Optimized integration of metabolomics and lipidomics reveals brain region-specific changes of oxidative stress and neuroinflammation in type 1 diabetic mice with cognitive decline.

INTRODUCTION: Type 1 diabetes (T1D) causes cognitive decline and has been associated with brain metabolic disorders, but its potential molecular mechanisms remain unclear. OBJECTIVES: The purpose of this study was to explore the molecular mechanisms underlying T1D-induced cognitive impairment using metabolomics and lipidomics. METHODS: We developed an optimized integration approach of metabolomics and lipidomics for brain tissue based on UPLC-Q-TOF-MS and analyzed a comprehensive characterization of metabolite and lipid profiles in the hippocampus and frontal cortex of T1D male mice with cognitive decline (T1DCD) and age-matched control (CONT) mice. RESULTS: The results show that T1DCD mice had brain metabolic disorders in a region-specific manner relative to CONT mice, and the frontal cortex exhibited a higher lipid peroxidation than the hippocampus in T1DCD mice. Based on metabolic changes, we found that microglia was activated under diabetic condition and thereby promoted oxidative stress and neuroinflammation, leading to neuronal injury, and this event was more pronounced in the frontal cortex than the hippocampus. CONCLUSION: Our results suggest that brain region-specific shifts in oxidative stress and neuroinflammation may contribute to diabetic cognitive decline, and the frontal cortex could be the more vulnerable brain region than the hippocampus.

Tonicity-responsive enhancer-binding protein promotes diabetic neuroinflammation and cognitive impairment via upregulation of lipocalin-2.

BACKGROUND: Diabetic individuals have increased circulating inflammatory mediators which are implicated as underlying causes of neuroinflammation and memory deficits. Tonicity-responsive enhancer-binding protein (TonEBP) promotes diabetic neuroinflammation. However, the precise role of TonEBP in the diabetic brain is not fully understood. METHODS: We employed a high-fat diet (HFD)-only fed mice or HFD/streptozotocin (STZ)-treated mice in our diabetic mouse models. Circulating TonEBP and lipocalin-2 (LCN2) levels were measured in type 2 diabetic subjects. TonEBP haploinsufficient mice were used to investigate the role of TonEBP in HFD/STZ-induced diabetic mice. In addition, RAW 264.7 macrophages were given a lipopolysaccharide (LPS)/high glucose (HG) treatment. Using a siRNA, we examined the effects of TonEBP knockdown on RAW264 cell' medium/HG-treated mouse hippocampal HT22 cells. RESULTS: Circulating TonEBP and LCN2 levels were higher in experimental diabetic mice or type 2 diabetic patients with cognitive impairment. TonEBP haploinsufficiency ameliorated the diabetic phenotypes including adipose tissue macrophage infiltrations, neuroinflammation, blood-brain barrier leakage, and memory deficits. Systemic and hippocampal LCN2 proteins were reduced in diabetic mice by TonEBP haploinsufficiency. TonEBP (+ / -) mice had a reduction of hippocampal heme oxygenase-1 (HO-1) expression compared to diabetic wild-type mice. In particular, we found that TonEBP bound to the LCN2 promoter in the diabetic hippocampus, and this binding was abolished by TonEBP haploinsufficiency. Furthermore, TonEBP knockdown attenuated LCN2 expression in lipopolysaccharide/high glucose-treated mouse hippocampal HT22 cells. CONCLUSIONS: These findings indicate that TonEBP may promote neuroinflammation and cognitive impairment via upregulation of LCN2 in diabetic mice.

Medial prefrontal area reductions, altered expressions of cholecystokinin, parvalbumin, and activating transcription factor 4 in the corticolimbic system, and altered emotional behavior in a progressive rat model of type 2 diabetes.

