Figure 4 - uploaded by Aniruddha Mukherjee
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Photomicrographs of hippocampal region of mice brain. (a) Control showing healthy neurons; (b) metabolic syndrome animals showing loss of hippocampal neurons at CA1 and CA3 regions when compared to control; (c) minocycline-treated metabolic syndrome group showing partial reversal of metabolic syndrome-induced neuronal damage; (d) metabolic syndrome animals showing significant loss of CA1 and CA3 neurons compared to control animals. This loss was partially reversed upon minocycline treatment. Representative image from each group (n = 5) stained with H and E (10 × 10). ***P < 0.001, **P < 0.01, *P < 0.05 all values are expressed as mean ± standard error of the mean d c
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OBJECTIVE
The objective of the study was to characterize the mechanism associated with metabolic syndrome (MetS)-associated cognitive decline and determine the effect of minocycline on the above condition in mice.
MATERIALS AND METHODS
We developed a HFHC diet-induced MetS model in mice. Diagnostic characteristics of MetS including waist circumfer...
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Background and aim:
Minocycline, a tetracycline derivative, has been found to exert neuroprotective properties. The current project aimed to assess the antioxidant status and cholinergic function in the amnesia induced by scopolamine.
Methods:
We evaluated the passive avoidance performance, acetylcholine esterase (AChE) enzyme activity, and the...
OBJECTIVE: The objective of the study was to characterize the mechanism associated with metabolic syndrome (MetS)-associated cognitive decline and determine the effect of minocycline on the above condition in mice. MATERIALs AND METHODS: We developed a HFHC diet-induced MetS model in mice. Diagnostic characteristics of MetS including waist circumfe...
Citations
... The choice of dose and duration of treatment period with minocycline was based on previous studies which demonstrated that treatment with minocycline at a dose of 50 mg/ kg for 4 weeks exerts important anti-inflammatory and therapeutic effects in mouse models of neurodegenerative diseases (Ferretti et al., 2012;Garcez et al., 2017). In fact, the anti-inflammatory effect of minocycline has been well described in the literature, including in animal models of metabolic diseases (Coker et al., 2022;Cope et al., 2018;Leigh et al., 2020;Mukherjee et al., 2018). ...
... Interestingly, minocycline treatment improved hippocampal memory performance in LDLr −/− mice. In line with this, several studies have shown that pharmacological intervention with minocycline improved spatial recognition memory in rodents subjected to a model of diet-induced obesity and metabolic syndrome (Cope et al., 2018;Leigh et al., 2020;Mukherjee et al., 2018). Cope and coauthors (Cope et al., 2018) pointed out that minocycline improves cognitive performance by modulating microglial reactivity. ...
Familial hypercholesterolemia (FH) is caused by mutations in the gene that encodes the low‐density lipoprotein (LDL) receptor, which leads to an excessive increase in plasma LDL cholesterol levels. Previous studies have shown that FH is associated with gliosis, blood–brain barrier dysfunction, and memory impairment, but the mechanisms associated with these events are still not fully understood. Therefore, we aimed to investigate the role of microgliosis in the neurochemical and behavioral changes associated with FH using LDL receptor knockout (LDLr−/−) mice. We noticed that microgliosis was more severe in the hippocampus of middle‐aged LDLr−/− mice, which was accompanied by microglial morphological changes and alterations in the immunocontent of synaptic protein markers. At three months of age, the LDLr−/− mice already showed increased microgliosis and decreased immunocontent of claudin‐5 in the prefrontal cortex (PFC). Subsequently, 6‐month‐old male C57BL/6 wild‐type and LDLr−/− mice were treated once daily for 30 days with minocycline (a pharmacological inhibitor of microglial cell reactivity) or vehicle (saline). Adult LDLr−/− mice displayed significant hippocampal memory impairment, which was ameliorated by minocycline treatment. Non‐treated LDLr−/− mice showed increased microglial density in all hippocampal regions analyzed, a process that was not altered by minocycline treatment. Region‐specific microglial morphological analysis revealed different effects of genotype or minocycline treatment on microglial morphology, depending on the hippocampal subregion analyzed. Moreover, 6‐month‐old LDLr−/− mice exhibited a slight but not significant increase in IBA‐1 immunoreactivity in the PFC, which was reduced by minocycline treatment without altering microglial morphology. Minocycline treatment also reduced the presence of microglia within the perivascular area in both the PFC and hippocampus of LDLr−/− mice. However, no significant effects of either genotype or minocycline treatment were observed regarding the phagocytic activity of microglia in the PFC and hippocampus. Our results demonstrate that hippocampal microgliosis, microglial morphological changes, and the presence of these glial cells in the perivascular area, but not increased microglial phagocytic activity, are associated with cognitive deficits in a mouse model of FH. image
... Especially, HFD is the main trigger for MetS, therefore commonly used to establish MetS model. For example, Mukherjee et al. [3] reported that main MetS characteristics including visceral fat accumulation, inflammation, and elevated blood cholesterol levels were caused by a long-term HFD diet. HFD is also related to metabolic disorders such as diabetes and lipid disorders, and disturbance of intestinal microecology in mice [4] . ...
