Sigma-1 receptor agonist, (+)-pentazocine, is neuroprotective in a Brown Norway rat microbead model of glaucoma

Barbara A Mysona; Jing Zhao; Oceane De Greef; August Beisel; Parth A Patel; Lindsay Berman; Sylvia B Smith; Kathryn Bollinger

doi:10.1016/j.exer.2022.109308

Sigma-1 receptor agonist, (+)-pentazocine, is neuroprotective in a Brown Norway rat microbead model of glaucoma

Exp Eye Res. 2023 Jan:226:109308. doi: 10.1016/j.exer.2022.109308. Epub 2022 Nov 15.

Authors

Barbara A Mysona¹, Jing Zhao², Oceane De Greef³, August Beisel⁴, Parth A Patel⁵, Lindsay Berman⁶, Sylvia B Smith⁷, Kathryn Bollinger⁸

Affiliations

¹ Department of Cellular Biology and Anatomy CB-2304, Medical College of Georgia at Augusta University, 1120 15th Street, Augusta, GA, 30912, USA; James and Jean Culver Vision Discovery Institute, Department of Ophthalmology, Medical College of Georgia at Augusta University, 1120 15th Street, Augusta, GA, 30912, USA. Electronic address: bmysona@augusta.edu.
² James and Jean Culver Vision Discovery Institute, Department of Ophthalmology, Medical College of Georgia at Augusta University, 1120 15th Street, Augusta, GA, 30912, USA; Department of Ophthalmology, Medical College of Georgia at Augusta University, Augusta, GA, 30912, USA. Electronic address: JINZHAO@augusta.edu.
³ Student Training and Research Program, Graduate School, Augusta University, 1120 15th Street, Augusta, GA, 30912, USA. Electronic address: oceane.degreef@alumni.emory.edu.
⁴ Medical College of Georgia at Augusta University, 1120 15th Street, Augusta, GA, 30912, USA; Department of Ophthalmology, Medical College of Georgia at Augusta University, Augusta, GA, 30912, USA. Electronic address: abeisel@augusta.edu.
⁵ Medical College of Georgia at Augusta University, 1120 15th Street, Augusta, GA, 30912, USA. Electronic address: PAPATEL1@augusta.edu.
⁶ Medical College of Georgia at Augusta University, 1120 15th Street, Augusta, GA, 30912, USA. Electronic address: LBERMAN@augusta.edu.
⁷ Department of Cellular Biology and Anatomy CB-2304, Medical College of Georgia at Augusta University, 1120 15th Street, Augusta, GA, 30912, USA. Electronic address: SBSMITH@augusta.edu.
⁸ James and Jean Culver Vision Discovery Institute, Department of Ophthalmology, Medical College of Georgia at Augusta University, 1120 15th Street, Augusta, GA, 30912, USA; Department of Ophthalmology, Medical College of Georgia at Augusta University, Augusta, GA, 30912, USA. Electronic address: KBollinger@augusta.edu.

Abstract

Purpose: Glaucoma is a worldwide leading cause of irreversible blindness. Standard treatments lower intraocular pressure (IOP). Novel treatments to prevent optic nerve (ON) degeneration are needed. Here, we investigate the hypothesis that sigma-1 receptor (S1R) agonist (+)-pentazocine (PTZ) is neuroprotective in a Brown Norway (BN) rat, microbead model of glaucoma.

Methods: BN rats (9-11 weeks, male and female) were treated by intraperitoneal injection, 3 times per week with (+)-PTZ (2 mg/kg) or vehicle (VEH) alone. Treatment started 1 week prior to intraocular injection of polystyrene microbeads to elevate IOP. IOP was measured 2-3 times per week. Five weeks post microbead injection, rats were euthanized. ONs were removed, then fixed and processed for 63x oil, light microscope imaging of toluidine blue stained ON cross sections. To facilitate comparison of ON morphology from VEH and (+)-PTZ treated rats with similar ocular hypertensive insults, rats were assigned to low (IOP ≤15.8 mmHg), moderate (15.8 < IOP <28.0 mmHg), and high (IOP ≥28.0 mmHg) groups based on average IOP in the microbead injected eye. Axon numbers, axon density, axonal and glial areas, axon loss, and axon size distributions of naïve, bead, and contralateral ONs were assessed using QuPath program for automated image analysis.

Results: (+)-PTZ treatment of BN rats protected ONs from damage caused by moderate IOP elevation. Treatment with (+)-PTZ significantly reduced axon loss and glial areas, and increased axon density and axonal areas compared to ONs from VEH treated rats with moderate IOP. (+)-PTZ-mediated neuroprotection was independent of IOP lowering effects. At average IOP ≥28.0 mmHg, (+)-PTZ treatment did not provide measurable neuroprotection. ONs from contralateral eyes exhibited subtle, complex changes in response to conditions in the bead eyes.

Conclusions: S1R agonist (+)-PTZ shows promise as a neuroprotective treatment for glaucoma. Future studies to understand the complex molecular mechanisms by which (+)-PTZ provides this neuroprotection are needed.

Keywords: Axon size distributions; Axons; Gliosis; Neuroprotection; QuPath; Retinal ganglion cells; Sigma-1 receptor.

Publication types

Research Support, N.I.H., Extramural

MeSH terms

Animals
Disease Models, Animal
Female
Glaucoma*
Injections, Intraocular / adverse effects
Intraocular Pressure
Male
Microspheres
Neuroprotection
Pentazocine* / pharmacology
Pentazocine* / therapeutic use
Rats
Rats, Inbred BN
Retinal Ganglion Cells
Sigma-1 Receptor

Substances

Pentazocine

Abstract

Publication types

MeSH terms

Substances

Grants and funding