Sasiwan Kerdphoo

Effects of high-fat diet on insulin receptor function in rat hippocampus and the level of neuronal corticosterone.

AIM Chronic consumption of a high-fat (HF) diet contributes to peripheral insulin resistance and elevated plasma corticosterone. However, the effect of HF consumption on the neurofunctional insulin receptors and neuronal corticosterone level is unclear. We tested the hypothesis that HF consumption can lead to peripheral insulin resistance, elevated neuronal corticosterone, and impaired neuronal responses to insulin. MAIN METHODS Male Wistar rats were fed with normal diet or HF diet for 4, 8 or 12weeks. At the end of each dietary period, plasma was collected for investigating peripheral insulin resistance parameters and corticosterone. Brains were then rapidly removed for studying the function of neuronal insulin receptors (IRs) by extracellular recording in CA1 hippocampus, neuronal IR signaling by immunoblot technique and neuronal corticosterone. KEY FINDINGS Elevated plasma corticosterone level was initially seen in 4-week HF-fed rats. Peripheral insulin resistance developed at 8-week HF-fed rats. However, the elevated neuronal corticosterone level was found at 12-week HF consumption. The neuronal IR response demonstrated by insulin-mediated long-term depression in CA1 hippocampus was diminished in 12-week HF-fed rats. The phosphorylation levels of neuronal IR, IR substrate 1 and Akt/PKB were decreased in 12-week HF-fed rats with no change in these proteins. There was a correlation among peripheral insulin resistance, neuronal stress (elevated neuronal corticosterone), and neuronal insulin resistance in HF group. SIGNIFICANCE Our findings suggest that HF consumption can lead to the elevation of corticosterone and peripheral insulin resistance, which could contribute to neuronal insulin resistance and neuronal stress.

FGF21 improves cognition by restored synaptic plasticity, dendritic spine density, brain mitochondrial function and cell apoptosis in obese-insulin resistant male rats.

Fibroblast growth factor 21 (FGF21) is an endocrine hormone which exerts beneficial effects on metabolic regulation in obese and diabetic models. However, the effect of FGF21 on cognition in obese-insulin resistant rats has not been investigated. We hypothesized that FGF21 prevented cognitive decline in obese-insulin resistant rats by improving hippocampal synaptic plasticity, dendritic spine density, brain mitochondrial function and brain FGF21 signaling as well as decreasing brain cell apoptosis. Eighteen male Wistar rats were divided into two groups, and received either a normal diet (ND) (n=6) or a high fat diet (HFD) (n=12) for 12weeks. At week 13, the HFD-fed rats were subdivided into two subgroups (n=6/subgroup) to receive either vehicle or recombinant human FGF21 (0.1mg/kg/day) for four weeks. ND-fed rats were given vehicle for four weeks. At the end of the treatment, cognitive function, metabolic parameters, pro-inflammatory markers, brain mitochondrial function, cell apoptosis, hippocampal synaptic plasticity, dendritic spine density and brain FGF21 signaling were determined. The results showed that vehicle-treated HFD-fed rats developed obese-insulin resistance and cognitive decline with impaired hippocampal synaptic plasticity, decreased dendritic spine density, brain mitochondrial dysfunction and increased brain cell apoptosis. Impaired brain FGF 21 signaling was found in these obese-insulin resistant rats. FGF21-treated obese-insulin resistant rats had improved peripheral insulin sensitivity, increased hippocampal synaptic plasticity, increased dendritic spine density, restored brain mitochondrial function, attenuated brain cells apoptosis and increased brain FGF21 signaling, leading to a prevention of cognitive decline. These findings suggest that FGF21 treatment exerts neuroprotection in obese-insulin resistant rats.

SGLT2-inhibitor and DPP-4 inhibitor improve brain function via attenuating mitochondrial dysfunction, insulin resistance, inflammation, and apoptosis in HFD-induced obese rats