In this study, the impacts of egg consumption on mice model of metabolic syndrome (MetS) were comparatively investigated. Mice were divided into five groups (n=8): normal diet group (ND), high-fat diet group (HFD), HFD with whole egg group (WE), HFD with free-yolk egg substitute group (YFES), and HFD with lovastatin group (Lov). Main biochemical indexes and a non-targeted lipidomic analysis were employed to insight the lipid profile changes in serum. It was revealed that WE could significantly improve serum biochemical indexes by reducing body weight, low-density lipoprotein cholesterol (LDL-C) and total cholesterol (TC), while increasing high-density lipoprotein cholesterol. YFES exhibited remarkably better performance in increasing phosphatidylglycerol and phosphatidic acids, while decreasing phosphatidylinositol than WE. A total of 50 differential lipids biomarkers tightly related to glycerophospholipids metabolism were screened out. Carnitine C18:2 and C12:1, SM (d18:0/12:0), and SM (d18:1/14:1) were significantly upregulated in YFES compared to WE. YFES reduced expression of SREBP-1c and Cpt1a, while did not affect the expression of PPAR-α. Sphingomyelin biomarkers were positively related to the TC (|r| > 0.6), while PPAR-α was negatively correlated with triglyceride and LDL-C levels. To sum up, YFES attenuated HFD-induced MetS by improving the serum phospholipids, which account for its modulation of glycerophospholipid metabolism.
... Insulin receptors are articulated in brain neurons and glia, mainly in the hippocampus, hypothalamus, and cerebral cortex [27,28]. Administration of low dose streptozotocin (STZ) directly within the brain impedes F I G U R E 2 . ...
Background
It is well accepted that PI3k/Akt signaling pathway is a potential therapeutic window which regulates metabolism and energy homeostasis within the brain, and is an important mediator of normal neuronal physiological functions. Dysregulation of this pathway results in impaired insulin signaling, learning and memory and neuronal survival.
Objectives
Elucidating the role of everolimus in intracerebroventricular (ICV) streptozotocin induced Insulin/IGF‐1 dependent PI3K/Akt/mTOR pathway dysregulation and associated neurobehavioral deficits.
Methods
Rats were administered with streptozotocin (3 mg/kg) intracerebroventricular, followed by administration of everolimus (1 mg/kg) orally for 21 days. After that, Morris water maze and passive avoidance tests were performed for assessment of memory. Animals were sacrificed to evaluate brain insulin pathway dysfunction, neurotrophic, apoptotic, inflammatory, and biochemical markers in rat brain. To elucidate the mechanism of action of everolimus, PI3K inhibitor, wortmannin was administered in the presence of everolimus in one group.
Results
Streptozotocin administration resulted in a significant decrease of brain insulin, insulin growth factor‐1 levels, and alterations in behavioral, neurotrophic (BDNF), inflammatory (TNF‐α), apoptotic (NF‐κB, Bcl2 and Bax) and biochemical (AChE and ChAT assay) parameters in comparison to sham group rats. Everolimus significantly mitigated the deleterious behavioral, biochemical, and molecular changes in rats having central insulin dysfunction. However, the protective effect of everolimus was completely abolished when it was administered in the presence of wortmannin.
