scholarly journals Necrostatin-1 Mitigates Cognitive Dysfunction in Prediabetic Rats With no Alteration in Insulin Sensitivity

2020 ◽  
Author(s):  
Ada Admin ◽  
Kewarin Jinawong ◽  
Nattayaporn Apaijai ◽  
Supawit Wongsuchai ◽  
Wasana Pratchayasakul ◽  
...  
Keyword(s):  
Synaptic Plasticity ◽  
Cognitive Function ◽  
Insulin Sensitivity ◽  
Cognitive Decline ◽  
High Fat Diet ◽  
Spine Density ◽  
High Fat ◽  
Dendritic Spine Density ◽  
Microglial Morphology ◽  
Brain Mitochondrial Function

Previous studies show that 12-week of high-fat diet (HFD) consumption caused not only prediabetes, but also cognitive decline and brain pathologies. Recently, necrostatin-1 (nec-1), a necroptosis inhibitor, showed beneficial effects in brain against stroke. However, the comparative effects of nec-1 and metformin on cognition and brain pathologies in prediabetes have not been investigated. We hypothesized that nec-1 and metformin equally attenuated cognitive decline and brain pathologies in prediabetic rats. Rats (n=32) were fed with either normal diet (ND) or high-fat diet (HFD) for 20 weeks. At week 13, ND-fed rats were given a vehicle (n=8) and HFD-fed rats were randomly assigned into 3 subgroups (n=8/subgroup) with vehicle, nec-1 or metformin for 8 weeks. Metabolic parameters, cognitive function, brain insulin receptor function, synaptic plasticity, dendritic spine density, microglial morphology, brain mitochondrial function, Alzheimer’s protein, and cell death were determined.<b> </b>HFD-fed rats exhibited prediabetes, cognitive decline, and brain pathologies. Nec-1 and metformin equally improved cognitive function, synaptic plasticity, dendritic spine density, microglial morphology, brain mitochondrial function, reduced hyperphosphorylated-tau and necroptosis in HFD-fed rats. Interestingly metformin, but not nec-1, improved brain insulin sensitivity in those rats.<b> </b><b> </b>In conclusion, necroptosis inhibition directly improved cognition in prediabetic rats without alteration in insulin sensitivity.

scholarly journals Necrostatin-1 Mitigates Cognitive Dysfunction in Prediabetic Rats With no Alteration in Insulin Sensitivity

2020 ◽  
Author(s):  
Ada Admin ◽  
Kewarin Jinawong ◽  
Nattayaporn Apaijai ◽  
Supawit Wongsuchai ◽  
Wasana Pratchayasakul ◽  
...  
Keyword(s):  
Synaptic Plasticity ◽  
Cognitive Function ◽  
Insulin Sensitivity ◽  
Cognitive Decline ◽  
High Fat Diet ◽  
Spine Density ◽  
High Fat ◽  
Dendritic Spine Density ◽  
Microglial Morphology ◽  
Brain Mitochondrial Function

Previous studies show that 12-week of high-fat diet (HFD) consumption caused not only prediabetes, but also cognitive decline and brain pathologies. Recently, necrostatin-1 (nec-1), a necroptosis inhibitor, showed beneficial effects in brain against stroke. However, the comparative effects of nec-1 and metformin on cognition and brain pathologies in prediabetes have not been investigated. We hypothesized that nec-1 and metformin equally attenuated cognitive decline and brain pathologies in prediabetic rats. Rats (n=32) were fed with either normal diet (ND) or high-fat diet (HFD) for 20 weeks. At week 13, ND-fed rats were given a vehicle (n=8) and HFD-fed rats were randomly assigned into 3 subgroups (n=8/subgroup) with vehicle, nec-1 or metformin for 8 weeks. Metabolic parameters, cognitive function, brain insulin receptor function, synaptic plasticity, dendritic spine density, microglial morphology, brain mitochondrial function, Alzheimer’s protein, and cell death were determined.<b> </b>HFD-fed rats exhibited prediabetes, cognitive decline, and brain pathologies. Nec-1 and metformin equally improved cognitive function, synaptic plasticity, dendritic spine density, microglial morphology, brain mitochondrial function, reduced hyperphosphorylated-tau and necroptosis in HFD-fed rats. Interestingly metformin, but not nec-1, improved brain insulin sensitivity in those rats.<b> </b><b> </b>In conclusion, necroptosis inhibition directly improved cognition in prediabetic rats without alteration in insulin sensitivity.

scholarly journals Dipeptidyl peptidase 4 inhibitor improves brain insulin sensitivity, but fails to prevent cognitive impairment in orchiectomy obese rats

2015 ◽  
Vol 226 (2) ◽  
pp. M1-M11 ◽  
Author(s):  
Hiranya Pintana ◽  
Wanpitak Pongkan ◽  
Wasana Pratchayasakul ◽  
Nipon Chattipakorn ◽  
Siriporn C Chattipakorn
Keyword(s):  
Insulin Resistance ◽  
Synaptic Plasticity ◽  
Cognitive Function ◽  
Insulin Sensitivity ◽  
Cognitive Decline ◽  
Hippocampal Synaptic Plasticity ◽  
Brain Insulin ◽  
Obese Rats ◽  
Brain Insulin Resistance ◽  
Brain Mitochondrial Function

