S-allyl Cysteine and Cannabidiol are Equally Effective as Metformin in Preserving Neurovascular Integrity, Retinal Structure, and Cognitive Function in db/db Type 2 Diabetic Mice

Abstract Type 2 diabetes mellitus (T2D) is associated with central nervous system (CNS) alterations marked by neurovascular, inflammatory, and oxidative damage, resulting in cognitive dysfunction and retinal neurodegeneration. This study explored the therapeutic potential of naturally derived S-allyl-cysteine (SAC) and cannabidiol (CBD) in LepR db/db mice, targeting blood-brain/retinal barrier (BBB/BRB) leakage, glial activation, and DNA oxidative damage to alleviate memory deficits and retinal neurodegeneration. Diabetic mice underwent 23 weeks of dietary treatments: diabetic db/db controls, SAC, CBD, SAC + CBD, and metformin, with nondiabetic db/+ mice as negative controls. Memory function was assessed using novel object recognition and passive avoidance tests, while retinal thickness was measured via in vivo OCT imaging. Immunofluorescence imaging quantified neurovascular leakage (IgG extravasation), glial activation (GFAP and Iba1) and DNA oxidation (8OHdG) in brain sections and retinal whole-mounts. In diabetic db/db mice with hallmark metabolic dysregulation, CNS alterations included BBB/BRB leakage, glial activation, and retinal neurodegeneration of the ganglion cell complex (GCC), correlating with memory impairments. SAC and CBD exhibited significant therapeutic effects against CNS pathophysiologies, attenuating glial activation and synergistically preventing BBB leakage. In the retina, these compounds attenuated BRB leakage risk and reduced glial-mediated neuroinflammation. SAC and CBD preserved GCC thickness and improved memory functions, proving to be as effective as or superior to metformin against diabetic-associated CNS pathophysiology.