[Fasudil improves cognition of APP/PS1 transgenic mice via inhibiting the activation of microglia and shifting microglia phenotypes from M1 to M2].
Jie‐Zhong YuQingfang GuYuqing YanHongqiang YuMinfang GuoChunyun LiuGuobin SongZhi ChaiQing WangBao‐Guo XiaoHanting ZhangYuqiang JiangCun‐Gen Ma
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Objective To examine the regulatory effects of Rho kinase inhibitor fasudil on cognition and microglia polarization in APP/PS1 transgenic (APP/PS1 Tg) mice, a widely used model of Alzheimer's disease (AD). Methods Male APP/PS1 Tg mice at 8 months of age were randomly divided into two groups: Fasudil (25 mg/kg) and saline, i.p., once daily for 2 months; age- and gender-matched wild type (WT) mice without treatment were used as the controls. The Morris water maze (MWM) test was applied to examine spatial cognition of mice. Aβ1-42 deposition, the microglia surface marker CD11b, and the M1 and M2 microglia surface markers [iNOS, arginase 1 (ARG1) and CD206] in the hippocampus and cerebral cortex were analyzed by immunohistochemistry and Western blotting. Results Compared with WT controls, APP/PS1 Tg mice (10 months old at the time of testing) treated with saline displayed increases in the latency to target, mean distance to target, latency 1st entrance to SW quadrant during the MWM test; they also showed increased latency and mean distance entering to the target in the MWM test, indicating their impaired cognition, which was reversed by fasudil. In addition, fasudil decreased the expressions of Aβ1-42 and iNOS and increased ARG1/CD206 in the hippocampus and cerebral cortex. further, the microglia marker CD11b had an overlap with the M1 marker iNOS or the M2 markers ARG1/CD206 in the cerebral cortex of the AD mice following fasudil treatment. Conclusion Fasudil reverses spatial cognitive dysfunction in APP/PS1 Tg mice via facilitating the transformation of Aβ1-42-activated microglia from the M1 to M2 phenotype.Keywords:
Fasudil
Rho kinase inhibitor
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Objective To examine the regulatory effects of Rho kinase inhibitor fasudil on cognition and microglia polarization in APP/PS1 transgenic (APP/PS1 Tg) mice, a widely used model of Alzheimer's disease (AD). Methods Male APP/PS1 Tg mice at 8 months of age were randomly divided into two groups: Fasudil (25 mg/kg) and saline, i.p., once daily for 2 months; age- and gender-matched wild type (WT) mice without treatment were used as the controls. The Morris water maze (MWM) test was applied to examine spatial cognition of mice. Aβ1-42 deposition, the microglia surface marker CD11b, and the M1 and M2 microglia surface markers [iNOS, arginase 1 (ARG1) and CD206] in the hippocampus and cerebral cortex were analyzed by immunohistochemistry and Western blotting. Results Compared with WT controls, APP/PS1 Tg mice (10 months old at the time of testing) treated with saline displayed increases in the latency to target, mean distance to target, latency 1st entrance to SW quadrant during the MWM test; they also showed increased latency and mean distance entering to the target in the MWM test, indicating their impaired cognition, which was reversed by fasudil. In addition, fasudil decreased the expressions of Aβ1-42 and iNOS and increased ARG1/CD206 in the hippocampus and cerebral cortex. further, the microglia marker CD11b had an overlap with the M1 marker iNOS or the M2 markers ARG1/CD206 in the cerebral cortex of the AD mice following fasudil treatment. Conclusion Fasudil reverses spatial cognitive dysfunction in APP/PS1 Tg mice via facilitating the transformation of Aβ1-42-activated microglia from the M1 to M2 phenotype.
Fasudil
Rho kinase inhibitor
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The effects of dysthyroidism on central 5-HT1A receptor subtype in adult Wistar rats were investigated. Hyperthyroidism and hypothyroidism were respectively produced with the administration of T3 and propylthiouracil (PTU) via gavage for 2 weeks. Heart rate, oxygen consumption, anal temperature and plasma T3 concentration were increased in hyperthyroid rats and decreased in hypothyroid rats significantly. Radioligand binding assay showed that the specific binding of [3H] 8-hydroxy-2-(di-n-propylamino) tetralin ([3H] 8-OH-DPAT) at 0.6 nmol/L concentration was highest in hippocampus, next in cerebral cortex, and lowest in hypothalamus, brain stem and corpus striatum in euthyroid rats. Hyperthyroidism increased the binding significantly in hippocampus but decreased in cortex. No change was found in the other brain regions. Scatchard analyses revealed that the Bmax was increased in hippocampus and decreased in cortex, whereas the KD was not consistently affected in hyperthyroid rats in comparison with that in euthyroid rats. However, there were no significant changes mentioned above in all these brain regions of hypothyroid rats. Our results indicate that there seems to exist an imbalance of the serotonergic activity mediated via 5-HT1A receptor between hippocampus and cerebral cortex in hyperthyroids. This might be one of the mechanisms leading to psychoneural disorders in hyperthyroidism.
