Increases in β-amyloid protein in the hippocampus caused by diabetic metabolic disorder are blocked by minocycline through inhibition of NF-κB pathway activation

doi:10.1016/S1734-1140(11)70504-7

Pharmacological Reports

Volume 63, Issue 2, March–April 2011, Pages 381-391

https://doi.org/10.1016/S1734-1140(11)70504-7 Get rights and content

Abstract

Activation of the NF-κB pathway plays an important role in the pathophysiology of Alzheimer’s disease (AD), and blocking NF-κB pathway activation has been shown to attenuate cognitive impairment. Diabetic metabolic disorder contributes to β-amyloid protein (Aβ) generation. The goal of this study was to determine the effect of minocycline on Aβ generation and the NF-κB pathway in the hippocampus of diabetic rats and to elucidate the neuroprotective mechanisms of minocycline for the treatment of diabetic metabolic disorder. The diabetic rat model was established using a high-fat diet and an intraperitoneal injection of streptozocin (STZ). Behavioral tests showed that the capacity of learning and memory was significantly lower in diabetic rats. The levels of NF-κB, COX-2, iNOS, IL-1β and TNF-α after the STZ injection were significantly increased in the hippocampus. Significant increases in A, BACE1, NF-κB, COX-2, iNOS, IL-1β and TNF-α were found in diabetic rats. The levels of Aβ, NF-κB, COX-2, iNOS, IL-1β and TNF-α were significantly decreased after minocycline administration; however, minocycline had no effect on BACE1 expression. In sum, diabetes contributes to the activation of the NF-κB pathway and upregulates BACE1 and Aβ. Minocycline downregulates Aβ in the hippocampus by inhibiting NF-κB pathway activation.

Introduction

Diabetes mellitus (DM) has been closely linked to the pathogenesis of Alzheimer’s disease (AD) [18, 34, 49, 56, 74] and it has been proposed that AD is type 3 diabetes [19, 34]. AD and DM have a similar pathogenesis; inflammation [53], oxidative stress [26], apoptosis [62] and vascular dysfunction [43, 55] are found in both diseases. Further evidence shows that Aβ generation and failure of Aβ clearance are symptoms of both AD and DM [6, 45].

NF-κB is a transcription factor that regulates the expression of the genes involved in the immune response [30], embryo or cell lineage development [2], cell apoptosis [13, 17], inflammation [39] and oxidative stress [69]. Tremendous attention has been focused on upstream signaling pathways leading to NF-κB activation. Many of these signaling molecules represent potential pharmaceutical targets for the specific inhibition of NF-κB activation and the subsequent interference with disease processes [5, 8, 72].

AD is a neurodegenerative disorder characterized by progressive memory loss and a decline of cognitive functions. Its histopathological hallmarks include extracellular Aβ deposition in neuritic plaques, intracellular deposits of hyperphosphorylated tau protein (causing formation of neurofibrillary tangles) and neuronal death [20]. Aβ generation and deposition represents a key feature and is the triggering mechanism of AD [41]. Aβ peptides are generated from amyloid precursor protein (APP) by the sequential actions of two proteolytic enzymes, i.e., the b-site APP cleavage enzyme and γ-secretase. β-Amyloid precursor protein cleavage enzyme 1 (BACE1) is the β-secretase that processes APP, and β-secretase activity is dependent on protein levels of BACE1 [27, 73].

Minocycline, a tetracycline derivative, is a potential neuroprotective agent that blocks inflammation, oxidative stress and apoptosis [35, 66]. Previously, we demonstrated that minocycline can inhibit oxidative stress and inflammation in the hippocampus of rats with permanent bilateral occlusion of both common carotid arteries and improve behavioral deficits [11, 12]. Because BACE1 is the β-secretase that processes APP and induces Aβ generation in the pathogenesis of AD and because activation of the NF-κB pathway is present in the pathogenesis of both DM and AD, it is possible that minocycline inhibits the activation of the NF-κB pathway and Aβ generation by downregulating BACE1. To test this hypothesis, we analyzed the influence of minocycline on the expression of A, BACE1 and upstream signal transduction molecules of the NF-κB pathway (such as COX-2, iNOS, IL-1β, TNF-α and NF-κB) in the hippocampus of diabetic rats with cognitive impairment induced by a high-fat diet and STZ injection [59, 63]. The aim of this study was to investigate the neuroprotective mechanisms of minocycline against diabetic brain injury.

