Inhibitory effect of minocycline on amyloid β fibril formation and human microglial activation
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.
[Show abstract] [Hide abstract] ABSTRACT: Background: We tested minocycline as an anti-proteinuric adjunct to renin-angiotensin-aldosterone system inhibitors (RAASi) in diabetic nephropathy (DN) and measured urinary biomarkers to evaluate minocycline's biological effects. Methods: Design: Prospective, single center, randomized, placebo-controlled, intention-to-treat pilot trial. Inclusion. Type 2 diabetes/DN; Baseline creatinine clearance > 30 mL/min; proteinuria ≥ 1.0 g/day; Age ≥30 years; BP <150/95 mm Hg; intolerant of/at maximum RAASi dose. Protocol. 3-wk screening; Baseline randomization; Urine and blood measures at months 1, 2, 4, and Month 6 study completion. Urine interleukin-6 (IL-6) and osteoprotegerin were measured in a subset. Primary outcome. Natural log of urine protein/creatinine (ln U P:Cr) ratio at Month 6 vs Baseline. Results: 30 patients completed the study. The 15% decline in U P: Cr in minocycline patients (6 month P:Cr ÷ Baseline P:Cr, 0.85 vs. 0.92) was not significant (p = 0.27). Creatinine clearance did not differ in the 2 groups. Urine IL-6:Cr (p = 0.03) and osteoprotegerin/Cr (p = 0.046) decrements were significant. Minocycline modified the relationship between urine IL-6 and proteinuria, suggesting a protective biological effect. Conclusions: Although the decline in U P:Cr in minocycline patients was not statistically significant, the significant differences in urine IL-6 and osteoprotegerin suggest that minocycline may confer cytoprotection in patients with DN, providing a rationale for further study. Trial registration: Clinicaltrials.gov NCT01779089.
- "Minocycline modulates inflammatory cell signaling pathways. Minocycline blocks NO-induced  and gentamicin-induced  mitogen-activated protein kinase (MAPK) activation in a stimulus-specific manner . We showed that the podocyte p38MAPK pathway is activated in experimental DN, and is associated with downstream CREB phosphorylation and mesangial fibronectin accumulation [27, 28], suggesting a mechanism by which minocycline might modulate DN. "
- "It has also been discovered that Aβ and PrP have similar mechanisms of action, with identical signalling cascades affected by stimulation of microglia with either type of fibril , and the toxicity to neurons upon microglial stimulation by both Aβ and PrP aggregates being exacerbated by addition of SAP and C1q [182, 224]. Minocycline has also been demonstrated to have beneficial effects in many diseases, such as AD , PD , HD , and ALS . It has been shown to inhibit cell proliferation through inhibition of p38 MAPK , which also seems to be a common theme in microglial activation by proteins [64, 179]. "
[Show abstract] [Hide abstract] 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.
- "At 20 min after administration of diazepam, non-treated seizure animals received saline injection (SE group) and treated animals received a single minocycline injection of 25 mg/kg i.p. (SE+Mino). The minocycline dose of 25 mg/kg was chosen because this dose was shown to be safe and effective222324. Alternatively, doses exceeding 25 mg/kg were showed to potentiate weight loss [25,26], cause skin irritation and liver toxicity [23,27]. "