Alan Saul - Academia.edu (original) (raw)

Papers by Alan Saul

Free Radical Biology and Medicine, Apr 1, 2019

Sigma 1 receptor (Sig1R), a putative molecular chaperone, has emerged as a novel therapeutic targ... more Sigma 1 receptor (Sig1R), a putative molecular chaperone, has emerged as a novel therapeutic target for retinal degenerative disease. Earlier studies showed that activation of Sig1R via the highaffinity ligand (+)-pentazocine ((+)-PTZ) induced profound rescue of cone photoreceptor cells in the rd10 mouse model of retinitis pigmentosa; however the mechanism of rescue is unknown.

Investigative Ophthalmology & Visual Science, Apr 22, 2011

Investigative Ophthalmology & Visual Science, Jun 11, 2015

Investigative Ophthalmology & Visual Science, Oct 22, 2019

PURPOSE. Retinitis pigmentosa (RP), a retinal photoreceptor degeneration, typically affects rod f... more PURPOSE. Retinitis pigmentosa (RP), a retinal photoreceptor degeneration, typically affects rod function and subsequently cones. Activation of sigma 1 receptor (Sig1R) has been shown to preserve cone function through 6 weeks in the rd10 mouse model of RP, when mice were treated systemically with the Sig1R ligand (þ)-pentazocine (PTZ). This study determined the extent to which cone function is preserved in rd10 mice when Sig1R is activated. METHODS. Rd10 mice were administered (þ)-PTZ (alternate days beginning at postnatal day [P]14) over a period of 180 days. Mouse visual function and structure were measured in vivo using optokinetic tracking response, scotopic and photopic electroretinography plus photopic assessment using ''natural'' noise stimuli, and optical coherence tomography (OCT). Immunofluorescent methods were used to detect cones in retinal cryosections. RESULTS. Visual acuity was maintained in rd10(þ)-PTZ-treated mice through P56, whereas rd10 nontreated mice showed marked decline by P28. Cone responses were detected in (þ)-PTZ-treated mice through P60, which were more robust when tested with natural noise stimuli; cone responses were minimal in nontreated rd10 mice. OCT revealed significantly thicker retinas in (þ)-PTZ-treated rd10 mice through P60 compared to nontreated mice. Cones were detected by immunofluorescence in (þ)-PTZ-treated rd10 retinas through P120. CONCLUSIONS. The extent to which cone rescue could be sustained in (þ)-PTZ-treated rd10 mice was evaluated comprehensively, showing that activation of Sig1R is associated with prolonged visual acuity, extended detection of cone function, and detection of cones in retinal histologic sections. The data reflect promising long-term neuroprotection when Sig1R is activated.

Visual Neuroscience, Jun 1, 1989

Cat striate cortical neurons were investigated using a new method of studying adaptation aftereff... more Cat striate cortical neurons were investigated using a new method of studying adaptation aftereffects. Stimuli were sinusoidal gratings of variable contrast, spatial frequency, and drift direction and rate. A series of alternating adapting ind test trials was presented while recording from single units. Control trials were completely integrated with the adapted trials in these experiments' dvery cortical cell tested showed selective adaptation aftereffects. Adapting at suprathreshold contrasts invariably reduced contrast sensitivity. Significant aftereffects could be observed even when adapting at low contrasts. The spatial-frequency tuning of aftereffects varied from cell to cell. Adapting at a given spatial frequency generally resulted in a broad response reduction at test frequencies above and below the adapting frequency' Many cells lost responses predominantly at frequencies lower than the adapting frequency. Tire tuning of altereffeits varied with the adapting frequency. In particular, the strongest aftereffects occurred neai the adapting frequency. Adapting at frequencies just above the optimum for a cell often altered the spatial-frequency tuning by shifting the peak toward lower frequencies. The fact that the tuning of aftereffeCts did noisimply matCtr the tuning of the cell, but depended on the adapting stimulus, implies that extrinsic mechanisms are involved in adaptation effects.