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Sensitivity to leptin is associated with a normal regulation of the adipose mass, whereas decreased leptin sensitivity results in elevated adipose tissue stores. To address whether the effects of chronic hyperleptinemia are sustained with age, we generated transgenic mice that overexpress leptin under the control of the fat specific aP2 promoter/enhancer. At 6–9 weeks of age, transgenic mice overexpressed 5-fold more human leptin than endogenous mouse levels and had consistently low body weights, with reduced brown and white fat depots characterized by adipocytes either devoid of or containing minute lipid droplets. However, at 33–37 weeks, despite continuous secretion of human leptin, the transgenic mice showed a rebound effect characterized by an increase in body weight, accumulation of adipose mass, and lipid-filled adipocytes. Thus, this mouse model exhibits a two-stage phenotype, with respect to fat accumulation. In addition, plasma glucose, triglycerides, and cholesterol levels were markedly depressed in young, but not older, transgenic mice. A detrimental consequence of early hyperleptinemia was a failure of the transgenic mice to acclimatize to the cold, as a result of depleted fat stores within their brown adipocytes. Cold exposure was tolerated after a 2-week high-fat diet or at an older age when fat depots had naturally accumulated. Treatment of the older transgenic mice with large doses of leptin stimulated weight loss, demonstrating that the leptin pathway still responds to pharmacological levels of leptin. Overall, these studies show that moderate hyperleptinemia in normal mice results in a sensitivity of the adipose mass to leptin at a younger (but not older) age. The mechanisms that lead to the accumulation of fat at an older age remain largely unknown, and this hyperleptinemic mouse model will allow the uncovering of at least some of these mechanisms.
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The aim of the present study was to investigate whether different estrogen manipulations have effects on the expression of muscarinic acetylcholine receptors (mAChRs) in the adult female rat hippocampus. Hippocampus was obtained from rats in proestrus (control), ovariectomized for 2, 10 and 15 days, ovariectomized for 15 days and treated with 17β-estradiol for 7 days, and treated with 17β-estradiol immediately after ovariectomy for 21 days. Rats’ estrogen status was monitored by measuring estradiol plasma levels and uterus relative weight. [<sup>3</sup>H]quinuclidinyl benzilate ([<sup>3</sup>H]QNB) binding studies indicated that ovariectomy time-dependently increases the number of mAChRs in hippocampus when compared to those obtained from control rats. Estradiol treatments for 21 days avoid the effect of ovariectomy. However, the estradiol treatments for 7 days after 15 days of ovariectomy slightly change the number of mAChRs. In conclusion, these results showed that ovariectomy time-dependently increases mAChRs number in the rat hippocampus. In addition, these data suggest that treatment with estradiol initiated within a specific period of time after the loss of ovarian function may be effective at preventing specific effects of hormone deprivation on hippocampus.
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Macrophages/microglia exhibit phenotypic and functional heterogeneity under physiological and pathological conditions. Owing to this heterogeneity, the polarization of macrophages/microglia is capable of effecting both detrimental and beneficial outcomes in various disease processes. In this study, murine microglial cell line BV-2 and primary microglia were used as cell models to elucidate the polarization of microglia. Using flow cytometry, Western blot, chemical/enzymatic determination, and immunohistochemistry, treatment with LPS primed microglia into the M1 phenotype in both BV-2 cells and primary microglia, while fasudil skewed LPS-stimulated M1 toward M2 microglia, which showed lower NF-κB activity and inflammatory cytokines IL-1ß, IL-6, and TNF-a, and increased anti-inflammatory cytokine IL-10. To examine whether the regulatory role of LPS and fasudil on microglia can occur in vivo, mice were administered LPS (25 µg/10 µl) via nasal instillation every other day for 1 month. The results demonstrated that LPS also triggered iNOS<sup>+</sup>/CD11b<sup>+</sup> M1 microglia in the brain, while fasudil increased Arg-1<sup>+</sup>/CD11b<sup>+</sup> M2 microglia, although the difference did not reach statistical significance. Fasudil-conditioned microglia medium promoted a neuroprotective effect against PC12 neurons, suggesting that fasudil-induced M2 microglia contribute to the survival of neurons. These results indicate a new treatment option whereby fasudil inhibits the inflammatory response by controlling a helpful polarization in microglia/macrophages.
