Target identification and validation of the alpha7 nicotinic acetylcholine receptor as a potential therapeutic target in retinal disease.

The role of acetylcholine (ACh) in visual processing in the mammalian retina has been the focus of research for many decades. Pioneering work on the localization of ACh discovered that the neurotransmitter is synthesized and stored in a distinct subpopulation of amacrine (starburst) cells. It has been shown that ACh release is regulated to a low resting "tonic" level, much like what is observed at the neuromuscular junction (NMJ).

Transcriptome Changes in Retinal Pigment Epithelium Post-PNU-282987 Treatment Associated with Adult Retinal Neurogenesis in Mice.

PNU-282987, a selective alpha7 nicotinic acetylcholine receptor agonist, has previously been shown to have both neurogenic and broad regenerative effects in the adult murine retina. The objective of this study was to assay the molecular mechanism by which PNU-282987 promotes the production of Muller-derived progenitor cells through signaling via the resident retinal pigment epithelium. These Muller-derived progenitor cells generate a myriad of differentiated neurons throughout the retina that have previously been characterized by morphology.

Stimulation of α7 nAChR leads to regeneration of damaged neurons in adult mammalian retinal disease models.

The adult mammal lacks the ability to regenerate neurons lost to retinal damage or disease in a meaningful capacity. However, previous studies from this laboratory have demonstrated that PNU-282987, an α7 nicotinic acetylcholine receptor agonist, elicits a robust neurogenic response in the adult murine retina. With eye drop application of PNU-282987, Müller glia cells re-enter the cell cycle and produce progenitor-like cells that can differentiate into various types of retinal neurons.

Glaucoma-inducing Procedure in an In Vivo Rat Model and Whole-mount Retina Preparation.

Glaucoma is a disease of the central nervous system affecting retinal ganglion cells (RGCs). RGC axons making up the optic nerve carry visual input to the brain for visual perception. Damage to RGCs and their axons leads to vision loss and/or blindness.

Neuroprotective Strategies in Glaucoma.

Background: Glaucoma is characterized as a neuropathic disease that causes progressive degeneration of retinal ganglion cells (RGCs) in the retina, resulting in irreversible loss of vision. All conventional treatments for glaucoma are focused on reducing intraocular pressure (IOP) in the anterior chamber of the eye. However, these treatments alone are insufficient to halt the progression of the disease.

Retinal ganglion cell neuroprotection induced by activation of alpha7 nicotinic acetylcholine receptors.

The α7nAChR agonist, PNU-282987, has previously been shown to have a neuroprotective effect against loss of retinal ganglion cells (RGCs) in an in vivo glaucoma model when the agent was injected into the vitreous chamber of adult Long Evans rat eyes. Here, we characterized the neuroprotective effect of PNU-282987 at the nerve fiber and retinal ganglion cell layer, determined that neuroprotection occurred when the agonist was applied as eye drops and verified detection of the agonist in the retina, using LC/MS/MS. To induce glaucoma-like conditions in adult Long Evans rats, hypertonic saline was injected into the episcleral veins to induce scar tissue and increase intraocular pressure.

A nicotinic acetylcholine receptor agonist prevents loss of retinal ganglion cells in a glaucoma model.

Purpose: The purpose of this study was to analyze the neuroprotective effect of an α7 nAChR agonist, PNU-282987, using an in vivo model of glaucoma in Long Evans rats.

Methods: One eye in each animal was surgically manipulated to induce glaucoma in control untreated animals and in animals that were treated with intravitreal injections of PNU-282987. To induce glaucoma-like conditions, 0.

Tropisetron as a neuroprotective agent against glutamate-induced excitotoxicity and mechanisms of action.

The objective of this study was to determine the neuroprotective role of tropisetron on retinal ganglion cells (RGCs) as well as to explore the possible mechanisms associated with alpha7 nAChR-induced neuroprotection. Adult pig RGCs were isolated from all other retinal tissue using a two-step panning technique. Once isolated, RGCs were cultured for 3 days under control untreated conditions, in the presence of 500 μM glutamate to induce excitotoxicity, and when tropisetron was applied before glutamate to induce neuroprotection.

ACh receptors link two signaling pathways to neuroprotection against glutamate-induced excitotoxicity in isolated RGCs.

Previous studies have reported that activation of nicotinic acetylcholine (ACh) receptors (nAChRs) on cultured pig retinal ganglion cells (RGCs) has a neuroprotective effect against glutamate-induced excitotoxicity. However, the mechanism linking nAChRs to neuroprotection is unknown. Here, we tested the hypothesis that signaling cascades involving p38 mitogen-activated protein kinase (MAPK) and phosphatidylinositol 3-kinase (PI3K) --> Akt are involved in linking activation of nAChRs to neuroprotection in isolated pig RGCs.

Acetylcholine protection of adult pig retinal ganglion cells from glutamate-induced excitotoxicity.

Purpose: To determine which glutamate receptor (GluR) subtypes are responsible for glutamate-induced excitotoxicity in cultured adult pig retinal ganglion cells (RGCs) and to characterize the neuroprotective effect of acetylcholine (ACh) on pig RGCs.

Methods: Adult pig RGCs were isolated from other retinal tissue by a modified panning technique using Thy 1.1 antibody.

Increased tonic activation of presynaptic metabotropic glutamate receptors in the rat supraoptic nucleus following chronic dehydration.

Chronic dehydration induces structural changes in the hypothalamic supraoptic nucleus (SON), including increased glutamate synapses and retraction of astroglial processes. We performed whole-cell recordings in acute hypothalamic slices to determine whether these changes increase tonic activation of presynaptic metabotropic glutamate receptors (mGluRs) by increasing ambient glutamate in the SON. Activation of presynaptic group III mGluRs caused a decrease in the frequency of miniature excitatory postsynaptic currents (mEPSCs) in SON neurones that was significantly attenuated in slices from dehydrated rats (-27.