Metabolic disorders are associated with a higher risk of psychiatric disorders. We previously reported that 20-week-old Otsuka Long-Evans Tokushima fatty (OLETF) rats, a model of progressive type 2 diabetes, showed increased anxiety-like behavior and regional area reductions and increased cholecystokinin-positive neurons in the corticolimbic system. However, in which stages of diabetes these alterations in OLETF rats occur remains unclear. We aimed to investigate anxiety-like behavior and its possible mechanisms at different stages of type 2 diabetes in OLETF rats. Eight- and 30-week-old OLETF rats were used as diabetic animal models at the prediabetic and progressive stages of type 2 diabetes respectively, and age-matched Long-Evans Tokushima Otsuka rats served as non-diabetic controls. In the open-field test, OLETF rats showed less locomotion in the center zone and longer latency to leave the center zone at 8 and 30 weeks old, respectively. The areas of the medial prefrontal cortex were smaller in the OLETF rats, regardless of age. The densities of cholecystokinin-positive neurons in OLETF rats were higher in the lateral and basolateral amygdala only at 8 weeks old and in the anterior cingulate and infralimbic cortices and hippocampal cornu ammonis area 3 at both ages. The densities of parvalbumin-positive neurons of OLETF rats were lower in the cornu ammonis area 2 at 8 weeks old and in the prelimbic and infralimbic cortices at both ages. No apoptotic cell death was detected in OLETF rats, but the percentage of neurons co-expressing activating transcription factor 4 and cholecystokinin and parvalbumin was higher in OLETF rats at both ages in the anterior cingulate cortex and basolateral amygdala, respectively. These results suggest that altered emotional behavior and related neurological changes in the corticolimbic system are already present in the prediabetic stage of OLETF rats.

Ephrin-B2 PB-mononuclear cells reduce early post-stroke deficit in diabetic mice but not long-term memory impairment.

BACKGROUND AND PURPOSE: Post-stroke cognitive impairment (PSCI) has become a major public health issue, as a leading cause of dementia. The inflammation that develops soon after cerebral artery occlusion and may persist for weeks or months after stroke is a key component of PSCI. Our aim was to take advantage of the immunomodulatory properties of peripheral blood mononuclear cells (PB-MNC) stimulated with ephrin-B2/fc (PB-MNC+) for preventing PSCI. METHODS: Cortical infarct was induced by thermocoagulation of the middle cerebral artery in male diabetic mice (streptozotocin IP). PB-MNC were isolated from diabetic human donors, washed with recombinant ephrin-B2/Fc and injected into the mice intravenously on the following day. Infarct volume, sensorimotor deficit, cell death and immune cell densities were assessed on day 3. Six weeks later, cognitive assessment was performed using the Barnes maze. RESULTS: PB-MNC+ transplanted in post-stroke diabetic mice reduced the neurological deficit, infarct volume and apoptosis at D3, without modification of microglial cells, astrocytes and T-lymphocytes densities in the brain. Barnes maze assessment of memory showed that the learning, retention and reversal phases were not significantly modified by cell therapy. CONCLUSIONS: Intravenous PB-MNC+ administration the day after stroke induction in diabetic mice improved sensorimotor deficit and reduced infarct volume at the short term, but was unable to prevent long-term memory loss. To what extent diabetes impacts on cell therapy efficacy will have to be specifically investigated in the future. Including vascular risk factors systematically in preclinical studies of cell therapy will provide a comprehensive understanding of the mechanisms potentially limiting cell efficacy and also to identify good and bad responders, particularly in the long term.

Dynamic expression of vascular endothelial growth factor (VEGF) and platelet-derived growth factor receptor beta (PDGFRß) in diabetic brain contributes to cognitive dysfunction.

