Pharmacological Inhibition of Spermine Oxidase Suppresses Excitotoxicity Induced Neuroinflammation in Mouse Retina

Abstract

Polyamine oxidation plays a major role in neurodegenerative diseases. Previous studies from our laboratory demonstrated that spermine oxidase (SMOX, a member of the polyamine oxidase family) inhibition using MDL 72527 reduced neurodegeneration in models of retinal excitotoxicity and diabetic retinopathy. However, the mechanisms behind the neuroprotection offered by SMOX inhibition are not completely studied. Utilizing the experimental model of retinal excitotoxicity, the present study determined the impact of SMOX blockade in retinal neuroinflammation. Our results demonstrated upregulation in the number of cells positive for Iba-1 (ionized calcium-binding adaptor molecule 1), CD (Cluster Differentiation) 68, and CD16/32 in excitotoxicity-induced retinas, while MDL 72527 treatment reduced these changes, along with increases in the number of cells positive for Arginase1 and CD206. When retinal excitotoxicity upregulated several pro-inflammatory genes, MDL 72527 treatment reduced many of them and increased anti-inflammatory genes. Furthermore, SMOX inhibition upregulated antioxidant signaling (indicated by elevated Nrf2 and HO-1 levels) and reduced protein-conjugated acrolein in excitotoxic retinas. In vitro studies using C8-B4 cells showed changes in cellular morphology and increased reactive oxygen species formation in response to acrolein (a product of SMOX activity) treatment. Overall, our findings indicate that the inhibition SMOX pathway reduced neuroinflammation and upregulated antioxidant signaling in the retina.

The Involvement of Polyamines Catabolism in the Crosstalk between Neurons and Astrocytes in Neurodegeneration

“…MDL 72527 has been used in a wide range of experimental settings of neurodegeneration models. For example, the increase in the expression of SMOX during retinal excitotoxicity was associated with the degeneration of neurons, while MDL 72527 treatment improved neuronal survival and reduced neuroinflammation and microglial activation [ 106 , 114 , 115 ]. In a diabetic mouse model, treatment with MDL 72527 is able to ameliorate the diabetic retinopathy, restoring the survival of retinal ganglion cells as well as the structure and function of the retina [ 56 ].…”

Research Progress on Mitochondrial Dysfunction in Diabetic Retinopathy

“…As a biomarker, FDP-lysine can reflect the content of acrolein, which is increased in hemoglobin and vitreous humor in patients with proliferative diabetic retinopathy [ 73 , 74 ], and its level in retinal Müller cells of diabetic animal models also parallels the progress of the disease [ 75 ]. Polyamine oxidation and lipid peroxidation are the main intrinsic pathways of acrolein generation during DR pathology [ 72 , 76 ]. By depleting antioxidants such as glutathione [ 77 ] and promoting oxidative stress by forming protein carbonyls [ 78 ], excessive acrolein reduces the membrane potential of mitochondria and the activity of complexes I, II, and IV, resulting in mitochondrial damage in retinal pigment epithelial cells [ 79 , 80 ].…”

Research Progress and Potential Applications of Spermidine in Ocular Diseases

“…Conversion between polyamines can also occur. For instance, spermine can gradually decompose into spermidine and putrescine under the catalysis of spermidine/spermine-N1-acetyltransferase (SSAT)—N1-acetylpolyamine oxidase (APAO) [ 33 ]; it can also be directly converted to spermidine under the action of spermine oxidase (SMO), but this process may generate harmful compounds such as hydrogen peroxide (H 2 O 2 ) and acrolein, which could be toxic and induce oxidative stress in excessive accumulation [ 34 , 35 , 36 ]. Therefore, the spermidine level in vivo is determined by polyamines, including spermine and putrescine, predominantly initiated by the amino acids ornithine, methionine, and arginine.…”