Chemischer Informationsdienst, Oct 26, 1982

ChemInform Abstract Chemische Wellen (sich ausbreitende Wellen chemischer Reaktivität) wurden in ... more ChemInform Abstract Chemische Wellen (sich ausbreitende Wellen chemischer Reaktivität) wurden in dünnen Filmen einer Lösung aus H3AsO3 und NaIO3 untersucht. In Reaktionsmischungen mit stöchiometrischem Iodat-Überschuss und Stärke-Indikator wird die farblose Lösung durch die Welle blau gefärbt (A). Bei stöchiometrischem H3AsO3-Überschuss wandert die Welle als schmales blaues Band durch die Lösung (B). Die Wellen wurden durch eine Pt-Elektrode im Zentrum einer Petri-Schale mit-l.O Vnegativer Vorspannung bez. einer Pt-Elektrode am Schalenrand elektrochemisch initiiert (Kreiswellen); ihre Ausbreitungsgeschwindigkeit wurde als Funktion der Konzentrationen gemessen. Ein Reaktionsmechanismus mit I'-Autokatalyse erklärt das Diffusionsverhalten.

Investigative Ophthalmology & Visual Science, Mar 26, 2012

Free Radical Biology and Medicine, Apr 1, 2019

Sigma 1 receptor (Sig1R), a putative molecular chaperone, has emerged as a novel therapeutic targ... more Sigma 1 receptor (Sig1R), a putative molecular chaperone, has emerged as a novel therapeutic target for retinal degenerative disease. Earlier studies showed that activation of Sig1R via the highaffinity ligand (+)-pentazocine ((+)-PTZ) induced profound rescue of cone photoreceptor cells in the rd10 mouse model of retinitis pigmentosa; however the mechanism of rescue is unknown.

Investigative Ophthalmology & Visual Science, Apr 22, 2011

Investigative Ophthalmology & Visual Science, Jun 11, 2015

Investigative Ophthalmology & Visual Science, Oct 22, 2019

PURPOSE. Retinitis pigmentosa (RP), a retinal photoreceptor degeneration, typically affects rod f... more PURPOSE. Retinitis pigmentosa (RP), a retinal photoreceptor degeneration, typically affects rod function and subsequently cones. Activation of sigma 1 receptor (Sig1R) has been shown to preserve cone function through 6 weeks in the rd10 mouse model of RP, when mice were treated systemically with the Sig1R ligand (þ)-pentazocine (PTZ). This study determined the extent to which cone function is preserved in rd10 mice when Sig1R is activated. METHODS. Rd10 mice were administered (þ)-PTZ (alternate days beginning at postnatal day [P]14) over a period of 180 days. Mouse visual function and structure were measured in vivo using optokinetic tracking response, scotopic and photopic electroretinography plus photopic assessment using ''natural'' noise stimuli, and optical coherence tomography (OCT). Immunofluorescent methods were used to detect cones in retinal cryosections. RESULTS. Visual acuity was maintained in rd10(þ)-PTZ-treated mice through P56, whereas rd10 nontreated mice showed marked decline by P28. Cone responses were detected in (þ)-PTZ-treated mice through P60, which were more robust when tested with natural noise stimuli; cone responses were minimal in nontreated rd10 mice. OCT revealed significantly thicker retinas in (þ)-PTZ-treated rd10 mice through P60 compared to nontreated mice. Cones were detected by immunofluorescence in (þ)-PTZ-treated rd10 retinas through P120. CONCLUSIONS. The extent to which cone rescue could be sustained in (þ)-PTZ-treated rd10 mice was evaluated comprehensively, showing that activation of Sig1R is associated with prolonged visual acuity, extended detection of cone function, and detection of cones in retinal histologic sections. The data reflect promising long-term neuroprotection when Sig1R is activated.

