Minocycline alleviates beta-amyloid protein and tau pathology via restraining neuroinflammation induced by diabetic metabolic disorder

Abstract

BackgroundCompelling evidence has shown that diabetic metabolic disorder plays a critical role in the pathogenesis of Alzheimer’s disease, including increased expression of β-amyloid protein (Aβ) and tau protein. Evidence has supported that minocycline, a tetracycline derivative, protects against neuroinflammation induced by neurodegenerative disorders or cerebral ischemia. This study has evaluated minocycline influence on expression of Aβ protein, tau phosphorylation, and inflammatory cytokines (interleukin-1β and tumor necrosis factor-α) in the brain of diabetic rats to clarify neuroprotection by minocycline under diabetic metabolic disorder.MethodAn animal model of diabetes was established by high fat diet and intraperitoneal injection of streptozocin. In this study, we investigated the effect of minocycline on expression of Aβ protein, tau phosphorylation, and inflammatory cytokines (interleukin-1β and tumor necrosis factor-α) in the hippocampus of diabetic rats via immunohistochemistry, western blotting, and enzyme-linked immunosorbent assay.ResultsThese results showed that minocycline decreased expression of Aβ protein and lowered the phosphorylation of tau protein, and retarded the proinflammatory cytokines, but not amyloid precursor protein.ConclusionOn the basis of the finding that minocycline had no influence on amyloid precursor protein and beta-site amyloid precursor protein cleaving enzyme 1 which determines the speed of Aβ generation, the decreases in Aβ production and tau hyperphosphorylation by minocycline are through inhibiting neuroinflammation, which contributes to Aβ production and tau hyperphosphorylation. Minocycline may also lower the self-perpetuating cycle between neuroinflammation and the pathogenesis of tau and Aβ to act as a neuroprotector. Therefore, the ability of minocycline to modulate inflammatory reactions may be of great importance in the selection of neuroprotective agents, especially in chronic conditions like diabetes and Alzheimer’s disease.

Minocycline upregulates cyclic AMP response element binding protein and brain-derived neurotrophic factor in the hippocampus of cerebral ischemia rats and improves behavioral deficits

“…MT group was given 50 mg/kg/d minocycline through douche via the stomach. The minocycline dosage used for animals was as described elsewhere 16,17…”

“…Five grades were employed to express the degrees of staining, which represent five reaction coefficients, respectively. The five products of every coefficient and the corresponding cell number were added up, which resulted in the value of a positive score 16,18. All slides were measured in duplicate.…”

“…Minocycline, a tetracycline derivative, protects against cerebral ischemia via inhibiting inflammation, oxidative stress, and apoptosis 16,17. Previously, we have found that minocycline retarded astrocytic reactivation, and restrained oxidative stress and neuroinflammation in the hippocampus of cerebral ischemia rats 18,19.…”

Non Antimicrobial Effects of Antibacterial Agents

“…Alzheimer hastalığı ile ilgili olarak tetrasiklinler (özellikle minosiklin) hastalığın gelişmesinde kilit rolü olan betaamiloid proteinini azaltarak etkilerini göstermektedirler [43,44] . Minosiklinin nöroprotektif etkisini, mikrogliyal aktivasyonu indüklemesi, proenflamatuvar sitokinlerin "down-regülasyonu" ve mitokondriyal geçirgenliğin kontrolünü sağlaması ile gösterdiği düşünülmektedir.…”

Treatment of Dementia: Pharmacological Approaches

“…Another example, Minocycline, a common antimicrobial with anti-infl ammatory properties usually used to treat acne, has been also tested in treating AD. Its signifi cance is derived from its anti-neuro-infl ammatory effect particularly on interleukin-1β and tumor necrosis factor-α in neurons which in turn reduces tau-hyperphosphorylation and consequently, minimizing axonal death [ 49 ]. Certainly, the fi ndings, although signifi cant, still warrant further investigation [ 50 ].…”