It is unclear whether the dipeptidyl peptidase 4 (DPP4) inhibitor can counteract brain insulin resistance, brain mitochondrial dysfunction, impairment of hippocampal synaptic plasticity and cognitive decline in testosterone-deprived obese rats. We hypothesized that DPP4 inhibitor vildagliptin improves cognitive function in testosterone-deprived obese rats by restoring brain insulin sensitivity, brain mitochondrial function and hippocampal synaptic plasticity. Thirty male Wistar rats received either a sham-operated (S, n=6) or bilateral orchiectomy (ORX, n=24). ORX rats were divided into two groups and fed with either a normal diet (ND (NDO)) or a high-fat diet (HFO) for 12 weeks. Then, ORX rats in each dietary group were divided into two subgroups (n=6/subgroup) to receive either a vehicle or vildagliptin (3 mg/kg per day, p.o.) for 4 weeks. After treatment, cognitive function, metabolic parameters, brain insulin sensitivity, hippocampal synaptic plasticity and brain mitochondrial function were determined in each rat. We found that HFO rats exhibited peripheral and brain insulin resistance, brain mitochondrial dysfunction, impaired hippocampal synaptic plasticity and cognitive decline. NDO rats did not develop peripheral and brain insulin resistance. However, impaired hippocampal synaptic plasticity and cognitive decline occurred. Vildagliptin significantly improved peripheral insulin sensitivity, restored brain insulin sensitivity and decreased brain mitochondrial reactive oxygen species production in HFO rats. However, vildagliptin did not restore hippocampal synaptic plasticity and cognitive function in both NDO and HFO rats. These findings suggest that vildagliptin could not counteract the impairment of hippocampal synaptic plasticity and cognitive decline in testosterone-deprived subjects, despite its effects on improved peripheral and brain insulin sensitivity as well as brain mitochondrial function.

scholarly journals Exosomal miR-132-3p from Mesenchymal Stromal Cells Improve Synaptic Dysfunction and Cognitive Decline in Vascular Dementia

2021 ◽  
Author(s):  
Xiaotang Ma ◽  
Yan Wang ◽  
Yumeng Shi ◽  
Suqing Li ◽  
Jinhua Liu ◽  
...  
Keyword(s):  
Synaptic Plasticity ◽  
Cognitive Function ◽  
Stromal Cells ◽  
Memory Deficit ◽  
Synaptic Dysfunction ◽  
Spine Density ◽  
Neuron Number ◽  
Neurite Elongation ◽  
Dendritic Spine Density ◽  
Gsk 3Β

Abstract Background/Aims: Vascular dementia (VD) results in cognition and memory deficit. Exosomes and their carried microRNAs (miRs) contribute to the neuroprotective effects of mesenchymal stromal cells, and miR-132-3p plays a key role in neuron plasticity. Here we investigated the role and underlying mechanism of MSC EX and their miR-132-3p cargo in rescuing cognition and memory deficit in VD mice. Methods: Bilateral carotid artery occlusion was used to generate a VD mouse model. MiR-132-3p and MSC EX levels in the hippocampus and cortex were measured. At 24 h post-VD induction, mice were administered with MSC EX infected with control lentivirus (EXCon), pre-miR-132-3p-expressing lentivirus (EXmiR−132−3p), or miR-132-3p antago lentivirus (EXantagomiR−132−3p) intravenously. Behavioral and cognitive tests were performed and the mice were sacrificed in 21 days after VD. The effects of MSC EX on neuron number, synaptic plasticity, dendritic spine density, and Aβ and p-Tau levels in the hippocampus and cortex were determined. The effects of MSC EX on oxygen-glucose deprivation (OGD)-injured neurons with respect to apoptosis, and neurite elongation and branching were determined. Finally, the expression levels of Ras, phosphorylation of Akt, GSK-3β, and Tau were also measured. Results: Compared with normal mice, VD mice exhibited significantly decreased miR-132-3p and MSC EX levels in the cortex and hippocampus. Compared with EXCon treatment, the infusion of EXmiR−132−3p was more effective at improving cognitive function and increasing miR-132-3p level, neuron number, synaptic plasticity, and dendritic spine density, while decreasing Aβ and p-Tau levels in the cortex and hippocampus of VD mice. Conversely, EXantagomiR−132−3p treatment significantly decreased miR-132-3p expression in cortex and hippocampus, as well as attenuated EXmiR−132−3p treatment-induced functional improvement. In vitro, EXmiR−132−3p treatment inhibited RASA1 protein expression, but increased Ras and the phosphorylation of Akt and GSK-3β, and decreased p-Tau levels in primary neurons by delivering miR-132-3p, which resulted in reduced apoptosis, and increased neurite elongation and branching in OGD-injured neurons. Conclusions: Our studies suggest that miR-132-3p cluster-enriched MSC EX promotes the recovery of cognitive function by improving neuronal and synaptic dysfunction through activation of the Ras/Akt/GSK-3β pathway induced by downregulation of RASA1.