Visual Neuroscience, Jun 1, 1989

Cat striate cortical neurons were investigated using a new method of studying adaptation aftereff... more Cat striate cortical neurons were investigated using a new method of studying adaptation aftereffects. Stimuli were sinusoidal gratings of variable contrast, spatial frequency, and drift direction and rate. A series of alternating adapting ind test trials was presented while recording from single units. Control trials were completely integrated with the adapted trials in these experiments' dvery cortical cell tested showed selective adaptation aftereffects. Adapting at suprathreshold contrasts invariably reduced contrast sensitivity. Significant aftereffects could be observed even when adapting at low contrasts. The spatial-frequency tuning of aftereffects varied from cell to cell. Adapting at a given spatial frequency generally resulted in a broad response reduction at test frequencies above and below the adapting frequency' Many cells lost responses predominantly at frequencies lower than the adapting frequency. Tire tuning of altereffeits varied with the adapting frequency. In particular, the strongest aftereffects occurred neai the adapting frequency. Adapting at frequencies just above the optimum for a cell often altered the spatial-frequency tuning by shifting the peak toward lower frequencies. The fact that the tuning of aftereffeCts did noisimply matCtr the tuning of the cell, but depended on the adapting stimulus, implies that extrinsic mechanisms are involved in adaptation effects.

Investigative Ophthalmology & Visual Science, Apr 17, 2010

Investigative Ophthalmology & Visual Science, Apr 17, 2010

Investigative Ophthalmology & Visual Science, Mar 9, 2020

PURPOSE. Activating the cell survival modulator sigma 1 receptor (Sig1R) delays cone photorecepto... more PURPOSE. Activating the cell survival modulator sigma 1 receptor (Sig1R) delays cone photoreceptor cell loss in Pde6βrd10/J (rd10) mice, a model of retinitis pigmentosa. Beneficial effects are abrogated in rd10 mice lacking NRF2, implicating NRF2 as essential to Sig1R-mediated cone neuroprotection. Here we asked whether activation of NRF2 alone is sufficient to rescue cones in rd10 mice. METHODS. Expression of antioxidant genes was evaluated in 661W cells and in mouse retinas after treatment with monomethylfumarate (MMF), a potent NRF2 activator. Rd10 mice were administered MMF (50 mg/kg) or the Sig1R ligand (+)-pentazocine (PTZ; 0.5 mg/kg) intraperitoneally (every other day, P14-42). Mice were evaluated for visual acuity (optokinetic tracking response), retinal function (electroretinography) and architecture (SD-OCT); histologic retinal sections were evaluated morphometrically. RESULTS. MMF treatment increased Nrf2, Nqo1, Cat, Sod1, and Hmox1 expression in vitro and in vivo. Visual acuity of (+)-PTZ-treated rd10 mice was similar to wild-type mice; however, MMF treatment did not alter acuity compared with nontreated rd10 mice. Cone electroretinography b-wave amplitudes were greater in PTZ-treated than nontreated or MMF-treated rd10 mice. SD-OCT assessment of retinal thickness was greater in (+)-PTZtreated mice versus nontreated or MMF-treated rd10 mice. Morphometric assessment of the outer nuclear layer revealed approximately 18 cells/100 μm retinal length in (+)-PTZ-treated rd10 mice, but only approximately 10 to 12 cells/100 μm in MMF-treated and nontreated rd10 retinas. CONCLUSIONS. Activation of NRF2 using MMF, at least at our dosing regimen, is insufficient to attenuate catastrophic photoreceptor damage characteristic of rd10 mice. The data prompt investigation of additional mechanisms involved in Sig1R-mediated retinal neuroprotection.

BackgroundExcessive oxidative stress and related chronic, sub-clinical inflammation is linked cau... more BackgroundExcessive oxidative stress and related chronic, sub-clinical inflammation is linked causally to the development and progression of degenerative diseases of the retina including diabetic retinopathy, age-related macular degeneration and glaucoma, leading causes of blindness worldwide. The above responses may be related directly to dysregulated retinal immunity and are potentiated by the combined actions of native retinal cells (e.g., retinal pigment epithelial (RPE) and microglial cells) and immune cells infiltrating from the periphery. Maintaining tight regulation of these cells such that effective control of pathogens is accomplished yet uncontrolled inflammation and consequent tissue damage is prevented is extremely important. However, the molecular mechanisms that control this delicate balance are poorly understood. We hypothesize that the hydroxycarboxylic acid receptor 2 (HCAR2/GPR109A) may play an important role. HCAR2/GPR109A has been shown to regulate immune cell r...

