Blockade of OGFr delays the onset and reduces the severity of diabetic ocular surface complications

Zagon, Ian S.; Sassani, Joseph W.; Purushothaman, Indira; McLaughlin, Patricia J.

doi:10.1177/1535370220972060

Cited by 13 publications

(24 citation statements)

References 20 publications

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“…Regarding the link between NTX and levels of OGF, serum levels of OGF were normal for rats receiving systemic NTX, and OGF tissue levels were normal for type 1 diabetic rats receiving twice-daily topical NTX, while OGFr levels remained elevated. These data support the role of OGF–OGFr binding in maintaining the onset of ocular surface complications and suggest the effect of NTX therapy may be useful in pre-diabetic and early diabetic states to prevent dry eye and aberrant corneal surface sensitivity [ 38 ].…”

Section: Discussionsupporting

confidence: 58%

“…The onset and magnitude of diabetes complications are associated with the elevations of OGF tissue and serum levels in diabetic rats [ 36 , 38 , 39 , 40 ]. These complications appear with more frequency and severity in female animal models, similarly associated with descended estradiol levels and elevated OGF levels [ 40 ].…”

Section: Discussionmentioning

confidence: 99%

“…In diabetic animal models, the corneal epithelium had elevated levels of OGF and OGFr. Because OGF is an inhibitory growth factor, the dysregulation of the pathway contributes to the delay’s re-epithelialization of corneal abrasions [ 38 , 41 ]. Experimental animals studies show how the continuous suppression of OGF receptor with topical NTX (2–3 times per day) or high systemic dosage of NTX are effective in the renewal of the ocular epithelium, normalized re-epithelization, and accelerating epithelial wound closure in diabetic animals though also in normal rats, mice and rabbits [ 30 , 42 , 43 , 44 , 45 , 46 ].…”

Section: Discussionmentioning

confidence: 99%

“…[ 47 ]. The early blockade of the OGF–OGFr axis with NTX could avoid the intensity and onset of complications of dysregulation of the axis in rats with diabetes type 1 [ 38 ].…”

Section: Discussionmentioning

confidence: 99%

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Opioids and Ocular Surface Pathology: A Literature Review of New Treatments Horizons

García-López

Gómez-Huertas

Sánchez‐González

et al. 2022

JCM

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This review discusses the role of opioids in the corneal surface and the different pathways and therapeutic methods of management. A literature review was performed using PubMed database. For the database search, the main searching words “opioid” and “topical opioid treatment” were used with the descriptors “cornea”, “ocular surface”, “neuropathic corneal pain”, “corneal sensitivity” and “naltrexone”; original scientific articles and reviews were included to achieve the purpose of the review. The endogenous opioid system has relevant functions in the organism, and in daily use, opioids are used as painkillers. However, these drugs may be employed for other indications as opioid pathways have a wide spectrum. The corneal surface for topical treatment is easily accessible, hence sparing the side effects of systemic opioids. Instillation of opioid antagonist substances, such as naltrexone, increases corneal healing rates and stimulates the division of corneal epithelium cells without deleterious effects. The natural modulation of endogenous opioids controls different forms of pain, including inflammatory and neuropathic pain, both in the ocular surface and in the central nervous system. There are diverse methods in controlling pain using opioids, especially in refractory forms. This review attempts to collect the literature about corneal surface and opioid pathways to provide an overview image and a possible direction of the news treatments.

