Inhibitory effect of minocycline on amyloid β fibril formation and human microglial activation
ABSTRACT Minocycline, a derivative of the antibiotic tetracycline, displays neuroprotective properties in various models of neurodegenerative diseases and is now used in clinical trials, because of its relative safety and tolerability. Minocycline passes the blood-brain barrier and is presumed to inhibit microglial activation. In Alzheimer's disease brain, a number of proteins, including serum amyloid P component (SAP) and complement factors such as C1q, accumulate in amyloid beta (Abeta) plaques. In a previous study, SAP and C1q were found to be required for clustering of activated microglia in Abeta plaques. Furthermore, SAP and C1q enhanced Abeta fibril formation and Abeta mediated cytokine release by human microglia in vitro. In the present study, we report that tetracycline and minocycline dose-dependently reduce TNF-alpha and IL-6 release by adult human microglia upon stimulation with a combination of Abeta, SAP, and C1q. In addition, minocycline and to a lesser extent tetracycline inhibit fibril formation of Abeta as determined in a thioflavin-S-based fluorescence test. This inhibitory effect was observed with Abeta alone as well as with Abeta in combination with SAP and C1q. Our data suggest that minocycline and tetracycline at tolerable doses can inhibit human microglial activation. This activity in part is exerted by inhibition of (SAP and C1q enhanced) Abeta fibril formation.
SourceAvailable from: Loukia Katsouri[Show abstract] [Hide abstract]
ABSTRACT: Over the past decade the process of inflammation has been a focus of increasing interest in the Alzheimer's disease (AD) field, not only for its potential role in neuronal degeneration but also as a promising therapeutic target. However, recent research in this field has provided divergent outcomes, largely due to the use of different models and different stages of the disease when the investigations have been carried out. It is now accepted that microglia, and possibly astrocytes, change their activation phenotype during ageing and the stage of the disease, and therefore these are important factors to have in mind to define the function of different inflammatory components as well as potential therapies. Modulating inflammation using animal models of AD has offered the possibility to investigate inflammatory components individually and manipulate inflammatory genes in amyloid precursor protein and tau transgenics independently. This has also offered some hints on the mechanisms by which these factors may affect AD pathology. In this review we examine the different transgenic approaches and treatments that have been reported to modulate inflammation using animal models of AD. These studies have provided evidence that enhancing inflammation is linked with increases in amyloid-beta (Abeta) generation, Abeta aggregation and tau phosphorylation. However, the alterations on tau phosphorylation can be independent of changes in Abeta levels by these inflammatory mediators.Journal of Neuroinflammation 02/2014; 11(1):25. DOI:10.1186/1742-2094-11-25 · 4.90 Impact Factor
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ABSTRACT: In rodents, olfactory bulbectomy (OBX) results in several behavioral and biochemical changes, useful as a screening model for antidepressants. Recent evidences suggest that quercetin; a bioflavonoid exhibits a variety of behavioral effects including anxiolytic, antidepressant, etc. Since microglia are commonly implicated in the neuroinflammation cascade of depression, we hypothesized that quercetin might involve microglial inhibition pathway in its antidepressant-like effects. To support such a possibility, we investigated the interaction of quercetin with a known microglial inhibitor (minocycline) against olfactory bulbectomy induced depression in male Wistar rats. In our study, ablation of olfactory bulbs caused hyperactivity in open field arena and increased immobility time in forced swim test which was coupled with enhanced serum corticosterone levels. Additionally, there were increased oxidative-nitrosative stress markers, inflammatory mediators (TNF-α and IL-6) along with enhanced apoptotic factor (caspase-3) in both cerebral cortex and hippocampal brain regions of OBX animals. These results were further supported by reports from histopathological analysis. After a surgical recovery period of two weeks, treatment with quercetin (40, 80 mg/kg; p.o., 14 days) significantly prevented OBX-induced behavioral, biochemical, molecular and histopathological alterations. Further, combination of sub effective doses of quercetin (20, 40 mg/kg; p.o.) with minocycline (25 mg/kg; p.o.) significantly potentiated their protective effects as compared to their effects alone. Based on our results, we propose that microglial inhibitory pathway might be involved in the neuroprotective effects of quercetin and suppression of oxidative-nitrosative stress mediated neuroinflammation- apoptotic cascade associated with olfactory bulbectomy rat model of depression.Neuroscience 10/2013; 255. DOI:10.1016/j.neuroscience.2013.09.044 · 3.33 Impact Factor
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ABSTRACT: Minocycline is an antibiotic agent that has been shown to have neuroprotective properties in animal models of ischemia, Huntington's disease and Parkinson's disease. However, data are lacking regarding the neuroprotective effects of minocycline treatment following pilocarpine-induced status epilepticus. Rats were treated with 25 mg/kg minocycline 2 hours after the onset of pilocarpine-induced SE. The hippocampus was examined for neuronal loss and microglia proliferation. The rats were monitored for the development of spontaneous recurrent seizures. Minocycline treatment was found to reduce seizure-induced neuronal loss in the hippocampus. Although minocycline treatment did not significantly inhibit microglia activation, a modest reduction in microglial cell number was related to greater neuroprotection. Finally, a single-dose of minocycline did not prevent the occurrence of spontaneous behavioral seizures. Taken together, the findings suggest that Minocycline treatment is neuroprotective after SE.