Free Radical Biology and Medicine, Apr 1, 2019

Sigma 1 receptor (Sig1R), a putative molecular chaperone, has emerged as a novel therapeutic targ... more Sigma 1 receptor (Sig1R), a putative molecular chaperone, has emerged as a novel therapeutic target for retinal degenerative disease. Earlier studies showed that activation of Sig1R via the highaffinity ligand (+)-pentazocine ((+)-PTZ) induced profound rescue of cone photoreceptor cells in the rd10 mouse model of retinitis pigmentosa; however the mechanism of rescue is unknown.

Investigative Ophthalmology & Visual Science, Apr 22, 2011

Investigative Ophthalmology & Visual Science, Jun 11, 2015

Investigative Ophthalmology & Visual Science, Oct 22, 2019

PURPOSE. Retinitis pigmentosa (RP), a retinal photoreceptor degeneration, typically affects rod f... more PURPOSE. Retinitis pigmentosa (RP), a retinal photoreceptor degeneration, typically affects rod function and subsequently cones. Activation of sigma 1 receptor (Sig1R) has been shown to preserve cone function through 6 weeks in the rd10 mouse model of RP, when mice were treated systemically with the Sig1R ligand (þ)-pentazocine (PTZ). This study determined the extent to which cone function is preserved in rd10 mice when Sig1R is activated. METHODS. Rd10 mice were administered (þ)-PTZ (alternate days beginning at postnatal day [P]14) over a period of 180 days. Mouse visual function and structure were measured in vivo using optokinetic tracking response, scotopic and photopic electroretinography plus photopic assessment using ''natural'' noise stimuli, and optical coherence tomography (OCT). Immunofluorescent methods were used to detect cones in retinal cryosections. RESULTS. Visual acuity was maintained in rd10(þ)-PTZ-treated mice through P56, whereas rd10 nontreated mice showed marked decline by P28. Cone responses were detected in (þ)-PTZ-treated mice through P60, which were more robust when tested with natural noise stimuli; cone responses were minimal in nontreated rd10 mice. OCT revealed significantly thicker retinas in (þ)-PTZ-treated rd10 mice through P60 compared to nontreated mice. Cones were detected by immunofluorescence in (þ)-PTZ-treated rd10 retinas through P120. CONCLUSIONS. The extent to which cone rescue could be sustained in (þ)-PTZ-treated rd10 mice was evaluated comprehensively, showing that activation of Sig1R is associated with prolonged visual acuity, extended detection of cone function, and detection of cones in retinal histologic sections. The data reflect promising long-term neuroprotection when Sig1R is activated.

Visual Neuroscience, Jun 1, 1989

Cat striate cortical neurons were investigated using a new method of studying adaptation aftereff... more Cat striate cortical neurons were investigated using a new method of studying adaptation aftereffects. Stimuli were sinusoidal gratings of variable contrast, spatial frequency, and drift direction and rate. A series of alternating adapting ind test trials was presented while recording from single units. Control trials were completely integrated with the adapted trials in these experiments' dvery cortical cell tested showed selective adaptation aftereffects. Adapting at suprathreshold contrasts invariably reduced contrast sensitivity. Significant aftereffects could be observed even when adapting at low contrasts. The spatial-frequency tuning of aftereffects varied from cell to cell. Adapting at a given spatial frequency generally resulted in a broad response reduction at test frequencies above and below the adapting frequency' Many cells lost responses predominantly at frequencies lower than the adapting frequency. Tire tuning of altereffeits varied with the adapting frequency. In particular, the strongest aftereffects occurred neai the adapting frequency. Adapting at frequencies just above the optimum for a cell often altered the spatial-frequency tuning by shifting the peak toward lower frequencies. The fact that the tuning of aftereffeCts did noisimply matCtr the tuning of the cell, but depended on the adapting stimulus, implies that extrinsic mechanisms are involved in adaptation effects.

