The acute effects of dioxidovanadium on blood glucose concentration and oxidative stress in the hippocampus of non-diabetic male Sprague Dawley rats and the chronic effects of dioxidovanadium on selected markers associated with hippocampal dysfunction in male streptozotocin-induced diabetic rats.
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Date
2022
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Abstract
Diabetes mellitus is a disease associated with derangements in glucose metabolism and chronic hyperglycaemia. Chronic hyperglycaemia induces oxidative stress and inflammation that affect glucose sensitive hippocampal neurons resulting in generation of amyloid plaques and tau tangles. These are the primary markers used in the detection of neurodegenerative diseases such as Alzheimer’s and dementia. Hence, there is a strong correlation between diabetes and memory impairment. Current therapeutic options such as bolus insulin have been successful in the management of the disease. Despite the efficacy of these therapies, they however have been shown to possess undesirable effects that exacerbate the secondary pathological effects of diabetes on the hippocampus thereby contributing to the detriment of cognitive tasks such as learning and memory. Therefore, there is a need to explore alternative treatments. Transition metals have been shown to possess therapeutic effects with vanadium possessing the greatest potency in lowering blood glucose concentrations. However, studies have demonstrated toxic accumulation of vanadium in the hippocampus which result in the generation of oxidative stress and neurodegeneration. In our laboratory, we have synthesised dioxidovanadium (V) complex by attaching organic ligands to reduce the toxicity and improve potency of the metal. This complex has been shown to efficiently reduce blood glucose and elicit cardio and reno-protective properties. Despite these advancements the effects of this complex on the hippocampus and learning and memory are yet to be established. Therefore, in this study the aim was to evaluate the effect of dioxidovanadium complex on selected learning and memory parameters.
Methodology
The effect of vanadium on the brain was studied acutely and chronically. In the acute study, animals were separated into 2 groups, non-diabetic control group and a non-diabetic animal group which was were treated with vanadium complex (40 mg.kg-1 p.o). The treatment was administered at time 0. Subsequently an n=3 from each group was sacrificed at regular time intervals (1 hour, 2 hours, 6 hours, 24 hours, 5 days, 10 days) in each group. Blood glucose concentration was monitored before sacrificing and hippocampal tissue was harvested for malonaldehyde (MDA) analysis and glutathione peroxidase (GPx1) and tumour necrosis alpha (TNF-α). The second study was conducted over 5 weeks and consisted of an untreated non-diabetic control, a diabetic control, a positive insulin treated group (0.175 mg.kg-1 s.c) and two dioxidovanadium (V) treated groups (40 mg.kg-1 p.o), a non-diabetic and a diabetic group. Blood glucose was monitored weekly and the Morris water maze was conducted on the last week of the study. After 5 weeks the animals were sacrificed and hippocampal tissue was harvested for malonaldehyde (MDA) analysis, glutathione peroxidase (GPx1) tumour necrosis alpha (TNF-α), amyloid beta (Aβ) and hyperphosphorylated tau (pTau) ELISA’s.
Results
Acutely, dioxidovandium (V) did not lower blood glucose significantly in comparison to the control group. Interestingly, MDA, GPx1 and (TNF-α) were also not significantly different from the control group over all time periods in the study. Chronically, the glucose concentration of the dioxidovandium (V) treated diabetic group was significantly lowered when compared to the untreated group which displayed significantly increased glucose concentration in comparison to the non-diabetic control. The non-diabetic dioxidovanadium (V) treated group did not show a significant difference in glycaemic level. Increased MDA concentration in the diabetic group was significantly lowered by dioxidovanadium(V) treatment. GPx1 concentration in the dioxidovanadium (V) treated group significantly improved in comparison to the diabetic untreated control. The non-diabetic dioxidovandium (V) treated group showed no significant change in MDA and Gpx1 after the 5-week period. There was no significant difference in TNF-α in dioxidovanadium (V) treated groups, diabetic and non-diabetic. The concentration of Amyloid β was significantly lower in the diabetic control when compared to the non-diabetic control. The dioxidovanadium (V) treated groups, both diabetic and non-diabetic did not have a significant difference in comparison to the diabetic control. pTau concentrations in all groups did not significantly differ. Latency times for the last day of training the Morris water maze followed the same trend. The probe test results, which measured spatial memory, for the diabetic untreated and dioxidovanadium (V) treated groups were significantly reduced in comparison to the non-diabetic control group. The non-diabetic untreated and non-diabetic dioxodivanadium (V) treated were not significantly different.
Conclusion
Dioxidovanadium (V) treatment in non-diabetic animals did not induce hypoglycaemia acutely however reduced blood glucose concentration in diabetic animals when administered chronically. Dioxidovanadium (V) did not induce oxidative stress and may protect against neurodegeneration by enhancing antioxidant status and therefore was considered as a pro-oxidant in the hippocampus.
Description
Masters Degree. University of KwaZulu-Natal, Durban.