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Background and purpose: We evaluated the effects of 1‐(3′,4′‐dichloro‐2‐fluoro[1,1′‐biphenyl]‐4‐yl)‐cyclopropanecarboxylic acid (CHF5074), a new γ‐secretase modulator, on brain β‐amyloid pathology and spatial memory in transgenic mice expressing the Swedish and London mutations of human amyloid precursor protein (hAPP). Experimental approach: Sixty 6‐month‐old hAPP mice were treated for 6 months with CHF5074 or ibuprofen (375 ppm in the diet) or standard diet. Twenty‐one wild‐type mice received standard diet. Key results: Compared with transgenic controls, CHF5074 treatment significantly reduced the area occupied by plaques in cortex ( P = 0.003) and hippocampus ( P = 0.004). The number of plaques were also reduced by CHF5074 in both cortex ( P = 0.022) and hippocampus ( P = 0.005). Plaque‐associated microglia in CHF5074‐treated animals was lower than in transgenic controls in cortex ( P = 0.008) and hippocampus ( P = 0.002). Ibuprofen treatment significantly reduced microglia area in cortex and hippocampus but not β‐amyloid burden. On the last day of the Morris water maze, transgenic controls performed significantly worse than the non‐transgenic animals and the CHF5074‐treated transgenic mice, on the swimming path to reach the hidden platform. Ibuprofen‐treated animals did not perform significantly better than transgenic controls. Conclusions and implications: Chronic CHF5074 treatment reduced brain β‐amyloid burden, associated microglia inflammation and attenuated spatial memory deficit in hAPP mice. This novel γ‐secretase modulator is a promising therapeutic agent for Alzheimer's disease.
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Rho-associated kinase (ROCK) is a key regulatory protein involved in inflammatory secretion in microglia in the central nervous system. Our previous studies showed that ROCK inhibition enhances phagocytic activity in microglia through the extracellular signal-regulated kinase (ERK) signaling pathway, but its effect on microglial migration was unknown. Therefore, in this study, we investigated the effects of the ROCK inhibitors Y27632 and fasudil on the migratory activity of primary cultured microglia isolated from the spinal cord, and we examined the underlying mechanisms. The microglia were treated with Y27632, fasudil and/or the ERK inhibitor U0126. Cellular morphology was observed by immunofluorescence. Transwell chambers were used to assess cell migration. ERK levels were measured by in-cell western blot assay. Y27632 and fasudil increased microglial migration, and the microglia were irregularly shaped and had many small processes. These inhibitors also upregulated the levels of phosphorylated ERK protein. The ERK inhibitor U0126 suppressed these effects of Y27632 and fasudil. These findings suggest that the ROCK inhibitors Y27632 and fasudil promote microglial migration in the spinal cord through the ERK signaling pathway.
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Transgenic mice that overexpress the entire glucokinase (GK) gene locus have been previously shown to be mildly hypoglycemic and to have improved tolerance to glucose. To determine whether increased GK might also prevent or diminish diabetes in diet-induced obese animals, we examined the effect of feeding these mice a high-fat high–simple carbohydrate low-fiber diet (HF diet) for 30 weeks. In response to this diet, both normal and transgenic mice became obese and had similar BMIs (5.3 ± 0.1 and 5.0 ± 0.1 kg/m2 in transgenic and nontransgenic mice, respectively). The blood glucose concentration of the control mice increased linearly with time and reached 17.0 ± 1.3 mmol/l at the 30th week. In contrast, the blood glucose of GK transgenic mice rose to only 9.7 ± 1.2 mmol/l at the 15th week, after which it returned to 7.6 ± 1.0 mmol/l by the 30th week. The plasma insulin concentration was also lower in the GK transgenic animals (232 ± 79 pmol/l) than in the controls (595 ± 77 pmol/l), but there was no difference in plasma glucagon concentrations. Together, these data indicate that increased GK levels dramatically lessen the development of both hyperglycemia and hyperinsulinemia associated with the feeding of an HF diet.
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Hyperinsulinemia
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