ABSTRACT Dipeptidyl peptidase‐4 inhibitor (vildagliptin) has been shown to exert beneficial effects on insulin sensitivity and neuroprotection in obese‐insulin resistance. Recent studies demonstrated the neuroprotection of the sodium‐glucose co‐transporter 2 inhibitor (dapagliflozin) in diabetes. However, the comparative effects of both drugs and a combination of two drugs on metabolic dysfunction and brain dysfunction impaired by the obese‐insulin resistance have never been investigated. Forty male Wistar rats were divided into two groups, and received either a normal‐diet (ND, n = 8) or a high‐fat diet (HFD, n = 32) for 16 weeks. At week 13, the HFD‐fed rats were divided into four subgroups (n = 8/subgroup) to receive either a vehicle, vildagliptin (3 mg/kg/day) dapagliflozin (1 mg/kg/day) or combined drugs for four weeks. ND rats were given a vehicle for four weeks. Metabolic parameters and brain function were investigated. The results demonstrated that HFD rats developed obese‐insulin resistance and cognitive decline. Dapagliflozin had greater efficacy on improved peripheral insulin sensitivity and reduced weight gain than vildagliptin. Single therapy resulted in equally improved brain mitochondrial function, insulin signaling, apoptosis and prevented cognitive decline. However, only dapagliflozin improved hippocampal synaptic plasticity. A combination of the drugs had greater efficacy in improving brain insulin sensitivity and reducing brain oxidative stress than the single drug therapy. These findings suggested that dapagliflozin and vildagliptin equally prevented cognitive decline in the obese‐insulin resistance, possibly through some similar mechanisms. Dapagliflozin had greater efficacy than vildagliptin for preserving synaptic plasticity, thus combined drugs could be the best therapeutic approach for neuroprotection in the obese‐insulin resistance. HighlightsHFD‐induced obesity increased brain dysfunction and cognitive decline.Dapagliflozin had greater efficacy than vildagliptin for preserving brain function.The combined drugs had the greatest efficacy improving brain function.

Humanin exerts cardioprotection against cardiac ischemia/reperfusion injury through attenuation of mitochondrial dysfunction

AIM Myocardial reperfusion via the re-canalization of occluded coronary arteries is gold standard for the treatment of acute myocardial infarction. However, reperfusion itself can cause myocardial damage due to increased reactive oxygen species (ROS) production, a process known as ischemia/reperfusion (I/R) injury. Cardiac mitochondria are the major organelle of ROS production in the heart. Cardiac mitochondrial dysfunction caused by an increased ROS production can increase cardiac arrhythmia incidence, myocardial infarct size, and cardiac dysfunction. Thus, preservation of cardiac mitochondrial function is a promising pharmacological approach to reduce cardiac I/R injury. Humanin (HN), a newly discovered 24-amino acid polypeptide, has been shown to exert antioxidative stress and antiapoptotic effects. Although the cardioprotective effects of HN against I/R injury has been reported, the effect of HN on cardiac mitochondrial function has not yet been investigated. Thus, we tested the hypothesis that HN exerts its cardioprotective effects against I/R injury through the attenuation of cardiac mitochondrial dysfunction. METHODS I/R protocol was carried out using a 30-minutes occlusion of a left anterior descending coronary artery followed by a 120-minutes of reperfusion. The plasma HN level, infarct size, arrhythmia incidence, left ventricular function, and cardiac mitochondrial function were determined. RESULTS Endogenous HN level before I/R injury showed no difference between groups, but was markedly decreased after I/R injury. HN analogue pretreatment decreased arrhythmia incidence and infarct size, improved cardiac mitochondrial function, and attenuated cardiac dysfunction. CONCLUSIONS Humanin analogue pretreatment exerted cardioprotective effects against I/R injury through the attenuation of cardiac mitochondrial dysfunction.

Effects of iron overload, an iron chelator and a T-Type calcium channel blocker on cardiac mitochondrial biogenesis and mitochondrial dynamics in thalassemic mice

Abstract Although cardiac mitochondrial dysfunction is involved in the pathophysiology of iron‐overload cardiomyopathy, the precise mechanisms of iron‐induced mitochondrial dysfunction, and the roles of the iron chelator deferiprone and the T‐type calcium channel blocker efonidipine on cardiac mitochondrial biogenesis in thalassemic mice are still unknown. &bgr;‐thalassemic (HT) mice were fed with a normal diet (ND) or a high iron‐diet (FE) for 90 days. Then, the FE‐fed mice were treated with deferiprone (75 mg/kg/day) or efonidipine (4 mg/kg/day) for 30 days. The hearts were used to determine cardiac mitochondrial function, biogenesis, mitochondrial dynamics and protein expressions for oxidative phosphorylation (OXPHOS) and apoptosis. ND‐fed HT mice had impaired heart rate variability (HRV), increased mitochondrial dynamic proteins and caspase‐3, compared with ND‐fed wild‐type mice. Iron overload led to increased plasma non‐transferrin bound iron, oxidative stress, and the impairments of HRV and left ventricular function, cardiac mitochondrial function and mitochondrial dynamics, and decreased complex IV in thalassemic mice. Our results suggested that deferiprone and efonidipine treatment showed similar benefit in attenuating cardiac iron deposit and oxidative stress, and improved cardiac mitochondrial function, leading to improved left ventricular function, without altering the cardiac mitochondrial biogenesis, and apoptosis proteins in iron‐overload thalassemic mice.

