*4.9. Compound 49b*

Compound 49b is a recently discovered β-adrenergic receptor agonist that has already demonstrated efficacy in preventing apoptosis in in vitro models of EC and Müller cells exposed to high glucose [127,128]. Recent evidence shows that compound 49b can inhibit HMGB1 expression, TLR-4 downstream signaling, and, therefore, NF-κB in both EC and Müller cells. This leads to the idea that this agonist may preserve vascular and neuronal integrity in the diabetic retina [126,129].

#### *4.10. Cyclosporine A (CyA)*

Cyclosporine A is a polypeptide derived from the fungi *Beauveria nevus* and *Tolypocladium inflatum*, and it is well known for its anti-inflammatory and immunosuppressive effects [130]. Wang et al. demonstrated that CyA attenuates the enhanced expression of IL-1β and TNF-κ in the retinas of diabetic rats, probably via the suppression of HMGB1. The intravitreal injection of CyA may represent a novel therapeutic strategy to treat DR [131].

CyA is also involved in the reduction of BRB permeability in diabetic rats. In particular, it reduces the levels of IL-1β, nitric oxide (through a decreased expression of iNOS), and IL-1β-induced cyclooxygenase-2 (COX-2) expression. Moreover, CyA decreases vitreous protein concentration in diabetic rats. The authors sugges<sup>t</sup> that this reduction in vitreous protein concentration can be linked to the reduction of BRB permeability [132].


