Abstract
Optic neuropathy is a major cause of irreversible blindness worldwide, and no effective treatment is currently available. Secondary degeneration is believed to be the major contributor to retinal ganglion cell (RGC) death, the endpoint of optic neuropathy. Partial optic nerve transection (pONT) is an established model of optic neuropathy. Although the mechanisms of primary and secondary degeneration have been delineated in this model, until now how this is influenced by therapy is not well-understood. In this article, we describe a clinically translatable topical, neuroprotective treatment (recombinant human nerve growth factor, rh-NGF) predominantly targeting secondary degeneration in a pONT rat model. Topical application of rh-NGF twice daily for 3 weeks significantly improves RGC survival as shown by reduced RGC apoptosis in vivo and increased RGC population in the inferior retina, which is predominantly affected in this model by secondary degeneration. Topical rh-NGF also promotes greater axonal survival and inhibits astrocyte activity in the optic nerve. Collectively, these results suggest that topical rh-NGF exhibits neuroprotective effects on retinal neurons via influencing secondary degeneration process. As topical rh-NGF is already involved in early clinical trials, this highlights its potential in multiple indications in patients, including those affected by glaucomatous optic neuropathy.
Highlights
Secondary degeneration occurs commonly in the central (CNS) and peripheral (PNS) nervous systems, where injury from initial lesions can lead to widespread damage to neurons far beyond the primary injury site[1]
To establish whether the neuroprotective effects of topical Nerve growth factor (NGF) occur via primary or secondary neurodegenerative processes, this study investigates the effect of this therapeutic intervention on patterns of retinal ganglion cell (RGC) loss in a partial optic nerve transection model[7,28,29]
Results are shown after normalizing RGC apoptosis counts to those in Partial optic nerve transection (pONT) alone, with significant (p < 0.01) protective effects of recombinant human NGF (rh-NGF) found with both 180 μg/ml and 540 μg/ml doses to a level comparable to naïve controls
Summary
Secondary degeneration occurs commonly in the central (CNS) and peripheral (PNS) nervous systems, where injury from initial lesions can lead to widespread damage to neurons far beyond the primary injury site[1]. Expression profiles of endogenous NGF and its receptors are found to be altered in the retina and optic nerve in experimental glaucoma associated with RGC loss[23,24,25]. To establish whether the neuroprotective effects of topical NGF occur via primary or secondary neurodegenerative processes, this study investigates the effect of this therapeutic intervention on patterns of RGC loss in a partial optic nerve transection (pONT) model[7,28,29]. The pONT is a well-established animal model, induced by transecting only the dorsal axons of the optic nerve, leaving ventral axons intact but vulnerable to secondary degeneration[25,28] Using this model, we have previously successfully quantified the components of primary and secondary degeneration and evaluated therapeutic strategies[30,31]. To evaluate its effects on RGC axons, we assessed RGC axonal health and astrocytic activity
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