SPG302 mitigates diabetic retinal neuropathy and inner retinal damage in a genetic mouse model of diabetes

Diabetic retinopathy (DR) is a leading cause of vision loss stemming from vascular and neurodegenerative sequelae of impaired glucose metabolism. Diabetic retinal neuropathy (DRN), an early feature of DR that can precede the microvasculopathy, is characterized by inner retinal degeneration with loss of ganglion cells (GCs) and impaired GC function, decreased inner retina synaptic markers, and increased reactive gliosis and cell death. Loss of glutamatergic synapses in the retina precedes, and may contribute to, overt neuron loss in DR, thus offering a potential new point for therapeutic intervention. SPG302, a novel pegylated benzothiazole derivative, promotes glutamatergic synaptogenesis and protects the inner retina in a mouse model of glaucoma, another leading cause of blindness associated with early synapse loss in the retina. To evaluate potential protective effects of SPG302 in DR, db/db mice (a diabetic mouse model with an inactivation mutation in the leptin receptor) were treated with intraperitoneal SPG302 or vehicle for 8 weeks (16-24 weeks of age). Db/+ mice served as an additional control. Db/db mice demonstrated weight gain, hyperglycemia, insulin intolerance, and glucose intolerance, while db/+ mice did not. SPG302 treatment did not change these metabolic parameters. Following treatment, GC function was assessed using electroretinography (ERG). Mice were then euthanized for quantification of retinal GCs, synaptic markers, glial markers, and markers of cell death using immunofluorescence staining and Western blot methods. Db/db mice demonstrated significant loss of GC ERG signal and GC cell number, decreased PSD95 and synaptophysin expression indicative of synapse loss, as well as increased reactive gliosis and expression of cell death markers such as pBAD and BAX. SPG302 treatment effectively preserved retinal integrity by reversing these changes. Thus, SPG302 has therapeutic potential for protecting the inner retina and mitigating DRN in diabetes.