BACKGROUND: Cognitive dysfunction is increasingly recognized as an important complication of diabetes mellitus (DM). Accumulating evidence indicates that the abnormality of cerebrovascular structure and function plays an essential role in diabetic cognitive impairment (DCI), however, changes in cerebrovascular factors have been blurred during the development of diabetes. OBJECTIVE: To evaluate the changes in the structure and function of cerebrovascular in DCI mice and to investigate the changes of cerebral angiogenesis and stability factors during the development of DM. METHODS: Diabetes was induced by feeding with high-fat diet combined with intraperitoneal injection of streptozotocin (STZ,120 mg/kg). Cognitive function was evaluated at different stages of DM, cerebral neovascularization, blood-brain barrier (BBB) permeability and hippocampal neurons were measured of DCI mice, and the expression of vascular endothelial growth factor (VEGF) and platelet-derived growth factor receptor ß (PDGFRß) in hippocampus was detected during the development of DM. RESULTS: With the progress of diabetes, the learning and memory ability of mice gradually decreased, and DCI mice showed neuronal degeneration, increased BBB permeability and pathological cerebral neovascularization. Moreover, the expression of VEGF in the hippocampus increased first and then decreased at DM+8week, PDGFRß decreased continuously with the development of diabetes. CONCLUSIONS: Our results demonstrate that DCI may be attributed to the dynamic expression of VEGF/PDGFRß in diabetic hippocampus, and pathological cerebral neovascularization, increased BBB permeability and neuronal degeneration are the key links.

The molecular mechanism underlying mitophagy-mediated hippocampal neuron apoptosis in diabetes-related depression.

Diabetes-related depression (DD) is a major complication of diabetes mellitus. Our previous studies indicated that glutamate (Glu) and hippocampal neuron apoptosis are key signal and direct factor leading to diabetes-related depression, respectively. However, the accurate pathogenesis remains to be unclear. We hypothesized that diabetes-related depression might be associated with the mitophagy-mediated hippocampal neuron apoptosis, triggered by aberrant Glu-glutamate receptor2 (GluR2)-Parkin pathway. To testify this hypothesis, here the rat model of DD in vivo and in vitro were both established so as to uncover the potential mechanism of DD based on mitophagy and apoptosis. We found that DD rats exhibit an elevated glutamate levels followed by monoamine neurotransmitter deficiency and depressive-like behaviour, and DD modelling promoted autophagosome formation and caused mitochondrial impairment, eventually leading to hippocampal neuron apoptosis via aberrant Glu-GluR2-Parkin pathway. Further, in vitro study demonstrated that the simulated DD conditions resulted in an abnormal glutamate and monoamine neurotransmitter levels followed by autophagic flux increment, mitochondrial membrane potential reduction and mitochondrial reactive oxygen species and lactic dehydrogenase elevation. Interestingly, both GluR2 and mammalian target of rapamycin (mTOR) receptor blocker aggravated mitophagy-induced hippocampal neuron apoptosis and abnormal expression of apoptotic protein. In contrast, both GluR2 and mTOR receptor agonist ameliorated those apoptosis in simulated DD conditions. Our findings revealed that mitophagy-mediated hippocampal neuron apoptosis, triggered by aberrant Glu-GluR2-Parkin pathway, is responsible for depressive-like behaviour and monoamine neurotransmitter deficiency in DD rats. This work provides promising molecular targets and strategy for the treatment of DD.

DRD1 agonist A-68930 improves mitochondrial dysfunction and cognitive deficits in a streptozotocin-induced mouse model.

Alzheimer's disease (AD) is the most prevalent neurodegenerative disorder characterized by irreversible cognitive deficits and memory dysfunction. Dopamine is the most abundant catecholaminergic neurotransmitter in the brain which regulates motivation, reward, movement, and cognition. Recently, increasing evidences have shown that dopaminergic system is disturbed in AD conditions, and pharmacological interventions targeting dopamine D1 receptor (DRD1) exhibit certain therapeutic benefits in AD models. However, the underlying link between DRD1 and AD remains elusive. This study sought to test whether the selective DRD1 agonist A-68930 could improve streptozotocin (STZ)-induced cognitive impairment in mice. Here we found that A-68930 treatment through intraperitoneal injection efficiently alleviated STZ-induced cognitive deficits in mice. Moreover, our mechanism researches revealed that the DRD1 signaling induced by A-68930 significantly rescued STZ-induced mitochondrial biogenesis deficit, mitochondrial dysfunction, Aß overexpression, and tau phosphorylation in mice hippocampus and cortex and SH-SY5Y cells, which may be mediated through stimulating AMPK/PGC-1α pathway. This study indicates that DRD1 agonist A-68930 can improve STZ-induced cognitive deficits and mitochondrial dysfunction in vivo and in vitro, and DRD1 may represent an appropriate target candidate for AD drug development.