Conclusion
Findings from the study reveal that mTOR inhibitors can be an important treatment strategy for neurobehavioral deficits occurring due to central insulin pathway dysfunction. Protective effect of drugs is via modulation of PI3K/Akt pathway.
Neurodegenerative disorders are accompanied by neuronal degeneration and glial dysfunction, resulting in cognitive, psychomotor, and behavioral impairment. Multiple factors including genetic, environmental, metabolic, and oxidant overload contribute to disease progression. Recent evidences suggest that metabolic syndrome is linked to various neurodegenerative diseases. Metabolic syndrome (MetS) is known to be accompanied by symptoms such as hyperglycemia, abdominal obesity, hypertriglyceridemia, and hypertension. Despite advances in knowledge about the pathogenesis of neurodegenerative disorders, effective treatments to combat neurodegenerative disorders caused by MetS have not been developed to date. Insulin growth factor-1 (IGF-1) deficiency has been associated with MetS-related pathologies both in-vivo and in-vitro. IGF-1 is essential for embryonic and adult neurogenesis, neuronal plasticity, neurotropism, angiogenesis, metabolic function, and protein clearance in the brain. Here, we review the evidence for the potential therapeutic effects of IGF-1 in the neurodegeneration related to metabolic syndrome. We elucidate how IGF-1 may be involved in molecular signaling defects that occurs in MetS-related neurodegenerative disorders and highlight the importance of IGF-1 as a potential therapeutic target in MetS-related neurological diseases.
Depression is a very common mental disorder and mechanism that is associated with mitochondrial dysfunction. In the present study, we examined the mechanisms of action of isolated brain mitochondria in rats with depression for the first time. This will help identify the mitochondrial protective pathways of the two drugs and shed light on new therapeutic goals for developing antidepressants. Forced swimming, tail suspension, and sucrose preference tests were used to assess depressive-like behaviors and the oxidative stress factors of brain tissue, and measure the gene expression of apoptotic and anti-apoptotic, neuroplasticity, and neuroinflammatory factors by RT-PCR and acetylcholinesterase (AChE) activity in brain tissue (hippocampus and prefrontal) and the serum levels of corticosterone and fasting blood sugar. The results showed that the separation of neonatal rats from their mothers induced depressive-like behaviors, weight loss, mitochondrial dysfunction, increased expression of genes involved in neuroinflammation, apoptosis, genes involved in the depressive process, and decreased expression of genes involved in mood in both the hippocampus and prefrontal cortex. Maternal separation increased serum corticosterone levels, caused dysfunction of the cholinergic system, and also increased AChE activity. Treatment with different concentrations of minocycline and edaravone (1, 20, and 50 mg/kg), 5MTHF, and citalopram for 14 days showed that these drugs improved depression-like behaviors and mitochondrial function. It also reduced the expression of genes involved in neuroinflammation, apoptosis, and depression and increased the expression of genes involved in mood. In conclusion, minocycline and edaravone have neuroprotective, mitochondrial protective, antioxidant, anti-inflammatory, and anti-apoptotic effects against depressive-like behaviors caused by chronic stress.
Graphical Abstract
Background
Metabolic syndrome patients are commonly prone to major health problems as cardiovascular diseases, diabetes mellitus, chronic kidney disease, cancer and neuropsychological complications including dementia.
Objectives
This research investigates mechanisms linking metabolic syndrome to cognitive impairment and possible impact of vitamin D supplementation.
Methods
Forty male Wistar rats were divided into 4 groups. Control, metabolic syndrome (20% fructose solution in drinking water for 12 weeks, vitamin D supplemented (500 IU/kg/day) and metabolic syndrome supplemented with vitamin D. Animals were assessed for spatial memory, hippocampal expression of SNAP 25, VAMP and mGlut2 receptor and hippocampus histological examination. Animals with metabolic syndrome showed prolonged acquisition and retention latencies in morris water maze, decreased hippocampal expression of SNAP 25 and VAMP and increased mGlut2 expression. Histologically CA1, CA3 regions and dentate nucleus revealed increase in degenerated neurons and glia cells with decreased pyramidal cell layer thickness. Vitamin D supplementation mitigated alterations induced by metabolic syndrome.