Hyperglycemia induced the Alzheimer’s proteins and promoted loss of synaptic proteins in advanced-age female Goto-Kakizaki (GK) rats

Although both type 2 diabetes mellitus (T2DM) and aging are related with Alzheimers disease (AD), the effects of aging on the Alzheimers proteins and the synaptic markers in T2DM have not been investigated. This study, we hypothesized that T2DM rats with advanced-age, aggravates the reduction of synaptic proteins and an increase in the Alzheimers protein markers. Goto-Kakizaki rats (GK) were used as a T2DM group and wild-type rats (WT) were used as a control group. Rats in each group were categorized by age into young-adult (7 months) and advanced-age rats (12.5 months). Blood was collected in all rats to determine plasma glucose and insulin levels. The brains were used for determining the level of Alzheimers and synaptic proteins. Our data demonstrated that GK rats had a decreased body weight and increased blood glucose levels, compared to their age-matched WT. p-Tau was increased in both advanced-age WT and GK, compared to their young-adult rats. Moreover, amyloid-beta (Aβ) level was higher in advanced-age GK than their age-matched WT. The synaptic proteins were decreased in advanced-age GK, compared to young-adult GK rats. However, no difference in the level of Alzheimers proteins and synaptic proteins in the brains of young-adult GK compared to age-matched WT was found. Our data suggested that aging contributes to the pathogenesis of AD and the reduction of synaptic proteins to greater extent in a diabetic than in a healthy condition.

FGF21 and DPP-4 inhibitor equally prevents cognitive decline in obese rats

The beneficial effects of Fibroblast Growth Factor 21 (FGF21) on metabolic function and neuroprotection have been shown in earlier research. We have previously shown that the Dipeptidyl Peptidase 4 inhibitor, vildagliptin, also led to improved insulin sensitivity and brain function in the obese-insulin resistant condition. However, the comparative efficacy on the improvement of metabolic function and neuroprotection between FGF21 and vildagliptin in the obese-insulin resistant condition has never been investigated. Twenty-four male Wistar rats were divided into two groups, and received either a normal diet (ND, n=6) or a high fat diet (HFD, n=18) for 16 weeks. At week 13, the HFD-fed rats were divided into three subgroups (n=6/subgroup) to receive either a vehicle, recombinant human FGF21 (0.1mg/kg/day) or vildagliptin (3mg/kg/day), for four weeks. ND-fed rats were given a vehicle for four weeks. The metabolic parameters and brain function were subsequently investigated. The results demonstrated that the rats fed on HFD had obese-insulin resistance, increased systemic inflammation, brain mitochondrial dysfunction, increased brain apoptosis, impaired hippocampal plasticity, and demonstrated cognitive decline. FGF21 and vildagliptin effectively attenuated peripheral insulin resistance, brain mitochondrial dysfunction, brain apoptosis and cognitive decline. However, only FGF21 treatment led to significantly reduced body weight gain, visceral fat, systemic inflammation, improved hippocampal synaptic plasticity, enhanced FGF21 mediated signaling in the brain leading to prevention of early cognitive decline. These findings suggest that FGF21 exerts greater efficacy than vildagliptin in restoring metabolic function as well as brain function in cases of obese-insulin resistant rats.

Differential temporal inhibition of mitochondrial fission by Mdivi-1 exerts effective cardioprotection in cardiac ischemia/reperfusion injury

Altered cardiac mitochondrial dynamics with excessive fission is a predominant cause of cardiac dysfunction during ischemia/reperfusion (I/R) injury. Although pre-ischemic inhibition of mitochondrial fission has been shown to improve cardiac function in I/R injury, the effects of this inhibitor given at different time-points during cardiac I/R injury are unknown. Fifty male Wistar rats were subjected to sham and cardiac I/R injury. For cardiac I/R injury, rats were randomly divided into pre-ischemia, during-ischemia, and upon onset of reperfusion group. A mitochondrial fission inhibitor, Mdivi-1 (mitochondrial division inhibitor 1) (1.2 mg/kg) was used. During I/R protocols, the left ventricular (LV) function, arrhythmia score, and mortality rate were determined. Then, the heart was removed to determine infarct size, mitochondrial function, mitochondrial dynamics, and apoptosis. Our results showed that Mdivi-1 given prior to ischemia, exerted the highest level of cardioprotection quantitated through the attenuated incidence of arrhythmia, reduced infarct size, improved cardiac mitochondrial function and fragmentation, and decreased cardiac apoptosis, leading to preserved LV function during I/R injury. Mdivi-1 administered during ischemia and upon the onset of reperfusion also improved cardiac mitochondrial function and LV function, but at a lower efficacy than when it was given prior to ischemia. Taken together, mitochondrial fission inhibition after myocardial ischemic insults still exerts cardioprotection by attenuating mitochondrial dysfunction and dynamic imbalance, leading to decreased infarct size and ultimately improved LV function after acute cardiac I/R injury in rats. These findings indicate its potential clinical usefulness.

