest dose tested was 4% of the highest safe dose. CONCLUSION: Our study suggests that PCDE is multi-targeting agent with multiple beneficial activities in combating features of AD. This study may provide a novel therapeutic strategy for AD treatment that warrants clinical studies.

Evaluation of the neuroprotective effect of donepezil in type 2 diabetic rats.

Recent studies raise the possibility that donepezil can delay the progression of Alzheimer's disease (AD). This research evaluated the efficacy of donepezil in an animal model with brain insulin resistance and AD-like alterations. Rats were fed with high-fat/high-fructose (HF/Hfr) diet during the study period (17 weeks) and received one injection of streptozotocin (STZ) (25 mg/kg) after 8 weeks of starting the study. Diabetic (T2D) rats were treated with donepezil (4 mg/kg; p.o.) or vehicle for 8 weeks after STZ injection. The influence of donepezil on AD-related behavioral, biochemical, and neuropathological changes was investigated in T2D rats. Treatment of diabetic rats with donepezil led to a significant decrease in both amyloid-ß deposition and the raised hippocampal activity of cholinesterase (ChE). It significantly increased the suppressed glutamate receptor expression (AMPA GluR1 subunit and NMDA receptor subunits NR1, NR2A, NR2B). It also improved cognitive dysfunction in the passive avoidance and the Morris water maze tests. However, donepezil treatment did not significantly decrease the elevated levels of P-tau, caspase-3, GSK-3ß, MDA, TNF-α, and IL-1ß in the hippocampus of diabetic rats. Also, it did not restore the suppressed levels of glutathione and superoxide dismutase in the brain of these rats. Moreover, donepezil did not alter the elevated serum level of glucose, insulin, and total cholesterol. These findings suggest that donepezil treatment could ameliorate learning and memory impairment in T2D rats through reversal of some of the AD-related alterations, including reduction of amyloid-ß burden and ChE activity as well as restoration of glutamate receptor expression. However, lack of any significant effect on P-tau load, oxidative stress, neuroinflammation, and insulin resistance raises the question about the ability of donepezil to delay the development or arrest the progression of T2D-induced AD and it is still a matter of debate that requires further studies.

Polyphenol-rich Boswellia serrata gum prevents cognitive impairment and insulin resistance of diabetic rats through inhibition of GSK3ß activity, oxidative stress and pro-inflammatory cytokines.

Type 2 diabetes (T2D) is associated with accelerated cognitive decline. To date, there is no T2D-specific treatment to prevent or ameliorate cognitive dysfunction. Boswellia serrate (BS) gum has been shown to possess multiple pharmacological actions including anti-inflammatory, anticancer and ant- apoptotic actions. The present study was aimed to investigate the effect of BS on cognitive impairment associated with T2D induced in rats by high fat/high fructose (HF/HFr) diet with a single injection of streptozotocin (STZ) and to explore the mechanism of action. The effect of 3 doses of BS extract and the reference drug on the behavioral, biochemical, histopathological and glutamate gene expression abnormalities in T2D rates was evaluated. HF/HFr diet/ STZ induces learning and memory deficits, which were reversed by BS extract. It showed a significant decrease in Aß deposits and p-tau positive cells. BS extract also reduced significantly the hippocampal elevated levels of caspase-3, cholinesterase (ChE), GSK-3ß, TNF-α, IL-1ß, IL-6, and MDA. Moreover, BS extract enhanced significantly the suppressed hippocampal level of GSH, SOD and glutamate receptor expression (GluR, NR1, NR2 A, and NR2B). In addition, BS extract alleviated insulin resistance and hyperlipidemia of T2D rats. Our findings suggest that BS extract reversed learning and memory impairment in HF/ HFr diet / STZ induced diabetic rats. This effect may be attributed to the inhibition of insulin resistance, pro-inflammatory cytokines, oxidative stress and hyperlipidemia.

Terpenoid-rich Elettaria cardamomum extract prevents Alzheimer-like alterations induced in diabetic rats via inhibition of GSK3ß activity, oxidative stress and pro-inflammatory cytokines.

PURPOSE: 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). METHODS: Phytochemical analysis was carried out. Behavioral tests, immunohistochemical examination, biochemical analysis and gene expression determination were performed in treated and controls rats. RESULTS: 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 Aß 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 ß1but not IL6 and reduced GSK-3ß in brainT2D rats. CONCLUSION: 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.