Section snippets

Animals and drugs

Eight-month-old male Wistar rats provided by the Experimental Animal Center of Chongqing Medical University, weighing 220–300 g, were housed in individual cages at a constant temperature (25°C) under a 12-h light-dark cycle. All rats were habituated to the cage for at least 5 days before the experiments. Animals were administered a high-fat and high-sugar diet for 2 months (food composition: 10% lard, 20% sucrose, 2.5% cholesterol, 1% bile salt and 6.5% conventional food) to induce insulin

Minocycline improved behavioral deficits caused by diabetes

Following STZ injection, rats were subjected to the Morris water maze as described in the Materials and Methods section. Escape times decreased significantly after one day of training. On days 3 and 4 of training, the latency to find the platform in STZ injected groups was considerably longer than in the control group (p < 0.01); however, minocycline administration considerably reduced the latency to find the platform (p < 0.01) (Fig. 1A and B). In the probe trials, the time spent in quadrant 1

Discussion

STZ, a powerful alkylating agent, can interfere with glucose transporters and glucokinase function and induce double-strand DNA breaks. To determine successful establishment of the DM animal model, a fasting blood glucose test and glucose tolerance test were conducted [68]. Animals that presented with hyperglycemia and uric acid and insulin resistance were classified as successful DM models. In this study, Morris water maze performance showed that cognitive impairment occurred in diabetic rats.

Acknowledgments

This study was supported in part by the Clinical Research Institute, Guangdong Medical College. The authors have no conflicts of interest.

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Increases in β-amyloid protein in the hippocampus caused by diabetic metabolic disorder are blocked by minocycline through inhibition of NF-κB pathway activation

Abstract

Introduction

Section snippets

Animals and drugs

Minocycline improved behavioral deficits caused by diabetes

Discussion

Acknowledgments

J Biol Chem

Neurobiol Dis

Toxicology

Neuroscience

Blood

Trends Pharmacol Sci

Neurobiol Dis

Nitric Oxide

Cell Signal

Hepatology

Behav Brain Res

Neurobiol Aging

Brain Res

Brain Res Mol Brain Res

Brain Behav Immun

Eur J Pharmacol

Toxicol In Vitro

Diabetes Metab

J Neurol Sci

Toxicon

Metabolism

Exp Eye Res

Pharmacol Res

Pharmacol Rep

Neurobiol Dis

Pharmacol Rep

Toxicol Appl Pharmacol

Lancet Neurol

J Biol Chem

Drugs used to treat Parkinson’s disease, present status and future directions

CNS Neurol Disord Drug Targets

Oxidative stress and apoptosis in immune diseases

Int J Immunopathol Pharmacol

Alzheimer research forum live discussion: is Alzheimer’s a type 3 diabetes? Alzheimers Dis J

Amyloid β-peptide stimulates nitric oxide production in astrocytes through an NF B-dependent mechanism

Proc Natl Acad Sci USA

Increased risk of Alzheimer’s disease in Type II diabetes: insulin resistance of the brain or insulin-induced amyloid pathology?

Biochem Soc Trans

Modulation of the oxidative stress and nuclear factor B activation by theaflavin 3,3’-gallate in the rats exposed to cerebral ischemia-reperfusion

Folia Biol (Praha)

Minocycline reduces astrocytic reactivation and neuroinflammation in the hippocampus of a vascular cognitive impairment rat model

Neurosci Bull

Minocycline attenuates cognitive impairment and restrains oxidative stress in the hippocampus of rats with chronic cerebral hypoperfusion

Neurosci Bull