Diabetic keratopathy and treatment by modulation of the opioid growth factor (OGF)–OGF receptor (OGFr) axis with naltrexone: A review

Abstract

The Opioid Growth Factor (OGF) -OGF receptors (OGFr) axis plays an important role in the homeostasis and re-epithelialization of the mammalian cornea. This tonically active growth regulatory inhibitory pathway is involved in cell replication, and the endogenous neuropeptide OGF targets cyclin dependent kinase inhibitors, p16 and/or p21. Blockade of OGF-OGFr interfacing by systemic or topical administration of opioid antagonists such as naltrexone (NTX) results in accelerated DNA synthesis, cell replication, and tissue repair. Molecular manipulation of OGFr using sense constructs delays corneal re-epithelialization, whereas antisense constructs accelerated repair of the corneal surface. Corneal keratopathy, a significant complication of diabetes mellitus, is manifested by delays in corneal re-epithelialization following surgery, injury, or disease. Tissue culture studies have shown that addition of NTX stimulates DNA synthesis and explant outgrowth of rabbit corneal epithelium, whereas OGF depresses DNA synthesis and explant outgrowth in a receptor-mediated manner. NTX accelerated corneal re-epithelialization in organ cultures of human and rabbit cornea. Systemic application of NTX to the abraded corneas of rats, and topical administration of NTX to the injured rabbit ocular surface, increased re-epithelialization. Systemic injections or topical administration of NTX facilitates re-epithelialization of the cornea in diabetic rats. Given the vital role of the corneal epithelium in maintaining vision, the frequency of corneal complications related to diabetes (diabetic keratopathy), and the problems occurring in diabetic individuals postoperatively (e.g., vitrectomy), and that conventional therapies such as artificial tears and bandage contact lenses have failed, topical application of NTX merits clinical consideration.

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

“…It was commented that oxidative stress has been described in human and animal diabetic corneas (28).…”

Design and Evaluation of Controlled-Release Niosomes and Discomes for Naltrexone Hydrochloride Ocular Delivery

“…The most characteristic signs of DK are dry eye, delayed corneal wound repair, and impaired corneal nerve sensation. [28][29][30] DK was estimated to affect 49%-60% of diabetic patients. 29 Naltrexone is a wellknown opioid antagonist and it is commonly used for treatment of opioid dependence and alcoholism.…”

Synergistic effect of methionine encephalin (MENK) combined with pidotimod(PTD) on the maturation of murine dendritic cells (DCs)

“…28,29 One native opioid peptide, MENK, has emerged as a modulator on several immunological functions both in vitro and in vivo such as enhancing the proliferation of peripheral blood lymphocytes and splenocytes. 30 MENK possesses bilateral regulation on immune cells, which means that MENK at higher concentrations such as 10 -6 M or lower concentrations such as 10 -18 M will delay immune cell growth and the possible mechanism is MENK can interact with OGFr to upregulate cyclin-dependent kinase inhibitory (CKI) pathways and markedly delay the G 1 /S phase of the cell cycle.…”

“…27,[40][41][42] PTD, a synthetic substance, has been shown to ameliorate different functions of innate and adaptive immune responses both in animals and humans. 28 It has been reported that PTD was able to enhance the effectors of the innate immunity responses by potentiating different functions of the professional phagocytes and NK cell activity; PTD also significantly increased the proliferation of spleen cells in response to Con-A and interleukin-2 (IL-2) stimulation. 28,43 On the other hand, large clinical trials have been conducted on patients shown that PTD displayed a beneficial activity in recurrent upper respiratory and urinary tract to which the innate immune system vigorously reacts, resulting in a generalized potentiation of the immune system so that the Ag coadministered with adjuvant can be taken up more effectively, processed and presented by activated DCs.…”

“…28 It has been reported that PTD was able to enhance the effectors of the innate immunity responses by potentiating different functions of the professional phagocytes and NK cell activity; PTD also significantly increased the proliferation of spleen cells in response to Con-A and interleukin-2 (IL-2) stimulation. 28,43 On the other hand, large clinical trials have been conducted on patients shown that PTD displayed a beneficial activity in recurrent upper respiratory and urinary tract to which the innate immune system vigorously reacts, resulting in a generalized potentiation of the immune system so that the Ag coadministered with adjuvant can be taken up more effectively, processed and presented by activated DCs. Dendritic cells are known to be the most professional APCs with a pivotal role in both immunity induction and antigen capture, processing and presentation, and express co-stimulation signals that activate T lymphocytes and NK cells.…”