minocycline and epigallocatechin-gallate

Inhibition of microglial over-activation is an important strategy to counter balance neurodegenerative progression. We previously demonstrated that the adenosine monophosphate-activated protein kinase (AMPK) may be a therapeutic target in mediating anti-neuroinflammatory responses in microglia. Brain-derived neurotrophic factor (BDNF) is one of the major neurotrophic factors produced by astrocytes to maintain the development and survival of neurons in the brain, and have recently been shown to modulate homeostasis of neuroinflammation. Therefore, the present study focused on BDNF-mediated neuroinflammatory responses and may provide an endogenous regulation of neuroinflammation. Among the tested neuroinflammation, epigallocatechin gallate (EGCG) and minocycline exerted BDNF upregulation to inhibit COX-2 and proinflammatory mediator expressions. Furthermore, both EGCG and minocycline upregulated BDNF expression in microglia through AMPK signaling. In addition, minocycline and EGCG also increased expressions of erythropoietin (EPO) and sonic hedgehog (Shh). In the endogenous modulation of neuroinflammation, astrocyte-conditioned medium (AgCM) also decreased the expression of COX-2 and upregulated BDNF expression in microglia. The anti-inflammatory effects of BDNF were mediated through EPO/Shh in microglia. Our results indicated that the BDNF-EPO-Shh novel-signaling pathway underlies the regulation of inflammatory responses and may be regarded as a potential therapeutic target in neurodegenerative diseases. This study also reveals a better understanding of an endogenous crosstalk between astrocytes and microglia to regulate anti-inflammatory actions, which could provide a novel strategy for the treatment of neuroinflammation and neurodegenerative diseases.

Topics: Animals; Anti-Inflammatory Agents; Astrocytes; Brain-Derived Neurotrophic Factor; Catechin; Cell Line; Culture Media, Conditioned; Cyclooxygenase 2; Erythropoietin; Hedgehog Proteins; Humans; Inflammation; Inflammation Mediators; Lipopolysaccharides; Mice; Microglia; Minocycline; Models, Biological; Neuroprotective Agents; Signal Transduction

Epigallocatechin-3-gallate (EGCG) is a polyhydroxyphenol constituent of green tea (e.g., Camellia sinensis) with known antioxidant properties. Due to these properties, others have proposed it as a potential therapeutic agent for the treatment of Parkinson's disease (PD). Previously, we demonstrated that EGCG prolonged the lifespan and locomotor activity in wild-type Canton-S flies exposed to the neurotoxicant paraquat (PQ), suggesting neuroprotective properties. Both gene mutations and environmental neurotoxicants (e.g., PQ) are factors involved in the development of PD. Thus, the first aim of this study was to create a suitable animal model of PD, which encompasses both of these factors. To create the model, we knocked down dj-1-β function specifically in the dopaminergic neurons to generate TH > dj-1-β-RNAi/+ Drosophila melanogaster flies. Next, we induced neurotoxicity in the transgenic flies with PQ. The second aim of this study was to validate the model by comparing the effects of vehicle, EGCG, and chemicals with known antioxidant and neuroprotective properties in vivo (e.g., propyl gallate and minocycline) on life-span, locomotor activity, lipid peroxidation, and neurodegeneration. The EGCG treatment provided protection and prevention from the PQ-induced reduction in the life-span and locomotor activity and from the PQ-induced increase in lipid peroxidation and neurodegeneration. These effects were augmented in the EGCG-treated flies when compared to the flies treated with either PG or MC. Altogether, these results suggest that the transgenic TH > dj-1-β-RNAi/+ flies treated with PQ serve as a suitable PD model for screening of potential therapeutic agents.

Topics: Animals; Animals, Genetically Modified; Antioxidants; Catechin; Disease Models, Animal; Dose-Response Relationship, Drug; Drosophila melanogaster; Drosophila Proteins; Female; Herbicides; Lipid Peroxidation; Locomotion; Male; Minocycline; Nerve Tissue Proteins; Neurodegenerative Diseases; Neuroprotective Agents; Oxidative Stress; Paraquat; Protein Deglycase DJ-1; Tyrosine 3-Monooxygenase

Surgical correction of congenital cardiac malformations mostly implies the use of cardiopulmonary bypass (CPB). However, a possible negative impact of CPB on cerebral structures like the hippocampus cannot be neglected. Therefore, we investigated the effect of CPB on hippocampus CA1 and CA3 regions without or with the addition of epigallocatechin-3-gallate (EGCG) or minocycline. We studied 42 piglets and divided them into six experimental groups: control without or with EGCG or minocycline, CPB without or with EGCG or minocycline. The piglets underwent 90 minutes CPB and subsequently, a 120-minute recovery and reperfusion phase. Thereafter, histology of the hippocampus was performed and the adenosine triphosphate (ATP) content was measured. Histologic evaluation revealed that CPB produced a significant peri-cellular edema in both CA regions. Moreover, we found an increased number of cells stained with markers for hypoxia, apoptosis and nitrosative stress. Most of these alterations were significantly reduced to or near to control levels by application of EGCG or minocycline. ATP content was significantly reduced within the hippocampus after CPB. This reduction could not be antagonized by EGCG or minocycline. In conclusion, CPB had a significant negative impact on the integrity of hippocampal neural cells. This cellular damage could be significantly attenuated by addition of EGCG or minocycline.

Topics: Adenosine Triphosphate; Animals; Apoptosis Inducing Factor; Brain Edema; CA1 Region, Hippocampal; CA3 Region, Hippocampal; Cardiopulmonary Bypass; Caspase 3; Catechin; Chromatography, High Pressure Liquid; Disease Models, Animal; Hypoxia-Inducible Factor 1, alpha Subunit; Minocycline; Neuroprotective Agents; Poly Adenosine Diphosphate Ribose; Swine; Tyrosine