The Possible Positive Mechanisms of Pirenoxine in Cataract Formation
Abstract
:1. Introduction
2. Effects of Pirenoxine on Age-Related Cataract: Evidence from In Vitro, Ex Vivo, In Vivo, and Clinical Studies
2.1. Effects of Pirenoxine on Calcium Dysregulation-Induced Age-Related Cataract
2.2. Effects of Pirenoxine on Oxidative Stress-Induced Age-Related Cataract
2.3. Effects of Pirenoxine on Selenium-Induced Age-Related Cataract
2.4. Effects of Pirenoxine on Ultraviolet (UV) Radiation-Induced Age-Related Cataract
2.5. Effects of Pirenoxine on Quinone-Induced Age-Related Cataracts
2.6. Effects of Pirenoxine on the Natural Progression of Cataract
3. Effects of Pirenoxine on Diabetic Cataract
4. Effects of Pirenoxine on Congenital Cataract
5. Safety of Pirenoxine on the Eyes
6. Conclusions and Future Directions
Author Contributions
Funding
Conflicts of Interest
References
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Induction of Cataract | Source of Lens | Name/Dose/Route/Duration of PRX | Major Findings | Interpretation | Ref | ||
---|---|---|---|---|---|---|---|
Lens Opacity | Oxidative Stress | Others | |||||
Ca or selenite (10 mM) | Pig lens homogenate | Pure PRX/0.03, 0.1, and 0.3 μM/ 0–4 d | ↓ | PRX decelerated Ca- and selenite-induced lens opacification. | [15] | ||
Ca or selenite (10 mM) | Pig lens homogenate | PRX/ 1 μM/5 d | ↓ | PRX decelerated Ca- and selenite-induced lens opacification. | [16] | ||
Selenite (10 mM) | SD-rat pup lens homogenate | Catalin/0.016, 0.032, 0.080, and 0.1 μM/ 0–4 d Only cataV in Catalin/ 0–4 d | 0.016 μM: ⟷ 0.032, 0.080, and 0.1 μM: ↓ (only at d1) ⟷ | ↓ degradation of water-insoluble lens proteins | High dose PRX decelerated early selenite-induced lens opacification by a deceleration of degradation of water-insoluble lens proteins. CataV in Catalin had no effect on selenite-induced lens opacification. | [15] | |
Fe3+ (10 μM)/ascorbate | Rat lens homogenate | Catalin/ 0.1–1000 μM/2 h | ↓ TBA ↓ lipid hydroperoxide | Catalin prevented ROS damage of the lens after induction with Fe3+/ascorbate. | [17] | ||
Fe3+/ascorbate, Hb (10 μM), fMLP-stimulated macrophages (10 nM) | Rat whole lens | Catalin/ 0.1–1000 μM/2 h | ↓ TBA ↓ lipid hydroperoxide | Catalin prevented ROS damage of the lens after an induction with either Fe3+/ascorbate, Hb, or stimulated macrophages. | [17] | ||
X (600 μM)/ XO (0.1 U/mL) | Rat whole lens | Catalin/ 0.1–1000 μM/2 h | ↓ lipid peroxidation ⟷ Superoxide ⟷ Urate | Catalin prevented ROS damage of the lens with mechanisms other than inhibition of X/XO system. | [17] | ||
UVC (4 h) | Pig lens homogenate | Pure PRX/ 0.1, 1, 10, 100, and 1000 μM/ 0–4 h | PRX (1000 μM): ↓ PRX (<1000 μM): ⟷ | Pure PRX and cataV provided comparable benefits in decelerating lens protein opacity via the deceleration of lens degradation. The combination therapy provided greater efficacy than the monotherapy. | [15] | ||
Catalin/ 16, 32, 80, and 100 μM PRX + cataV/ 0–4 h Only cataV in Catalin/ 0–4 h | ↓ ↓ | ↓ degradation of γ-crystallins ↓ degradation of γ-crystallins | |||||
m-calpain activated by Ca | Pig lens homogenate | Catalin/ 0, 32, 80, and 100 μM Pure PRX/100 μM | ⟷ degradation of β- and α-crystallins | Catalin failed to decelerated proteolysis of lens induced by m-calpain. | [15] | ||
