Reduced AMPK activation and increased HCAR activation drive anti-inflammatory response and neuroprotection in glaucoma.

Reduced AMPK activation and increased HCAR activation drive anti-inflammatory response and neuroprotection in glaucoma.

Harun-Or-Rashid Mohammad; Inman Denise M

Journal of neuroinflammation

2018

2018-11

BACKGROUND: Glaucoma is a chronic degenerative disease for which inflammation is considered to play a pivotal role in the pathogenesis and progression. In this study, we examined the impact of a ketogenic diet on the inflammation evident in glaucoma as a follow-up to a recent set of experiments in which we determined that a ketogenic diet protected retinal ganglion cell structure and function. METHODS: Both sexes of DBA/2J (D2) mice were placed on a ketogenic diet (keto) or standard rodent chow (untreated) for 8 weeks beginning at 9 months of age. DBA/2J-Gpnmb(+) (D2G) mice were also used as a non-pathological genetic control for the D2 mice. Retina and optic nerve (ON) tissues were micro-dissected and used for the analysis of microglia activation, expression of pro- and anti-inflammatory molecules, and lactate- or ketone-mediated anti-inflammatory signaling. Data were analyzed by immunohistochemistry, quantitative RT-PCR, ELISA, western blot, and capillary tube-based electrophoresis techniques. RESULTS: Microglia activation was observed in D2 retina and ON as documented by intense microglial-specific Iba1 immunolabeling of rounded-up and enlarged microglia. Ketogenic diet treatment reduced Iba1 expression and the activated microglial phenotype. We detected low energy-induced AMP-activated protein kinase (AMPK) phosphorylation in D2 retina and ON that triggered NF-kappaB p65 signaling through its nuclear translocation. NF-kappaB induced pro-inflammatory TNF-alpha,

AMP-activated protein kinase; AMP-Activated Protein Kinases/*metabolism; Animal; Animals; Biological; Calcium Binding Proteins – Metabolism; Calcium-Binding Proteins/metabolism; Cells – Drug Effects; Cells – Pathology; Diet; Disease Models; Eye Proteins/genetics; Female; G-Protein-Coupled – Metabolism; G-Protein-Coupled/*metabolism; Glaucoma; Glaucoma – Complications; Glaucoma – Pathology; Glaucoma/*complications/pathology; Impact of Events Scale; Inbred DBA; Inflammation – Etiology; Inflammation – Prevention and Control; Inflammation hydroxycarboxylic acid receptor; Inflammation/*etiology/*prevention & control; Ketogenic diet; Ketogenic/methods; Male; Membrane Glycoproteins; Membrane Glycoproteins/genetics; Mice; Microfilament Proteins – Metabolism; Microfilament Proteins/metabolism; Microglia/drug effects/pathology; Models; Mutation; Mutation/genetics; Neuroprotection/drug effects/*physiology; NLR Family; Optic Nerve – Pathology; Optic Nerve/pathology; Phosphotransferases – Metabolism; Proteins; Pyrin Domain-Containing 3 Protein/genetics/metabolism; Receptors; Retina – Drug Effects; Retina – Pathology; Retinal Ganglion Cells/drug effects/*pathology; Transgenic

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