Table 1.

Summary of direct and indirect high-mobility group box (HMGB1) inhibitors with therapeutic potential in diabetic retinopathy. HRECs = human retinal endothelial cells; TLR = toll like receptor; TNF-α = tumor necrosis factor-α; GCL = ganglion cell layer; STZ = streptozotocin; SIRT1 = sirtuin 1; BDNF = brain-derived neurotrophic factor; ROS = reactive oxygen species; ICAM-1= intercellular adhesion molecule-1; NF-κB = nuclear factor-κB; HIF-1α = hypoxia induced factor-1α; pSTAT-3 = phosphorylated signal transducer and activator of transcription-3; VEGF = vascular endothelial growth factor; siRNA = small interfering RNAs; shRNA = short hairpin RNA; RAGE = receptors for AGEs; MMP = metalloproteinases; IL = interleukin; SOCS3 = suppressor of cytokine signaling 3; ROP = Retinopathy of prematurity; SOD = superoxide dismutase; IGFBP-3 = insulin-like growth factor-binding protein-3; iNOS = inducible nitric oxide synthase; COX-2 = cyclooxygenase; BRB = blood retinal barrier.

Drug	Target Test	Diabetic Inducement	Mechanism of Action	Results	Reference
Glycyrrhizin	HRECs	High glucose concentrations	Inhibition of TLR-4 and TNF-α; cleavage of caspase 3 through inactivation of HMGB1	Increased insulin receptor signal transduction	[99,100]
	Mice	Ischemia/reperfusion damage	Block of the loss of retinal thickness	Protects GCL and retinal capillaries	[99,100]
	Mice	STZ	Upregulation of SIRT1, inhibition of inflammatory factors. Attenuates BDNF downregulation, reduces ROS, ICAM-1, NF-κB, and HIF-1α	Reduced vascular permeability, increased retinal thickness. Protection from diabetes-induced retinal damages and inflammation	[101] [67,68,85,90] [93]
	Retinal Muller Cells	High glucose concentrations	Attenuates p-STAT3 expression	Inhibition of VEGF expression	[69]
Small interfering RNAs	Mice	STZ	Intravitreal injection of HMGB1 siRNA	Protected morphological changes, and improved the function of the retina	[105]
	Retinal ganglion cells	High glucose concentrations	Transfection with HMGB1 siRNA reduced the expression of TLR-4 and NF-κB	Increased cell survival rate	[77]
	HRECs	High glucose concentrations	Transfection with HMGB1 siRNA reduced the expression of caspase 3	Inhibition the early stage of apoptosis	[105]
Short hairpin RNAs	Rat retinas	High glucose concentrations	Transfection with HMGB1 shRNA reduced the expression TNF-α and NF-κB	Increased cell survival rate and vascular permeability	[83]
Polygonum cuspidatum	Mice	STZ	Reduced RAGE and NF-κB expression	Reduced vascular permeability	[109]
Paeoniflorin	Mice	STZ	Inhibition of MMP-9 and IL-1β	Alleviated microglial activation	[113]
	BV2 modified microglial cells	High glucose concentrations	Inhibition of NF-κB expression and SOCS3	Reduced MMP-9 and TLR-4 concentrations	[113]
Salicin	HRECs	Incubated with IL-1β (inflammatory response)	Suppression of NF-κB pathway and the release of MMP	Inhibition of IL-1β mediated inflammatory pathways	[118]
Ethyl pyruvate	Mice	Induction of ROP through exposition to hyperoxia	Reduction of ROS, NF-κB, IL-6, VEGF and TNF-α	Reduction of neoangiogenesis and areas of ischemic retina	[120]
Bradykinin	HRECs	High glucose concentrations	Suppression of NF-κB, caspase 3, VEGF, TNF-α, IL-1β. Increase in SOD activity	Promotion of retinal cells survival/ inhibition of apoptosis. Reduction of vascular permeability	[122]
Kallistatin	HRECs	High glucose concentrations	Suppression of VEGF expression	Reduction of neoangiogenesis	[126]
Compound 49b	HRECs and rat retinal Muller cells	High glucose concentrations	Increase of IGFBP-3 levels and inhibition of TLR-4 pathway	Prevention of cellular apoptosis	[127,129]
	Mice	SZT	Increase of IGFBP-3 levels	Prevention of the decrease in retinal thickness and loss of cells in GCL	[127]
Cyclosporine A	Mice	STZ	Reduction of TNF-α and IL-1β	Amelioration of retinal thickness, regression of retinal edema	[131]
	Mice	STZ	Reduction of iNOS, IL-1β and COX-2	Reduction of BRB permeability	[132]