piperidines and Retinal-Degeneration

Neurodegeneration caused with retinal ischemia or high intraocular pressure is irreversible in general. We have focused on the role of hypoxia-inducible factor (HIF) in retinal homeostasis and revealed that HIF inhibition may be effective against retinal neovascular and neurodegeneration. In this study, we performed in vitro screening of natural products and found halofuginone, which is a derivative of febrifugine extracted from hydrangea, as a novel HIF inhibitor. Administration of halofuginone showed a significant neuroprotective effect by inhibiting HIF-1α expression in a murine retinal ischemia-reperfusion model histologically and functionally. These results indicate that halofuginone can be a neuroprotective agent in ischemic retinal degenerative diseases.

Topics: 3T3 Cells; Animals; Hypoxia-Inducible Factor 1, alpha Subunit; Male; Mice; Mice, Inbred C57BL; Neuroprotective Agents; Piperidines; Quinazolinones; Reperfusion Injury; Retinal Degeneration; Retinal Vessels

Endocannabinoid system involves in neuroprotective effects on the central neural system. The cannabinoid receptor 1 (CB1R) is widely expressed in the mouse retina. However, the role of cannabinoid receptors in the retina remains unclear. In this work, we established a photoreceptor degeneration mouse model via N-methyl-N-nitrosourea (MNU) administration to identify the neuroprotective effects of cannabinoid receptors. The MNU-induced retinal degeneration behaves similarly to that in the human retinitis pigmentosa (RP). Administration of the CB1R antagonist SR141716A distinctly recovered the photoreceptor loss, decreased glial reactivity and reduced abnormal vascular complexes in an MNU-induced mouse model. The BC dendrites were shrunk in the MNU-treated retina with eliminated ON-BCs responses and partially diminished OFF-BCs responses in patch-clamp recordings. In the MNU + SR1 group, both the function and structure of ON-BCs recovered. Taken together, our study showed that the inhibition of CB1R can effectively prevent MNU-induced retinal degeneration, suggesting a potential therapeutic effect of the CB1R antagonist SR1 in retinal degeneration diseases.

Topics: Alkylating Agents; Animals; Biomarkers; Blotting, Western; Cannabinoid Receptor Antagonists; Disease Models, Animal; Fluorescent Antibody Technique, Indirect; Methylnitrosourea; Mice; Mice, Inbred C57BL; Neuroprotective Agents; Patch-Clamp Techniques; Photoreceptor Cells, Vertebrate; Piperidines; Pyrazoles; Receptor, Cannabinoid, CB1; Retina; Retinal Degeneration; Rimonabant

The endocannabinoid system is involved in some neurodegenerative diseases such as Alzheimer's disease. An endogenous constellation of proteins related to cannabinoid

Topics: Animals; Cannabinoid Receptor Antagonists; Cell Death; Cell Line; Gene Expression Regulation; Light; Male; Mice; Piperidines; Pyrazoles; Receptors, Cannabinoid; Retinal Cone Photoreceptor Cells; Retinal Degeneration; Rimonabant

Transgenic mice overexpressing serum retinol-binding protein (RBP4-Tg) develop progressive retinal degeneration, characterized by microglia activation, yet the precise mechanisms underlying retinal degeneration are unclear. Previous studies showed RBP4-Tg mice have normal ocular retinoid levels, suggesting that degeneration is independent of the retinoid visual cycle or light exposure. The present study addresses whether retinal degeneration is light-dependent and RBP4-dependent by testing the effects of dark-rearing and pharmacological lowering of serum RBP4 levels, respectively.. RBP4-Tg mice reared on normal mouse chow in normal cyclic light conditions were directly compared to RBP4-Tg mice exposed to chow supplemented with the RBP4-lowering compound A1120 or dark-rearing conditions. Quantitative retinal histological analysis was conducted to assess retinal degeneration, and electroretinography (ERG) and optokinetic tracking (OKT) tests were performed to assess retinal and visual function. Ocular retinoids and bis-retinoid A2E were quantified.. Dark-rearing RBP4-Tg mice effectively reduced ocular bis-retinoid A2E levels, but had no significant effect on retinal degeneration or dysfunction in RBP4-Tg mice, demonstrating that retinal degeneration is light-independent. A1120 treatment lowered serum RBP4 levels similar to wild-type mice, and prevented structural retinal degeneration. However, A1120 treatment did not prevent retinal dysfunction in RBP4-Tg mice. Moreover, RBP4-Tg mice on A1120 diet had significant worsening of OKT response and loss of cone photoreceptors compared to RBP4-Tg mice on normal chow. This may be related to the very significant reduction in retinyl ester levels in the retina of mice on A1120-supplemented diet.. Retinal degeneration in RBP4-Tg mice is RBP4-dependent and light-independent.