Effects of Gestational Diabetes in Cognitive Behavior, Oxidative Stress and Metabolism on the Second-Generation Off-Spring of Rats.

Gestational diabetes (GD) has a negative impact on neurodevelopment, resulting in cognitive and neurological deficiencies. Oxidative stress (OS) has been reported in the brain of the first-generation offspring of GD rats. OS has been strongly associated with neurodegenerative diseases. In this work, we determined the effect of GD on the cognitive behavior, oxidative stress and metabolism of second-generation offspring. GD was induced with streptozotocin (STZ) in pregnant rats to obtain first-generation offspring (F1), next female F1 rats were mated with control males to obtain second-generation offspring (F2). Two and six-month-old F2 males and females were employed. Anxious-type behavior, spatial learning and spatial working memory were evaluated. In cerebral cortex and hippocampus, the oxidative stress and serum biochemical parameters were measured. Male F2 GD offspring presented the highest level of anxiety-type behavior, whilst females had the lowest level of anxiety-type behavior at juvenile age. In short-term memory, adult females presented deficiencies. The offspring F2 GD females presented modifications in oxidative stress biomarkers in the cerebral cortex as lipid-peroxidation, oxidized glutathione and catalase activity. We also observed metabolic disturbances, particularly in the lipid and insulin levels of male and female F2 GD offspring. Our results suggest a transgenerational effect of GD on metabolism, anxiety-like behavior, and spatial working memory.

Exercise and Urtica dioica extract ameliorate hippocampal insulin signaling, oxidative stress, neuroinflammation, and cognitive function in STZ-induced diabetic rats.

INTRODUCTION: Diabetes mellitus is related to cognitive impairments and molecular abnormalities of the hippocampus. A growing body of evidence suggests that Urtica dioica (Ud) and exercise training (ET) have potential therapeutic effects on diabetes and its related complications. Therefore, we hypothesized that the combined effect of exercise training (ET) and Ud might play an important role in insulin signaling pathway, oxidative stress, neuroinflammation, and cognitive impairment in diabetic rats. METHODS: Forty animals were divided into five groups (N = 8): healthy-sedentary (H-sed), diabetes-sedentary (D-sed), diabetes-exercise training (D-ET), diabetes-Urtica dioica (D-Ud), diabetes-exercise training-Urtica dioica (D-ET-Ud). Streptozotocin (STZ) (Single dosage; 45 mg/kg, i.p.) was used to induce diabetes. Then, ET (moderate intensity/5day/week) and Ud extract (50 mg/kg, oral/daily) were administered for six weeks. We also investigated the effects of ET and Ud on cognitive performance (assessed through Morris Water Maze tests), antioxidant capacity, and lipid peroxidation markers in hippocampus. Furthermore, we measured levels of insulin sensitivity and signaling factors (insulin-Ins, insulin receptor-IR and insulin-like growth factor-1 receptor-IGF-1R), and neuroinflammatory markers (IL-1 ß, TNF-α). This was followed by TUNEL assessment of the apoptosis rate in all regions of the hippocampus. RESULTS: D-sed rats compared to H-sed animals showed significant impairments (P < 0.001) in hippocampal insulin sensitivity and signaling, oxidative stress, neuroinflammation, and apoptosis, which resulted in cognitive dysfunction. Ud extract and ET treatment effectively improved these impairments in D-ET (P < 0.001), D-Ud (P < 0.05), and D-ET-Ud (P < 0.001) groups compared to D-sed rats. Moreover, diabetes mediated hippocampal oxidative stress, neuroinflammation, insulin signaling deficits, apoptosis, and cognitive dysfunction was further reversed by chronic Ud+ET administration in D-ET-Ud rats (P < 0.001) compared to D-sed animals. CONCLUSIONS: Ud extract and ET ameliorate cognitive dysfunction via improvement in hippocampal oxidative stress, neuroinflammation, insulin signaling pathway, and apoptosis in STZ-induced diabetic rats. The results of this study provide new experimental evidence for using Ud+ET in the treatment of hippocampal complications and cognitive dysfunction caused by diabetes.

