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

Webster, Sarah E.; Spitsbergen, Jake B.; Linn, David M.; Webster, Mark K.; Otteson, Deborah C.; Cooley-Themm, Cynthia A.; Linn, Cindy L.

doi:10.1007/s12031-022-02049-z

Cited by 3 publications

(3 citation statements)

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“…These results support the RT-PCR results indicating the location of the a7 nAChR to the GCL and possibly amacrine and bipolar cells (68) in the mammalian retina. These results also support the localization of a7 nAChRs to the photoreceptor outer segments and retinal pigment epithelium (RPE), as reported by Webster et al (72) and Webster et al (73). It appears that the b-actin labeling is specific to cones, but this cannot be confirmed.…”

Section: Resultssupporting

confidence: 83%

“…( 72 ) and Webster et al. ( 73 ). It appears that the β-actin labeling is specific to cones, but this cannot be confirmed.…”

Section: Resultsmentioning

confidence: 97%

“…( 72 ) elegantly demonstrated that this effect is mediated by α7 nAChRs on the RPE, which then direct Müller glia (MG) to dedifferentiate to produce other retinal neurons. The most recent evidence ( 73 ) indicates that PNU-282987 causes a bi-modal signaling event in which early activation primes the retina with an inflammatory response and developmental signaling cues, followed by an inhibition of gliotic mechanisms and a decrease in the immune response. This culminates with the upregulation of genes associated with specific types of retinal neuron generation.…”

Section: Discussionmentioning

confidence: 99%

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

Linn¹

2023

Front. Ophthalmol.

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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). If there were a dysfunction in the tonic release of ACh, might post-synaptic changes render the targets of ACh [i.e., retinal ganglion cells (RGCs)] vulnerable to disease? During my time at Pharmacia & Upjohn (PNU), selective nicotinic ACh receptor (nAChR) agonists (e.g., PNU-282987) were developed as a possible therapy for central nervous system (CNS) diseases. As RGCs are the main targets of neurodegeneration in glaucoma, could the activation of this target provide neuroprotection? In response to this question, experiments to identify alpha7 nAChRs in the retina (i.e., target ID studies) followed by “proof-of-concept” experiments were conducted. Target ID studies included binding studies with retinal homogenates, [125I]-alpha-bungarotoxin (α-BTX) autoradiography, and fluorescently tagged α-BTX binding in retinal slices. Imaging studies of intracellular calcium dynamics in the retinal slice were conducted. Reverse transcription-polymerase chain reaction (RT-PCR) analysis with alpha7 nAChR knockout mice using the “laser-capture microdissection” technique, in situ hybridization studies, and RT-PCR analysis of the human retina were conducted. Collectively, these experiments confirmed the presence of alpha7 nAChRs on specific cells in the retina. “Proof-of-concept” neuroprotection studies demonstrated that PNU-282987 provided significant protection for RGCs. This protection was dose dependent and was blocked with selective antagonists. More recently, evidence for the generation of new RGCs has been reported with PNU-282987 in rodents. Interestingly, the appearance of new RGCs is more pronounced with eye-drop application than with intravitreal injection. One could postulate that this reflects the neurogenic activation of alpha7 receptors on the retinal pigment epithelium (RPE) (eye drops) vs. a neuroprotective effect on RGCs (injections). In conclusion, there does appear to be a cholinergic retinal “tone” associated with RGCs that could be utilized as a neuroprotective therapy. However, a distinct cholinergic neurogenic mechanism also appears to exist in the outer retina that could possibly be exploited to generate new RGCs lost through various disease processes.

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Section: Resultssupporting

confidence: 83%

“…( 72 ) and Webster et al. ( 73 ). It appears that the β-actin labeling is specific to cones, but this cannot be confirmed.…”

Section: Resultsmentioning

confidence: 97%