Topics: Animals; Dark Adaptation; Electroretinography; Female; Gene Expression Regulation; Light; Male; Mice; Mice, Inbred C57BL; Mice, Transgenic; Piperidines; Radiation Injuries, Experimental; Retina; Retinal Degeneration; Retinoids; Retinol-Binding Proteins, Plasma

Although a blockade of acetylcholine esterase has been reported to suppress neuronal cell death induced by exogenous glutamate and beta-amyloid, information is still limited regarding the neuroprotective effects of the acetylcholine esterase inhibitor donepezil. We histologically examined the effects of donepezil on neuronal injury induced by ischemia-reperfusion. Intravenous and intravitreous treatment with donepezil 15 min prior to ischemia dramatically reduced the retinal damage. The protective effect of donepezil in the ganglion cell layer was not affected by mecamylamine, a nicotinic acetylcholine-receptor antagonist, nor scopolamine, a muscarinic acetylcholine-receptor antagonist. The protective effect of donepezil in the inner plexiform layer was reduced not by mecamylamine, but by scopolamine. Neostigmine, a choline-esterase inhibitor, and pilocarpine, a muscarinic acetylcholine-receptor agonist, have protective effects in the inner plexiform layer and the inner nuclear layer. These results suggest that not only the activation of acetylcholine receptors but also a mechanism unrelated to acetylcholine-esterase inhibition contribute to the protective effect of donepezil on the ganglion cells in the ischemic-reperfused rat retina. Donepezil may be useful as a therapeutic drug against retinal diseases that cause neuronal cell death such as glaucoma with high intraocular pressure.

Topics: Animals; Donepezil; Indans; Male; Neurodegenerative Diseases; Neuroprotective Agents; Piperidines; Rats; Rats, Sprague-Dawley; Reperfusion Injury; Retinal Degeneration; Retinal Vessels; Vitreous Body

OT-551 (1-hydroxy-4-cyclopropanecarbonyloxy-2,2,6,6-tetramethylpiperidine hydrochloride), is a novel small molecule with antioxidant and anti-inflammatory effects. Protective efficacy of OT-551 and its metabolite TEMPOL-H (TP-H) against light-induced degeneration of retinal pigment epithelium (RPE) was tested. Albino rats were intraperitoneally injected with OT-551, TP-H, or water approximately 30 min prior to a 6 h exposure to 2700 lux white fluorescent light. Retinal protection was evaluated histologically by counting the RPE cell nuclei and measuring the extent of RPE damage on the retinal sections as RPE damage index (%). Following light exposure, the number of RPE cell nuclei was significantly reduced in light-exposed eyes from water-treated animals, while the number was not significantly different between light-exposed and unexposed eyes from the animals treated with 100 mg/kg TP-H or with any dose of OT-551 in the inferior hemisphere, and with 100 mg/kg OT-551 in the superior hemisphere. RPE damage index was significantly lower in the animals treated with any dose of OT-551 compared to water-treated animals both in the inferior and superior hemispheres. Systemic administration of OT-551 and TP-H provides RPE cell protection against acute light damage, and the protection by OT-551 was greater than by TP-H.

Topics: Animals; Cell Count; Cyclic N-Oxides; Hydroxylamine; Injections, Intraperitoneal; Light; Piperidines; Radiation Injuries, Experimental; Radiation-Protective Agents; Rats; Rats, Sprague-Dawley; Retinal Degeneration; Retinal Pigment Epithelium