UVB (6 h) | Pig lens homogenate | Catalin/ 0.1, 1, 10, and 100 μM/2 h | ⟷ | Catalin had no protective effect against UVB-induced cataract. | [15] |
Study Types | Models | Induction of Cataract | Name/Dose/Route/Duration of PRX | Major Findings | Interpretation | Ref | ||
---|---|---|---|---|---|---|---|---|
Lens Opacity/ Evaluation Time | Oxidative Stress | Others | ||||||
Ex vivo | Rabbit lens | Fe3+/ ascorbate | Catalin/0.005%, 2 drops q 1 h/topical/8 h daily (total 2 d) before incubation with FeCl3 | ↓ conjugated- dienes ↓ lipid soluble fluorescent compound | Catalin decreased oxidative degradation of lipids in the lens after induction with Fe3+. | [17] | ||
In vivo | Rabbit | IVT 50 µM, 100 µM Hb at 2, 4, 6, and 8 d | Catalin/0.005%, 2 drops q 1 h/topical/8 h daily (total 4 d) before IVT Hb | ↓ conjugated- dienes ↓ lipid soluble fluorescent compound | Catalin decreased oxidative degradation of lipids in the lens after induction with IVT Hb. | [17] | ||
In vivo | Rabbit | IVT diquat (300 μM) | Catalin/0.005%, 2 drops q 1 h/topical/8 h daily (total 4 d) before IVT diquat | ↓ conjugated- dienes ↓ lipid soluble fluorescent compound | Catalin decreased oxidative degradation of lipids in the lens after induction with IVT diquat. | [17] | ||
In vivo | Wistar rat | A single dose of 19 µmol/kg of selenite via SC route at d3 | PRX/0.8 mg/15 mL, tid/topical/7 d | Serum: ↑ SOD ↑ CAT ↓ MDA Lens: ↑ SOD ↑ CAT ↑ GSH | PRX increased antioxidative enzymes in both lens and serum after induction with selenite. PRX decreased oxidative degradation of lipids in serum. | [19] | ||
In vivo | Mouse | Senescence-accelerated inbred | Catalin/0.005%, qid/120 d | ↓ progression ↓ wedge opacity formation | PRX decelerated progression of age-related cataract. | [28] | ||
In vivo | Dog with age-related incipient cataract | None | PRX/0.05%, 1–2 drops, 3–5 times/d/average 8 mo | ↓ opacity or ↓ progression: 72.2% % improvement: Cortical type: 62% Cortical and nuclear type: 30% | PRX reversed opacity and retarded progression of age-related cataract particularly at the cortical region of the lens. | [27] | ||
In vivo | SD-rat pup | A single dose of 19 µmoL/kg of selenite via SC route | Catalin/2.5 and 5 mg/kg single dose/SC/3 d before selenite injection | 2.5 mg/kg: ⟷/d 3 ⟷/d 4 5 mg/kg ↓/d 3 ⟷/d 4 | Pretreatment with high-dose subcutaneous Catalin only prevented early gross lens opacity in selenite-induced cataract. IVT Catalin also failed to decelerate gross lens opacity. | [15] | ||
Catalin/ 2 mg/mL single dose/IVT/after selenite injection | ⟷/d 5 | |||||||
In vivo | Wistar rat | A single dose of 19 µmol/kg of selenite via SC route | Catalin solution/0.03%/topical/1 time 1.5 h before selenite injection and qid for 1 wk after selenite injection Catalin liposome/ 0.24 mg/mL (particle size 100 nm)/topical/1 time 1.5 h before selenite injection and qid for 1 wk after selenite injection | By Scheimpflug camera/d 0–7: ⟷ By slit-lamp microscope/ d 1–4: ⟷ | Neither solution or liposomal forms of Catalin could prevent or decelerated selenite-induced cataract. | [25] | ||
By Scheimpflug camera/d 0–7: ⟷ By slit-lamp microscope/ d 1–4: ⟷ | ||||||||