Cannabidiol induces antidepressant and anxiolytic-like effects in experimental type-1 diabetic animals by multiple sites of action.

Cannabidiol (CBD), a phytocannabinoid compound, presents antidepressant and anxiolytic-like effects in the type-1 diabetes mellitus(DM1) animal model. Although the underlying mechanism remains unknown, the type-1A serotonin receptor (5-HT1A) and cannabinoids type-1 (CB1) and type-2 (CB2) receptors seem to play a central role in mediating the beneficial effects on emotional responses. We aimed to study the involvement of these receptors on an antidepressant- and anxiolytic-like effects of CBD and on some parameters of the diabetic condition itself. After 2 weeks of the DM1 induction in male Wistar rats by streptozotocin (60 mg/kg; i.p.), animals were treated continuously for 2-weeks with the 5-HT1A receptor antagonist WAY100635 (0.1 mg/kg, i.p.), CB1 antagonist AM251 (1 mg/kg i.p.) or CB2 antagonist AM630 (1 mg/kg i.p.) before the injection of CBD (30 mg/kg, i.p.) or vehicle (VEH, i.p.) and then, they were submitted to the elevated plus-maze and forced swimming tests. Our findings show the continuous treatment with CBD improved all parameters evaluated in these diabetic animals. The previous treatment with the antagonists - 5-HT1A, CB1, or CB2 - blocked the CBD-induced antidepressant-like effect whereas only the blockade of 5-HT1A or CB1 receptors was able to inhibit the CBD-induced anxiolytic-like effect. Regarding glycemic control, only the blockade of CB2 was able to inhibit the beneficial effect of CBD in reducing the glycemia of diabetic animals. These findings indicated a therapeutic potential for CBD in the treatment of depression/anxiety associated with diabetes pointing out a complex intrinsic mechanism in which 5-HT1A, CB1, and/or CB2 receptors are differently recruited.

Ameliorative effects of endurance training and Matricaria chamomilla flowers hydroethanolic extract on cognitive deficit in type 2 diabetes rats.

Diabetes mellitus is mainly associated with degeneration of the central nervous system, which eventually leads to cognitive deficit. Although some studies suggest that exercise can improve the cognitive decline associated with diabetes, the potential effects of endurance training (ET) accompanied by Matricaria chamomilla (M.ch) flowers extract on cognitive impairment in type 2 diabetes has been poorly understood. Forty male Wistar rats were randomized into 5 equal groups of 8: healthy-sedentary (H-sed), diabetes-sedentary (D-sed), diabetes-endurance training (D-ET), diabetes-Matricaria chamomilla. (D-M.ch), and diabetes-endurance training-Matricaria chamomilla. (D-ET-M.ch). Nicotinamide (110 mg/kg, i.p.) and Streptozotocin (65 mg/kg, i.p.) were utilized to initiate type 2 diabetes. Then, ET (5 days/week) and M.ch (200 mg/kg body weight/daily) were administered for 12 weeks. After 12 weeks of the experiment, cognitive functions were assessed using the Morris Water Maze (MWM) test and a passive avoidance paradigm using a shuttle box device. Subsequently, using crystal violet staining, neuron necrosis was examined in the CA3 area of the hippocampus. Diabetic rats showed cognitive impairment following an increase in the number of necrotic cells in region CA3 of the hippocampal tissue. Also, diabetes increased serum levels of lipid peroxidation and decreased total antioxidant capacity in serum and hippocampal tissue. ET + M.ch treatment prevented the necrosis of neurons in the hippocampal tissue. Following positive changes in hippocampal tissue and serum antioxidant enzyme levels, an improvement was observed in the cognitive impairment of the diabetic rats receiving ET + M.ch. Therefore the results showed that treatment with ET + M.ch could ameliorate memory and inactive avoidance in diabetic rats. Hence, the use of ET + M.ch interventions is proposed as a new therapeutic perspective on the death of hippocampal neurons and cognitive deficit caused by diabetes.

