Topical application of naltrexone facilitates reepithelialization of the cornea in diabetic rabbits

Abstract

Delayed corneal re-epithelialization is a complication of diabetes, and may lead to ulcers and erosions, which cause ocular morbidity and visual loss. This study examined the efficacy of naltrexone (NTX), a long-acting, potent opioid antagonist, applied topically, to facilitate the repair of standarized corneal abrasions in diabetic (alloxan-induced) New Zealand white rabbits (glucose levels). NTX at a concentration of 10 −4 M, or sterile vehicle (SV), was administered topically 4 times per day for 7 days to the abraded eye of uncontrolled type 1 diabetic (DB), insulin-controlled type 1 diabetic (DB-IN), or nondiabetic (Normal) rabbits. Wound healing was monitored, and noninvasive (tonopen, pachymeter, hand-held slit lamp, and retinal camera) and invasive (histopathology) measurements evaluated. Corneal re-epithelialization in the uncontrolled DB rabbits was significantly enhanced (up to a 47% reduction in wound area) following treatment with NTX relative to both Normal SV and DB SV rabbits at 24, 48, and 56 hr following surgery. At 72 hr, DB NTX rabbits had residual defects that were 64%-82% smaller than Normal and DB SV animals. NTX treated DB-IN rabbits had residual defects that were 9-37% smaller than DB-IN rabbits receiving SV, and 6-40% smaller than Normal rabbits. No signs of toxicity from topical applications were noted. These data confirm and extend those documented in rats that demonstrated a lack of toxicity of NTX at a wide range of dosages, as well as efficacy for enhanced corneal epithelialization. These studies set the stage for clinical trials using NTX as a therapy for diabetic keratopathy.

Effect of Stem Cell Therapy on Induced Diabetic Keratopathy in Albino Rat

“…However, apoptosis and necrosis levels were similar (4). Naltrexone topically treated diabetic rabbits had residual corneal defects that were 23% smaller than diabetic rabbits (5).…”

“…HMSC were trypsinized and washed twice with PBS. A total number of 1×10 5 HSC were used for each run. To evaluate the HSC marker profile, cells were incubated in 100 μl of PBS with 3 μl of CD34-FITC for 20 min at room temperature.…”

Duration of opioid receptor blockade determines biotherapeutic response

“…Naltrexone, systemically or topically administered, at high dosages can reverse and restore these defects [e.g., 55,[57][58][59][60][61][62][63][64].…”

“…A comprehensive series of investigations have been conducted on the role of the OGF-OGFr axis to repair ocular surface abnormalities [51][52][53][54][55][56][61][62][63][64]. Corneal surface integrity maintains the required barrier to enable vision.…”

Remodeling of the Corneal Epithelial Scaffold for Treatment of Persistent Epithelial Defects in Diabetic Keratopathy

“…In addition to these various treatment options, experimental treatments specific to diabetic keratopathy include topical administration of insulin [14], a galactose reductase inhibitor [15], or naltrexone [16]. Furthermore, we have previously shown that eyedrops containing the substance P-derived peptide FGLM-NH 2 plus IGF-1 [17] or PHSRN [18] facilitated corneal epithelial wound closure in diabetic rats.…”