Chemischer Informationsdienst, Oct 26, 1982

ChemInform Abstract Chemische Wellen (sich ausbreitende Wellen chemischer Reaktivität) wurden in ... more ChemInform Abstract Chemische Wellen (sich ausbreitende Wellen chemischer Reaktivität) wurden in dünnen Filmen einer Lösung aus H3AsO3 und NaIO3 untersucht. In Reaktionsmischungen mit stöchiometrischem Iodat-Überschuss und Stärke-Indikator wird die farblose Lösung durch die Welle blau gefärbt (A). Bei stöchiometrischem H3AsO3-Überschuss wandert die Welle als schmales blaues Band durch die Lösung (B). Die Wellen wurden durch eine Pt-Elektrode im Zentrum einer Petri-Schale mit-l.O Vnegativer Vorspannung bez. einer Pt-Elektrode am Schalenrand elektrochemisch initiiert (Kreiswellen); ihre Ausbreitungsgeschwindigkeit wurde als Funktion der Konzentrationen gemessen. Ein Reaktionsmechanismus mit I'-Autokatalyse erklärt das Diffusionsverhalten.

Investigative Ophthalmology & Visual Science, Mar 26, 2012

Free Radical Biology and Medicine, Apr 1, 2019

Sigma 1 receptor (Sig1R), a putative molecular chaperone, has emerged as a novel therapeutic targ... more Sigma 1 receptor (Sig1R), a putative molecular chaperone, has emerged as a novel therapeutic target for retinal degenerative disease. Earlier studies showed that activation of Sig1R via the highaffinity ligand (+)-pentazocine ((+)-PTZ) induced profound rescue of cone photoreceptor cells in the rd10 mouse model of retinitis pigmentosa; however the mechanism of rescue is unknown.

Investigative Ophthalmology & Visual Science, Apr 22, 2011

Investigative Ophthalmology & Visual Science, Jun 11, 2015

Investigative Ophthalmology & Visual Science, Oct 22, 2019

PURPOSE. Retinitis pigmentosa (RP), a retinal photoreceptor degeneration, typically affects rod f... more PURPOSE. Retinitis pigmentosa (RP), a retinal photoreceptor degeneration, typically affects rod function and subsequently cones. Activation of sigma 1 receptor (Sig1R) has been shown to preserve cone function through 6 weeks in the rd10 mouse model of RP, when mice were treated systemically with the Sig1R ligand (þ)-pentazocine (PTZ). This study determined the extent to which cone function is preserved in rd10 mice when Sig1R is activated. METHODS. Rd10 mice were administered (þ)-PTZ (alternate days beginning at postnatal day [P]14) over a period of 180 days. Mouse visual function and structure were measured in vivo using optokinetic tracking response, scotopic and photopic electroretinography plus photopic assessment using ''natural'' noise stimuli, and optical coherence tomography (OCT). Immunofluorescent methods were used to detect cones in retinal cryosections. RESULTS. Visual acuity was maintained in rd10(þ)-PTZ-treated mice through P56, whereas rd10 nontreated mice showed marked decline by P28. Cone responses were detected in (þ)-PTZ-treated mice through P60, which were more robust when tested with natural noise stimuli; cone responses were minimal in nontreated rd10 mice. OCT revealed significantly thicker retinas in (þ)-PTZ-treated rd10 mice through P60 compared to nontreated mice. Cones were detected by immunofluorescence in (þ)-PTZ-treated rd10 retinas through P120. CONCLUSIONS. The extent to which cone rescue could be sustained in (þ)-PTZ-treated rd10 mice was evaluated comprehensively, showing that activation of Sig1R is associated with prolonged visual acuity, extended detection of cone function, and detection of cones in retinal histologic sections. The data reflect promising long-term neuroprotection when Sig1R is activated.