Conclusions
Metabolic syndrome decreased hippocampal synaptic proteins and altered glutamatergic transmission and increased hippocampal neuronal degeneration. Vitamin D supplementation offered neuroprotective effects.
Metabolic syndrome (MeTS) is a well-known health-related problem with several end-organ damages and the resulted side effects such as rising in the blood glucose and lipid and blood pressure. Although MeTS might show several skin symptoms such as acanthosis nigricans, skin tags, acne, and androgenic alopecia, it could also be implicated in the pathophysiology of numerous dermatologic disorders. Furthermore, some dermatologic drugs might be implicated in the incidence or exacerbation of MeTS. Consequently, MeTS and skin problem could interfere closely with each other and each one could predispose the patient to the other one and vice versa. Remembering these close relationships help us to have better therapeutic choices regarding each inflammatory skin conditions. Moreover, some of the skin symptoms should be followed cautiously to define the underlying MeTS.
Diets rich in sugar and saturated fat are associated with cognitive impairments in both humans and rodents with several potential mechanisms proposed. To test the involvement of diet-induced pro-inflammatory signaling, we exposed rats to a high-fat, high-sugar cafeteria diet, and administered the anti-inflammatory antibiotic minocycline. In the first experiment minocycline was coadministered across the diet, then in a second, independent cohort it was introduced following 4 weeks of cafeteria diet. Cafeteria diet impaired novel place recognition memory throughout the study. Minocycline not only prevented impairment in spatial recognition memory but also reversed impairment established in rats following 4 weeks cafeteria diet. Further, minocycline normalized diet-induced increases in hippocampal pro-inflammatory gene expression. No effects of minocycline were seen on adiposity or dietary intake across the experiments. Cafeteria diet and minocycline treatment significantly altered microbiome composition. The relative abundance of Desulfovibrio_OTU31, uniquely enriched in vehicle-treated cafeteria-fed rats, negatively and significantly correlated with spatial recognition memory. We developed a statistical model that accurately predicts spatial recognition memory based on Desulfovibrio_OTU31 relative abundance and fat mass. Thus, our results show that minocycline prevents and reverses a dietary-induced diet impairment in spatial recognition memory, and that spatial recognition performance is best predicted by changes in body composition and Desulfovibrio_OTU31, rather than changes in pro-inflammatory gene expression.
Background:
Minocycline a tetracycline antibiotic is known for anti-inflammatory and neuroprotective actions. Here we determine the therapeutic potential of minocycline against type 2 diabetes associated cognitive decline in rats.
Methods:
High fat diet (HFD) and low dose streptozotocin (STZ; 25 mg/kg) were used to induce diabetes in Sprague-Dawley rats. Fasting blood glucose and haemoglobin (Hb) A1c were measured in these animals. Cognitive parameters were measured using passive avoidance and elevated plus maze test. Hippocampal Acetylcholine esterase (AchE), reduced glutathione (GSH), cytokines, chemokine levels were measured and histopathological evaluations were conducted. The diabetic animals were then given minocycline (50 mg/kg; 15 days) and the above parameters were reassessed. MTT and Lactate dehydrogenase (LDH) assays were conducted on neuronal cells in the presence of glucose with or without minocycline treatment.
Results:
We induced diabetes using HFD and STZ in these animals. Animals showed high fasting blood glucose levels (>245 mg/dl) and HbA1c compared to control animals. Diabetes significantly lowered step down latency and increased transfer latency. Diabetic animals showed significantly higher AchE, Tumor necrosis factor (TNF)-α, Interleukin (IL)-1β and Monocyte chemoattractant protein (MCP)-1 and lower GSH levels and reduced both CA1 and CA3 neuronal density compared to controls. Minocycline treatment partially reversed the above neurobehavioral and biochemical changes and improved hippocampal neuronal density in diabetic animals. Cell line studies showed glucosemediated neuronal death, which was considerably reversed upon minocycline treatment.
Conclusions:
Minocycline, primarily by its anti-inflammatory and antioxidant actions prevented hippocampal neuronal loss thus partially reversing the diabetes-associated cognitive decline in rats.