scholarly journals Energy restriction combined with dipeptidyl peptidase-4 inhibitor exerts neuroprotection in obese male rats

2016 ◽  
Vol 116 (10) ◽  
pp. 1700-1708 ◽  
Author(s):  
Hiranya Pintana ◽  
Pongpan Tanajak ◽  
Wasana Pratchayasakul ◽  
Piangkwan Sa-nguanmoo ◽  
Titikorn Chunchai ◽  
...  
Keyword(s):  
Insulin Resistance ◽  
Synaptic Plasticity ◽  
Cognitive Function ◽  
Insulin Sensitivity ◽  
Mitochondrial Function ◽  
Male Rats ◽  
Insulin Resistant ◽  
Hippocampal Synaptic Plasticity ◽  
Brain Insulin ◽  
Brain Mitochondrial Function

AbstractDipeptidyl peptidase-4 (DDP-4) inhibitors and energy restriction (ER) are widely used to treat insulin resistance and type 2 diabetes mellitus. However, the effects of ER or the combination with vildagliptin on brain insulin sensitivity, brain mitochondrial function, hippocampal synaptic plasticity and cognitive function in obese insulin-resistant rats have never been investigated. We hypothesised that ER with DDP-4 inhibitor exerts better efficacy than ER alone in improving cognition in obese insulin-resistant male rats by restoring brain insulin sensitivity, brain mitochondrial function and hippocampal synaptic plasticity. A total of twenty-four male Wistar rats were divided into two groups and fed either a normal diet or a high-fat diet (HFD) for 12 weeks. At week 13, the HFD rats were divided into three subgroups (n 6/subgroup) to receive one of the following treatments: vehicle, ER (60 % of energy received during the previous 12 weeks) or ER plus vildagliptin (3 mg/kg per d, p.o.) for 4 weeks. At the end of the treatment, cognitive function, metabolic parameters, brain insulin sensitivity, hippocampal synaptic plasticity and brain mitochondrial function were determined. We found that HFD-fed rats demonstrated weight gain with peripheral insulin resistance, dyslipidaemia, oxidative stress, brain insulin resistance, impaired brain mitochondrial function and cognitive dysfunction. Although HFD-fed rats treated with ER and ER plus vildagliptin showed restored peripheral insulin sensitivity and improved lipid profiles, only ER plus vildagliptin rats had restored brain insulin sensitivity, brain mitochondrial function, hippocampal synaptic plasticity and cognitive function. These findings suggest that only a combination of ER with DPP-4 inhibitor provides neuroprotective effects in obese insulin-resistant male rats.

Maternal High-Fat Diet Multigenerationally Impairs Hippocampal Synaptic Plasticity and Memory in Male Rat Offspring

Endocrinology ◽  
2020 ◽  
Vol 162 (1) ◽  
Author(s):  
Cheng Lin ◽  
YanYan Lin ◽  
Ji Luo ◽  
JunRu Yu ◽  
YaNi Cheng ◽  
...  
Keyword(s):  
Insulin Resistance ◽  
Synaptic Plasticity ◽  
Cognitive Function ◽  
Learning And Memory ◽  
High Fat Diet ◽  
Maternal Diet ◽  
High Fat ◽  
Hippocampal Synaptic Plasticity ◽  
Insulin Replacement

Abstract As advances are made in the field of developmental origins of health and disease, there is an emphasis on long-term influence of maternal environmental factors on offspring health. Maternal high-fat diet (HFD) consumption has been suggested to exert detrimental effects on cognitive function in offspring, but whether HFD-dependent brain remodeling can be transmitted to the next generations is still unclear. This study tested the hypothesis that HFD consumption during rat pregnancy and lactation multigenerationally influences male offspring hippocampal synaptic plasticity and cognitive function. We observed that hippocampus-dependent learning and memory was impaired in 3 generations from HFD-fed maternal ancestors (referred as F1-F3), as assessed by novel object recognition and Morris water maze tests. Moreover, maternal HFD exposure also affected electrophysiological and ultrastructure measures of hippocampal synaptic plasticity across generations. We observed that intranasal insulin replacement partially rescued hippocampal synaptic plasticity and cognitive deficits in F3 rats, suggesting central insulin resistance may play an important role in maternal diet-induced neuroplasticity impairment. Furthermore, maternal HFD exposure enhanced the palmitoylation of GluA1 critically involved in long-term potentiation induction, while palmitoylation inhibitor 2-bromopalmitate counteracts GluA1 hyperpalmitoylation and partially abolishes the detrimental effects of maternal diet on learning and memory in F3 offspring. Importantly, maternal HFD-dependent GluA1 hyperpalmitoylation was reversed by insulin replacement. Taken together, our data suggest that maternal HFD exposure multigenerationally influences adult male offspring hippocampal synaptic plasticity and cognitive performance, and central insulin resistance may serve as the cross-talk between maternal diet and cognitive impairment across generations.

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