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Editors Selection IGR 17-1

Basic Science: Neuroprotection after Optic Nerve Injury

Comment by Derek Welsbie on:

95416 Agonist of growth hormone-releasing hormone enhances retinal ganglion cell protection induced by macrophages after optic nerve injury, Cen LP; Ng TK; Liang JJ et al., Proceedings of the National Academy of Sciences of the United States of America, 2021; 118:

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Growth hormone releasing hormone (GHRH) is classically thought of as a neuropeptide released from the hypothalamus onto the pituitary, where it binds GHRH receptors (GHRH-R) and stimulates the release of growth hormone. However, GHRH-R signaling has been demonstrated in many extra-pituitary pathologies, including inflammation and neoplasia. As such, GHRH analogs like MIA-602 (GHRH-R antagonist) and MR-409 (GHRH-R agonist) are being developed for a wide variety of conditions. In this paper, Cen et al. tested whether GHRH-R signaling might have a neuroprotective role in optic neuropathy.

The authors first demonstrated that GHRH-R is expressed in the ganglion cell and inner plexiform layers of retina. They then tested both peptides in the rat optic nerve crush model. Interestingly, when given subcutaneously, both the antagonist and agonist modestly increased RGC survival. This was associated with small changes in inflammatory gene expression and the number of microglia in the retina. Lens injury is known to increase RGC survival after optic nerve crush by stimulating intraocular inflammation, the recruitment of macrophages and the secretion of oncomodulin. The authors tested whether GHRH analogs might influence this response to intraocular inflammation. This time they found that RGC survival was mildly potentiated by the agonist (MR-409) but modestly reduced by the antagonist (MIA-602). Similar results were obtained when intraocular inflammation was triggered with intravitreal yeast cell wall extract.

In the absence of inflammation, both the agonist and antagonist produce the same phenotype. While certainly possible, it suggests the possibility of off-target effects

The work has several important shortcomings. First, in the absence of inflammation, both the agonist and antagonist produce the same phenotype. While certainly possible, it suggests the possibility of off-target effects. It will be essential to demonstrate similar findings with unrelated pharmacologic inhibitors and/or genetic models. Secondly, even the most robust protective combination (MR-409 + intraocular inflammation) barely protected more than 50% of RGCs (and no long-term time points were included), far less than other neuroprotective interventions. Finally, neither the mechanism, nor the link to intraocular inflammation, were thoroughly explored. While potentially interesting because of the clinical development of GHRH analogs, more work is needed to confirm a role of GHRH-R signaling in RGC survival.

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