Estrogen and DPP-4 inhibitor share similar efficacy in reducing brain pathology caused by cardiac ischemia-reperfusion injury in both lean and obese estrogen-deprived rats

Objective: Cardiac ischemia-reperfusion injury (I/R) caused an oxidative burst, increased beta-amyloid production, and decreased dendritic spine density in the brain. However, the effect of cardiac I/R in the brain of estrogen-deprived rats who were or were not obese have not been investigated. Moreover, the benefits of estrogen or dipeptidyl peptidase-4 (DDP-4) inhibitor therapies in those conditions have never been determined. We hypothesized that cardiac I/R aggravates brain pathology in estrogen-deprived obese rats, to a greater extent when compared with estrogen-deprived lean rats, and treatment with either estrogen or a DPP-4 inhibitor attenuates those adverse effects. Methods: In protocol 1, rats were divided into sham operation (n = 12) or ovariectomy (n = 24). Sham-operated rats were fed with normal diet (ND) and ovariectomized rats were fed with either ND or high-fat diet (HF) for 12 weeks. Then, rats were subdivided to sham operation or cardiac I/R injury. In protocol 2, ovariectomized rats were given either ND (n = 18) or HF (n = 18). At week 13, ovariectomized rats were subdivided to receive vehicle, estradiol, or DPP-4 inhibitor for 4 weeks. Then, all rats were subjected to cardiac I/R. Results: Cardiac I/R injury aggravated brain oxidative stress, beta-amyloid production, and decreased dendritic spine density in either sham-operated or ovariectomized ND-fed rats, but not in ovariectomized HF-fed rats. Either estrogen or DPP-4 inhibitor therapies reduced those conditions in all rats with cardiac I/R. Conclusions: Cardiac I/R aggravates brain toxicity in estrogen-deprived lean rats, but not in the estrogen-deprived obese rats. Estrogen and DPP-4 inhibitor treatments attenuate those effects in all groups.

Atorvastatin and insulin equally mitigate brain pathology in diabetic rats

ABSTRACT Although insulin and atorvastatin have been shown to exert glycemic control and could improve brain function, the effects of atorvastatin or insulin as well as the combination of atorvastatin plus insulin on brain pathology in diabetes mellitus type 1 (T1DM) are unclear. Therefore, this study investigated the effect of atorvastatin, insulin or combined drugs on brain pathology in streptozotocin‐induced diabetic rats. Thirty‐six male rats were divided into two groups, a control group (n = 12) and a diabetic or experimental group (n = 24). Diabetic rats were further divided into four groups (n = 6/group) and the groups received either a vehicle (normal saline), atorvastatin (10 mg/kg/day), insulin (4 U/day) or a combination of the drugs for 4 weeks. The control group rats were divided into two groups (n = 6/group) to receive either just the vehicle or atorvastatin for 4 weeks. We found that streptozotocin‐induced diabetic rats developed hyperglycemia, showing evidence of increased brain oxidative stress, impaired brain mitochondrial function, increased brain apoptosis, increased tau protein expression, increased phosphorylation of tau protein expression and amyloid beta levels, and decreased dendritic spine density. Although atorvastatin and insulin therapies led to an equal reduction in plasma glucose level in these diabetic rats, the combined drug therapy showed the greatest efficacy in decreasing plasma glucose level. Interestingly, atorvastatin, insulin and the combined drugs equally mitigated brain pathology. Our findings indicate that the combined drug therapy showed the greatest efficacy in improving metabolic parameters. However, atorvastatin, insulin and the combined drug therapy shared a similar efficacy in preventing brain damage in T1DM rats. HighlightsDiabetic rats developed hyperglycemia and brain pathology.Atorvastatin and insulin therapies led to an equal reduction in hyperglycemia.Combined drug showed the greatest efficacy on improving metabolic parameters.Atorvastatin, insulin and the combined drugs equally mitigated brain pathology.