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.

Region-specific metabolic characterization of the type 1 diabetic brain in mice with and without cognitive impairment.

Type 1 diabetes (T1D) has been reported to cause cognitive decline, but brain metabolic changes during this process are still far from being fully understood. Here, we found that streptozotocin (STZ)-induced T1D mice exhibited impaired learning and memory at 11 weeks after STZ treatment but not at 3 weeks. Therefore, we studied metabolic alterations in six different brain regions of T1D mice with and without cognitive decline, and attempted to identify key metabolic pathways related to diabetic cognitive dysfunction. The results demonstrate that lactate had already increased in all brain regions of T1D mice prior to cognitive decline, but a decreased TCA cycle was only observed in hippocampus, cortex and striatum of T1D mice with cognitive impairment. Reduced N-acetylaspartate and choline were found in all brain regions of T1D mice, irrespective of cognitive decline. In addition, disrupted neurotransmitter metabolism was noted to occur in T1D mice before cognitive deficit. Of note, we found that the level of uridine was significantly reduced in cerebellum, cortex, hypothalamus and midbrain of T1D mice when cognitive decline was presented. Therefore, brain region-specific metabolic alterations may comprise possible biomarkers for the early-diagnosis and monitoring of diabetic cognitive decline. Moreover, down-regulated TCA cycle and pyrimidine metabolism could be closely related to T1D-associated cognitive impairment.

Insulin deficiency, but not resistance, exaggerates cognitive deficits in transgenic mice expressing human amyloid and tau proteins. Reversal by Exendin-4 treatment.

Epidemiological studies have pointed at diabetes as a risk factor for Alzheimer's disease (AD) and this has been supported by several studies in animal models of both type 1 and type 2 diabetes. However, side-by-side comparison of the two types of diabetes is limited. We investigated the role of insulin deficiency and insulin resistance in the development of memory impairments and the effect of Exendin-4 (Ex4) treatment in a mouse model of AD. Three-4-month-old female wild type (WT) mice and mice overexpressing human tau and amyloid precursor protein (TAPP) were injected with streptozotocin (STZ) or fed a high-fat diet (HFD). A second study was performed in TAPP-STZ mice treated with Ex4, a long-lasting analog of GLP-1. Plasma and brain were collected at study termination for ELISA, Western blot, and immunohistochemistry analysis. Learning and memory deficits were impaired in TAPP transgenic mice compared with WT mice at the end of the study. Deficits were exaggerated by insulin deficiency in TAPP mice but 12 weeks of insulin resistance did not affect memory performances in either WT or TAPP mice. Levels of phosphorylated tau were increased in the brain of WT-STZ and TAPP-STZ mice but not in the brain of WT or TAPP mice on HFD. In the TAPP-STZ mice, treatment with Ex4 initiated after established cognitive deficits ameliorated learning, but not memory, impairments. This was accompanied by the reduction of amyloid ß and phosphorylated tau expression. Theses studies support the role of Ex4 in AD, independently from its actions on diabetes.

Betaine Alleviates Cognitive Deficits in Diabetic Rats via PI3K/Akt Signaling Pathway Regulation.

