Purpose: To explore whether retrobulbar administration of nerve growth factor (NGF) can restore visual function of streptozotocin-induced diabetes rats.
Methods: A high-sucrose/high-fat diet and single injection of streptozotocin (STZ) were used in modeling diabetes. During week 13-15 after STZ injection, diabetic rats were received retrobulbar βNGF injection. On week 17 after STZ injection, the rats were tested with flash visual evoked potential (FVEP) to reflect visual function and with both optical coherence tomography (OCT) and hematoxylin and eosin (H&E) staining to show retinal morphological changes. Furthermore, periodic acid-Schiff (PAS) staining for retinal vascular digest preparations was performed to investigate retinal microvascular alterations, and immunofluorescences for slides of the optic nerve or retina were checked to assess astrocyte activation, autophagy level, and the unfolded protein response (UPR).
Results: Retrobulbar βNGF injection significantly improved FVEP of diabetic rats. It also significantly alleviated retinal ganglion cell (RGC) loss and scarcely elicited other retinal/microvascular morphological changes, in OCT, H&E staining, and microvascular preparation. Moreover when diabetes rats treated with NGF, immunostaining of the optic nerve showed downregulation of complement 3d (C3d) and upregulations of glial fibrillary acidic protein (GFAP), S100-A10, microtubule-associated proteins 1A/1B light chain 3b (LC3b), and activating transcription factor 4 (ATF-4), while immunostaining of the retina showed upregulation of LC3b and no expression of ATF-4.
Conclusion: Our findings demonstrate that retrobulbar administration of βNGF reduces visual impairment with RGC-loss attenuation and without retinal-microvascular morphological alteration in diabetic rats. Furthermore, enhancements of A2 astrocyte activation, autophagy-protein expression, and ATF-4-mediated UPR may play crucial roles in the protective mechanism of NGF in diabetic visual-pathway neurodegeneration.
Keywords: Astrocyte; Autophagy; Diabetic neurodegeneration; Nerve growth factor; Retrobulbar injection; The unfolded protein response.