In vivo | Wistar rat lens homogenate | A single dose of 19 µmol/kg of selenite via SC route | Catalin solution/0.03%/topical/1 time 1.5 h before selenite injection and qid for 1 wk after selenite injection | ⟷ GSH | ⟷ Na/K ratio ⟷ Ca | Neither soluble or liposomal forms of Catalin changed GSH, Na, K, or Ca level of the lens exposed to selenite. | [25] | |
Catalin liposome/ 0.24 mg/mL (particle size 100 nm)/topical/1 time 1.5 h before selenite injection and qid for 1 wk after selenite injection | ⟷ GSH | ⟷ Na/K ratio ⟷ Ca | ||||||
Clinical | Patients aged > 40 yr with initial cortical cataract | None | Catalin/24 mo | By slit-lamp microscope: ↓ opacity and ↓ progression/mo3, 6, 12, 18, and 24 (especially in age <59 years and after 18 mo use) % increased opacification • Catalin: 1.425 • Control: 9.228 | Catalin decelerated lens opacity and slowed progression of cortical type of presenile and aged-related cataract. The change was more obvious in those younger than 59 years. Peak effect was observed after 18 months of treatment. | [12] | ||
Clinical (double blinded RCT) | Patients with early idiopathic cataract, mean age 60.3 yr (PRX vs. BA, BA vs. control) | None | Catalin/ q 8 h/topical/ 22 mo | % decrease/ q 1 mo (mo 1–14), mo 18, mo 22: • Catalin: none • BA: high • Control: none | VA/1, 2 mo: • Catalin ↓ • BA ↑ • Control ↓ % operated-eyes/22 mo • Catalin: high • BA: low • Control: high | In age-related cataract BA decelerated or reversed lens opacity, and VA more extensively than PRX. BA also had greater impact on the reduction of the number of cataract operations. From the raw data, PRX seemed not to have effects on lens opacity, VA, and number of cataract operation. (No direct comparison between PRX and control.) | [26] | |
Clinical (double blinded RCT) | Patients with age-related cataract (<50% extension), age ≥ 40 yr | None | Catalin/6 times/day/topical/24 mo | ⟷ progression | ⟷ VA | PRX had no effect on early age-related cataract. | [29] |
Study Types | Source of Lens | Induction of Cataract | Name/Dose/Route/Duration of PRX | Major Findings of the Lens | Interpretation | Ref | ||||
---|---|---|---|---|---|---|---|---|---|---|
Opacity | GSH | Water-Soluble Protein | S-Containing Amino Acids | Others | ||||||
1. Diabetic Cataract | ||||||||||
In vitro | SD rat lens | Hypergalactosemic diet (50% galactose + 50% standard food) | PRX/10−7 M, 10−6 M, 10−5 M, or 10−4 M/11–96 h | 10−7 M: ⟷ 10−6 to 10−4 M: ↑ | 10−7 M and 10−6 M: ⟷ 10−5 M and 10−4 M: ↑ | 10−6 to 10−5 M: ⟷ 10−4 M: ↑ | Only a high concentration of PRX increased GSH and preserved lens protein by binding to sulfhydryl group. | [16] | ||
In vitro | Wistar rat whole lens | D-galactose (250 mmol/L) | Pure PRX/0.0053%/ 6–24 h | ↓ opacity ↓ progression of lens opacity | PRX delayed progression and improved lens transparency. | [29] | ||||
In vitro | Rat lens | D-galactose (250 mM) | Catalin/100 μL/24 h | ↓ opacity (h 12, h 18, and h 24) | PRX improved lens transparency. | [30] | ||||
In vitro | Goat whole lens | Glucose or galactose: 50,100, and 200% over the normal glucose concentration at 0.99 g/L | Catalin/0.001% and 0.01%/7 d | ↓ onset of opacity by 12–24 h (effect of 0.001% PRX = 0.01% PRX) ↓ opacity at 12–18 h (effect of 0.001% PRX = 0.01% PRX) | 0.001% and 0.01% Catalin delayed the onset of opacity and improved lens transparency. | [31] | ||||