Visual Neuroscience, Jun 1, 1989

Cat striate cortical neurons were investigated using a new method of studying adaptation aftereff... more Cat striate cortical neurons were investigated using a new method of studying adaptation aftereffects. Stimuli were sinusoidal gratings of variable contrast, spatial frequency, and drift direction and rate. A series of alternating adapting ind test trials was presented while recording from single units. Control trials were completely integrated with the adapted trials in these experiments' dvery cortical cell tested showed selective adaptation aftereffects. Adapting at suprathreshold contrasts invariably reduced contrast sensitivity. Significant aftereffects could be observed even when adapting at low contrasts. The spatial-frequency tuning of aftereffects varied from cell to cell. Adapting at a given spatial frequency generally resulted in a broad response reduction at test frequencies above and below the adapting frequency' Many cells lost responses predominantly at frequencies lower than the adapting frequency. Tire tuning of altereffeits varied with the adapting frequency. In particular, the strongest aftereffects occurred neai the adapting frequency. Adapting at frequencies just above the optimum for a cell often altered the spatial-frequency tuning by shifting the peak toward lower frequencies. The fact that the tuning of aftereffeCts did noisimply matCtr the tuning of the cell, but depended on the adapting stimulus, implies that extrinsic mechanisms are involved in adaptation effects.

Investigative Ophthalmology & Visual Science, Apr 17, 2010

Investigative Ophthalmology & Visual Science, Apr 17, 2010

Investigative Ophthalmology & Visual Science, Mar 9, 2020

PURPOSE. Activating the cell survival modulator sigma 1 receptor (Sig1R) delays cone photorecepto... more PURPOSE. Activating the cell survival modulator sigma 1 receptor (Sig1R) delays cone photoreceptor cell loss in Pde6βrd10/J (rd10) mice, a model of retinitis pigmentosa. Beneficial effects are abrogated in rd10 mice lacking NRF2, implicating NRF2 as essential to Sig1R-mediated cone neuroprotection. Here we asked whether activation of NRF2 alone is sufficient to rescue cones in rd10 mice. METHODS. Expression of antioxidant genes was evaluated in 661W cells and in mouse retinas after treatment with monomethylfumarate (MMF), a potent NRF2 activator. Rd10 mice were administered MMF (50 mg/kg) or the Sig1R ligand (+)-pentazocine (PTZ; 0.5 mg/kg) intraperitoneally (every other day, P14-42). Mice were evaluated for visual acuity (optokinetic tracking response), retinal function (electroretinography) and architecture (SD-OCT); histologic retinal sections were evaluated morphometrically. RESULTS. MMF treatment increased Nrf2, Nqo1, Cat, Sod1, and Hmox1 expression in vitro and in vivo. Visual acuity of (+)-PTZ-treated rd10 mice was similar to wild-type mice; however, MMF treatment did not alter acuity compared with nontreated rd10 mice. Cone electroretinography b-wave amplitudes were greater in PTZ-treated than nontreated or MMF-treated rd10 mice. SD-OCT assessment of retinal thickness was greater in (+)-PTZtreated mice versus nontreated or MMF-treated rd10 mice. Morphometric assessment of the outer nuclear layer revealed approximately 18 cells/100 μm retinal length in (+)-PTZ-treated rd10 mice, but only approximately 10 to 12 cells/100 μm in MMF-treated and nontreated rd10 retinas. CONCLUSIONS. Activation of NRF2 using MMF, at least at our dosing regimen, is insufficient to attenuate catastrophic photoreceptor damage characteristic of rd10 mice. The data prompt investigation of additional mechanisms involved in Sig1R-mediated retinal neuroprotection.

BackgroundExcessive oxidative stress and related chronic, sub-clinical inflammation is linked cau... more BackgroundExcessive oxidative stress and related chronic, sub-clinical inflammation is linked causally to the development and progression of degenerative diseases of the retina including diabetic retinopathy, age-related macular degeneration and glaucoma, leading causes of blindness worldwide. The above responses may be related directly to dysregulated retinal immunity and are potentiated by the combined actions of native retinal cells (e.g., retinal pigment epithelial (RPE) and microglial cells) and immune cells infiltrating from the periphery. Maintaining tight regulation of these cells such that effective control of pathogens is accomplished yet uncontrolled inflammation and consequent tissue damage is prevented is extremely important. However, the molecular mechanisms that control this delicate balance are poorly understood. We hypothesize that the hydroxycarboxylic acid receptor 2 (HCAR2/GPR109A) may play an important role. HCAR2/GPR109A has been shown to regulate immune cell r...