BACKGROUND: Diabetes mellitus is a metabolic disease which also causes cognitive deficits. Betaine (N,N,N-trimethylglycine), also known as trimethylglycine, has been shown to ameliorate diabetic symptoms in diabetic animals and improve cognitive ability in Alzheimer disease (AD) animals. However, the effects of betaine on cognitive deficits in diabetic animals have not been described yet. Therefore, in the current study, the effects of betaine on cognition in diabetic rats were evaluated. METHODS: We established a diabetic rat model by injecting streptozotocin (STZ) into rats and administrated betaine to these diabetic rats. We monitored the metabolism index, and glucose and insulin levels in blood and cerebrospinal fluid. We measured inflammatory cytokine levels, including TNF-α, IL-1ß, and IL-6, in serum and hippocampus. We also monitored oxidative stress in the hippocampus by measuring malondialdehyde (MDA) level and superoxide dismutase (SOD) activity. We measured the learning and memory ability of diabetic rats using the Morris water and Y maze tests and tested the phosphatidylinositol 3-kinase (PI3K)/Akt activation and p-mTOR level in the hippocampus. RESULTS: Betaine improved glucose metabolism and suppressed the production of inflammatory cytokines, including TNF-α, IL-1ß, and IL-6. Also, betaine decreased MDA concentration and increased SOD activity in the hippocampus of diabetic rats. Betaine ameliorated cognitive deficits in diabetic rats, and it promoted PI3K expression and Akt activation and decreased p-mTOR expression. CONCLUSION: Betaine alleviates cognitive deficits in STZ-induced diabetic rats via regulating the PI3K/Akt signaling pathway.

Jiawei Shengmai San herbal formula ameliorates diabetic associate cognitive decline by modulating AKT and CREB in rats.

Memory loss is a complication of diabetes which requires new approaches to its treatment. Shengmai San (SMS) is a famous traditional Chinese formula containing Panax ginseng, Ophiopogon japonicas, and Schisandra chinensis, whereas Radix puerariae has many reported pharmacological uses. In this study the combination, as Jiawei SMS (J-SMS) was screened for its ability to reverse diabetes-associated cognitive decline in rats. This was assessed behaviorally in diabetic rats (Streptozotocin, 45 mg/kg), with biochemical and western blot analysis (Akt and CREB). Diabetic rats showed fasting blood glucose (FBG) in the range of 13-15 mM throughout the study. J-SMS (0.5, 1.5, 4.5 g/kg) treatment significantly improved learning and memory deficit among diabetic rats as evidenced by preference for novel object, reduced escape latency and increased number of platform crossings (p < .05) in the NORT and MWM tests. Treatment with J-SMS also significantly improved the histopathological changes in the diabetic brain and increased the protein expression of AKT and CREB, required for proper memory function (p < .01). This study highlighted that J-SMS can reverse reference and working memory deficit among diabetic rats by modulating AKT and CREB proteins activation. Thus, J-SMS formulation might be possible candidate for further development.

Exercise and Curcumin in Combination Improves Cognitive Function and Attenuates ER Stress in Diabetic Rats.

Type 2 diabetes mellitus (T2DM) is a metabolic disease associated with chronic low-grade inflammation that is mainly associated with lifestyles. Exercise and healthy diet are known to be beneficial for adults with T2DM in terms of maintaining blood glucose control and overall health. We investigated whether a combination of exercise and curcumin supplementation ameliorates diabetes-related cognitive distress by regulating inflammatory response and endoplasmic reticulum (ER) stress. This study was performed using male Otsuka Long-Evans Tokushima Fatty (OLETF) rats (a spontaneous diabetes Type 2 model) and Long-Evans Tokushima Otsuka (LETO) rats (LETO controls) by providing them with exercise alone or exercise and curcumin in combination. OLETF rats were fed either a diet of chow (as OLETF controls) or a diet of chow containing curcumin (5 g/kg diet) for five weeks. OLETF rats exercised with curcumin supplementation exhibited weight loss and improved glucose homeostasis and lipid profiles as compared with OLETF controls or exercised OLETF rats. Next, we examined cognitive functions using a Morris water maze test. Exercise plus curcumin improved escape latency and memory retention compared to OLETF controls. Furthermore, OLETF rats exercised and fed curcumin had lower IL6, TNFα, and IL10 levels (indicators of inflammatory response) and lower levels of ER stress markers (BiP and CHOP) in the intestine than OLETF controls. These observations suggest exercise plus curcumin may offer a means of treating diabetes-related cognitive dysfunction.

Antidepressant effect in diabetes-associated depression: A novel potential of RAAS inhibition.