In vitro | Cow lens | Sorbitol | Catalin/ 60 µM/48 h | ↓ sorbitol | Catalin decreased sorbitol content in lens | [32] | ||||
In vivo | SD rat | Hypergalactosemic diet (50% galactose + 50% standard food) | PRX/0.005%, 0.01, or 2%, 2 drops tid/topical/30 d simultaneously with galactose administration | ↓ incidence of cataract by 40% | ↑ | ↑ | ↑ | PRX increased GSH and preserved lens protein by binding to the sulfhydryl group. PRX prevented diabetic cataract. | [16] | |
In vivo | Rat | 10 mL/kg of 50% D-galactose bid/IP/90 d + 10% D-galactose water and food/oral/90 d | Catalin/ 0.8 mg/15 mL/topical/3 drops tid/90 d simultaneously with galactose administration | ↓ opacity (d 20, d 30, d40, d60 and d90) | PRX improved lens transparency of diabetic cataract. | [30] | ||||
In vivo | Wistar rat | 10 mL/kg of 50% D-galactose bid/IP/30 d + 10% D-galactose water/oral/ 30 d | Pure PRX/0.0053% tid/topical/60 d after d30 of galactose administration | ↓ opacity (10 d–90 d) ↓ progression of lens opacity (10 d–90 d) | PRX delayed progression and reversed lens opacification of diabetic cataract. | [29] | ||||
In vivo | Rabbit | Alloxan | Catalin | ↓ opacity | ↓ Na ↑ K | PRX prevented and delayed lens transparency of diabetic cataract by controlling electrolytes. | [33] | |||
In vivo | Rat | Alloxan 50 mg/kg IV | Catalin/20 mg/kg/IP/daily for 6 wk | 100% delayed onset of opacity 81.6% had no lens opacity (wk 5 and wk 6 | PRX delayed onset and progression of diabetic cataract. | [65] | ||||
In vitro | Rat lens | Glucose 55.5 mM/5 d | PRX/5 d | ↑ | ↑ | PRX preserved lens protein by binding to the sulfhydryl group. | [52] | |||
In vivo | Rat | Hypergalactosemic diet | PRX/20 d | ↑ | ↓ aldose reductase activity | PRX increased GSH and decreased aldose reductase activity. | [52] | |||
2. Congenital Cataract | ||||||||||
In vivo | Pigmented rabbit | Tryptophan-free diet (30 d) | PRX/0.005%, 0.01 or 2%, 2 drops tid/topical/30 d | ↓ incidence of cataract by 40%/d 30 | ↑ | ↑ | ↑ | PRX prevented cataract. PRX increased GSH and preserved lens protein by binding to the sulfhydryl group. | [16] | |
In vivo | Rabbit | Tryptophan-free diet | PRX/20 d | ↑ | ↑ | ↑ | ↓ | PRX increased GSH and preserved lens protein by binding to the sulfhydryl group. PRX decreased aldose reductase activity. | [52] | |
Clinical (double blinded RCT) | Patients with congenital cataract (age 6–8 wk) | None | Catalin/ 6 times/day/topical/16 wk | ⟷ progression | PRX had no effect on congenital cataract. | [27] |
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Upaphong, P.; Thonusin, C.; Choovuthayakorn, J.; Chattipakorn, N.; Chattipakorn, S.C. The Possible Positive Mechanisms of Pirenoxine in Cataract Formation. Int. J. Mol. Sci. 2022, 23, 9431. https://doi.org/10.3390/ijms23169431
Upaphong P, Thonusin C, Choovuthayakorn J, Chattipakorn N, Chattipakorn SC. The Possible Positive Mechanisms of Pirenoxine in Cataract Formation. International Journal of Molecular Sciences. 2022; 23(16):9431. https://doi.org/10.3390/ijms23169431
Chicago/Turabian StyleUpaphong, Phit, Chanisa Thonusin, Janejit Choovuthayakorn, Nipon Chattipakorn, and Siriporn C. Chattipakorn. 2022. "The Possible Positive Mechanisms of Pirenoxine in Cataract Formation" International Journal of Molecular Sciences 23, no. 16: 9431. https://doi.org/10.3390/ijms23169431