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Retinal Neuroprotective effect of Rosiglitazone – indication for Parkinsons Disease and other diseases involving neurodegeneration

Cordeiro, FM; Davis, B; Somavarapu, S; (2016) Retinal Neuroprotective effect of Rosiglitazone – indication for Parkinsons Disease and other diseases involving neurodegeneration.

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Abstract

Rosiglitazone maleate is an anti-diabetes oral drug manufactured by GSK, which binds to PPAR (Peroxisome proliferator-activated receptors) in adipose cells to make them more sensitive to insulin, thereby acting as an oral hypoglycaemic agent. The PPAR-γ stimulation pathway is also implicated in rosiglitazone’s anti-apoptotic effect. Avandia was licenced for the treatment of Diabetes in 1999 and its patent expired last year. However, it has been associated with an increase risk of myocardial infarction and death.5,6 After much debate, in June 2013, the FDA decided that Avandia could continue to be prescribed, with some restrictions, but there has been a real decline in its use. Peroxisome proliferator-activated receptors (PPARs) are ligand-activated transcription factors belonging to the superfamily of nuclear hormonal receptors. These receptors were identified in the hepatocytes of rodents in 1990, and the name comes from their ability to induce peroxisome proliferation364. PPARs interact directly with PPAR gamma coactivators 1-alpha (PGC-1α) and 1-beta (PGC-1β) in the regulation of mitochondrial biogenesis365, through the detection and control of lipid homeostasis. These receptors also regulate the expression of genes coding for uncoupling proteins (UCPs). UCPs are transporters in the inner mitochondrial membrane366 involved in the control of thermogenesis, ROS production, and oxidative function. By binding to a specific sequence in the promoter region of target genes, PPARs are able to regulate gene transcription. Activated PPARs can also directly inhibit transcription factors367. These functions allow PPARs to encourage lipid consumption in the production of ATP when there is a cellular demand for energy368. Rosiglitazone is an exogenous agonist of PPAR-γ, and belongs to the group of thiazolidinediones which act as insulin sensitizers. By binding to PPAR-γ, rosiglitazone regulates the production of adipocytes, secretion of fatty acids and glucose metabolism, thus determining an increase in insulin sensitivity in adipose tissue, liver, and skeletal muscle393. Furthermore, rosiglitazone also has anti-inflammatory properties. It reduces the secretion of IL-8, a mediator of inflammation, induced by TNF-α in cells of the monocyte-macrophage line394. It has also been shown that in a mouse model of PD, rosiglitazone has an anti-inflammatory action and attenuates gliosis as highlighted by Carta A.R. and colleagues. Furthermore it modulates microglial activation, attenuates Cox-1 production in a rat model of PD, and reversibly inhibits monoamine oxidase B (MAO B), which is a crucial enzyme for neurotransmitter metabolism such as dopamine. The work here shows for the first time in vivo, that Rosiglitazone is neuroprotective in the retina, and that its formulation within liposomes, prolongs its effects. We believe that this data suggests: a) RSG can be reformulated and reprofiled as a neuroprotective drug in PD b) The formulation shown here, although given intraperitoneally, is very similar to the formulations given intranasally. We therefore think it may be administered clinically as an intranasal drug, which therefore will also cross the BBB to affect the brain. c) As such, we belive it can be considered as treatment for: a. Alzheimer’s b. Glaucoma c. Leber’s Hereditary Optic Neuropathy d. AION

Type: Patent
Title: Retinal Neuroprotective effect of Rosiglitazone – indication for Parkinsons Disease and other diseases involving neurodegeneration
Keywords: rosiglitazone, liposomes
UCL classification: UCL > Provost and Vice Provost Offices
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Brain Sciences
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Brain Sciences > Institute of Ophthalmology
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Life Sciences
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Life Sciences > UCL School of Pharmacy
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Life Sciences > UCL School of Pharmacy > Pharmaceutics
URI: http://discovery.ucl.ac.uk/id/eprint/1520791
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