The incidence of depression doubles in diabetic patients and is associated with poor outcomes. Studies indicate that renin-angiotensin-aldosterone system inhibitors (RAASi) might relieve depression, however the mechanism of action is not well understood. We recently showed that angiotensin receptor blockers have antidepressant effects in experimental diabetes comorbid depression. Here we investigated whether all types of RAASi exhibit antidepressant and neuroprotective properties. Diabetes was induced by streptozotocin in adult male Wistar rats. After 5 weeks of diabetes, rats were treated per os with non-pressor doses of enalapril, ramipril, spironolactone or eplerenone for 2 weeks. Behavior was evaluated using forced swim test and open field test. Inflammatory response and brain-derived neurotrophic factor (BDNF) signaling were investigated in the hippocampus. Both ACEi and MR antagonists reversed diabetes-induced behavioral despair confirming their antidepressant-like effect. This may occur via alterations in hippocampal cytokine-mediated inflammatory response. Repressed BDNF production was restored by RAASi. Both ACEi and MR antagonists facilitated the BDNF-tropomyosin receptor kinase B-cAMP response element-binding protein signaling pathway as part of their neuroprotective effect. These data highlight the important benefits of ACEi and MR antagonists in the treatment of diabetes-associated depressive symptoms. Our novel findings support the link between diabetes comorbid depression, inflammation and repressed BDNF signaling. RAASi could provide new therapeutic options to improve the outcomes of both disorders.

Myrtus communis subsp. communis improved cognitive functions in ovariectomized diabetic rats.

AIM: The purpose of this study was to investigate the possible effects of Myrtus communis subsp. communis (MC) on cognitive impairment in ovariectomized diabetic rats. MATERIAL AND METHOD: Female Sprague-Dawley rats were divided into 5 groups consisting of 15 rats each; Control (C), Diabetes (D), Ovariectomy and diabetes (OVX + D), Ovariectomy, diabetes and donepezil (OVX + D + Don), Ovariectomy, diabetes and Myrtus communis subsp. communis (OVX + D + MC). Blood glucose measurements were made at the beginning and end of the experiments. The animals underwent the novel object recognition test (NORT) and their performance was evaluated. In hippocampal tissues; amyloid beta (Aß) and neprilysin levels, acetylcholinesterase (AChE), and choline acetyltransferase (ChAT) activities, polysialylated neural cell adhesion molecule (PSA-NCAM), α7 subunit of neuronal nicotinic acetylcholine receptor (α7-nAChR) and brain derived neurotrophic factor (BDNF) gene expressions were examined. RESULTS: Animals with ovariectomy and diabetes showed increased levels of blood glucose, AChE activity and Aß levels, and decreased neprilysin levels, ChAT activity, α7-nAChR, PSA-NCAM and BDNF gene expressions in parallel with a decrease in NORT performance score. On the other hand, in the MC-treated OVX + D group, there was a significant decrease observed in blood glucose levels and AChE activities while there was improvement in NORT performances and an increase in hippocampal ChAT activity, neprilysin levels, α7-nAChR, PSA-NCAM and BDNF expressions. CONCLUSION: These results suggest that MC extract could improve cognitive and neuronal functions with its anticholinesterase and antihyperglycemic properties.

Advanced glycation end products inhibit neural stem cell differentiation via upregualtion of HDAC3 expression.

Diabetes mellitus (DM) is a highly prevalent chronic systemic disease, which may cause cognitive decline and degenerative change of the brain. Neuronal differentiation defects of neural stem cells (NSCs) played an important role in the development and progression of diabetes-associated cognitive decline (DACD), but the intrinsic pathological mechanism remains largely unclear. In the present study, we demonstrated that expression level of HDAC3 was upregulated in diabetic mice with reduced learning and memory abilities and in cultured NSCs after advanced glycation end products (AGEs) induction. In addition, AGEs interfered with normal differentiation of the cultured NSCs, and knocking down the expression of HDAC3 could partially attenuate the inhibitory effect of AGEs on NSCs differentiation. Findings in this study demonstrate that HDAC3 may serve as an experimental clue for revealing the pathogenesis of DACD.