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Section: Discussionsupporting

confidence: 58%

Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

“…[ 47 ]. The early blockade of the OGF–OGFr axis with NTX could avoid the intensity and onset of complications of dysregulation of the axis in rats with diabetes type 1 [ 38 ].…”

Section: Discussionmentioning

confidence: 99%

See 2 more Smart Citations

Opioids and Ocular Surface Pathology: A Literature Review of New Treatments Horizons

García-López

Gómez-Huertas

Sánchez‐González

et al. 2022

JCM

View full text Add to dashboard Cite

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“…These changes in the balance of cell proliferation contribute to the onset and magnitude of ocular surface abnormalities observed in T1D. Despite the nearly equal proportion of males and females with diabetes, most preclinical studies, including our own, utilize male rodents as a model for study [e.g., 14 , 15 ], with an independent focus on female adult rats [ 16 ]. The OGF-OGFr regulatory pathway functions in normal rodents and humans, but in the diabetic model, healing of corneal epithelial defects and other ocular surface abnormalities are significantly delayed providing a reproducible model for studying the mechanism underlying delayed epithelial wound healing in diabetes.…”

Section: Introductionmentioning

confidence: 99%

Sex Differences in Diabetic Ocular Surface Complications and Dysregulation of the OGF-OGFr Pathway

Zagon

Sassani

McLaughlin

2022

Journal of Diabetes and Clinical Research

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Background: Diabetes is a chronic disorder that affects more than 500 million individuals worldwide. It is a life-long disease with complications that attack nearly all other systems within the body. Although there is a slight increase in the prevalence of diabetes in males, ocular surface complications are equally present in males and females. Aim:This review provides a discussion on preclinical studies related to the dysregulation of a biological pathway that appears to be causally related to diabetic ocular surface complications including dry eye, delayed corneal epithelial healing, and decreased corneal sensitivity. Most basic science and clinical studies focus on male sex in animal models in order to avoid confounders related to hormonal cycling. However, with approximately 10.2% of all women in the US aged 18-44 being diagnosed with diabetes and nearly 4% additional women having undiagnosed disease, it is prudent to examine the onset of these dysregulations also in females and to note any sex-related differences in the timing of onset or severity of ocular surface complications. Summary: Data from several well-controlled investigations have documented that female rats with type 1 diabetes develop ocular surface complications before male rats. In part, this finding may be due to the increase in the inhibitory peptide Opioid Growth Factor (OGF) that occurs within 2 weeks of the induction of hyperglycemia in female animals in comparison to the changes in OGF levels in male rats which occur at 4 weeks. It was noted that estrogen levels drop within weeks of induction of hyperglycemia and could serve as another marker for the onset of disease activity and/or its complications. Finally, insulin does not appear to protect against early changes in OGF levels or estrogen secretion in diabetic female rats, setting the stage for a distinction in the disease profile of diabetes between males and females. These data encourage further studies on both sexes in order to establish a complete understanding of the underlying pathologies associated with complications associated with diabetes.

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Safety study of topical naltrexone therapy for diabetic skin wounds is confirmed in Göttingen mini‐pigs

McLaughlin

Sassani

Zagon

2023

Drug Development Research

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This study was conducted to determine the safety of topical naltrexone treatment in Göttingen swine. Efficacy of topical naltrexone was performed previously in Sprague‐Dawley rats. In this study, 25 male and female mini‐pigs received topical naltrexone once daily for 30 days. The gel at doses of 1%, 2%, and 10% naltrexone was applied at a dose volume of 0.01 ml/cm2 to an area of unbroken skin encompassing 10% of the animal's surface. Body and food consumption, skin and organ morphology, and clinical signs, including blood analyses were taken periodically. Naltrexone levels in serum were measured at the time of death. No adverse observations were made in the cutaneous skin, autopsied organs, or biochemical parameters. The no‐observed adverse effect level (NOAEL) was considered to be 2% topical application daily. The conclusions from the veterinarians and researchers are that topical naltrexone at 1% or 2% can be used safely in clinical efficacy studies.

show abstract

Blockade of OGFr delays the onset and reduces the severity of diabetic ocular surface complications

Cited by 13 publications

References 20 publications

Opioids and Ocular Surface Pathology: A Literature Review of New Treatments Horizons

Opioids and Ocular Surface Pathology: A Literature Review of New Treatments Horizons

Sex Differences in Diabetic Ocular Surface Complications and Dysregulation of the OGF-OGFr Pathway

Safety study of topical naltrexone therapy for diabetic skin wounds is confirmed in Göttingen mini‐pigs

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