A New Transgenic Mouse Model for Studying the Neurotoxicity of Spermine Oxidase Dosage in the Response to Excitotoxic Injury

Abstract

Spermine oxidase is a FAD-containing enzyme involved in polyamines catabolism, selectively oxidizing spermine to produce H2O2, spermidine, and 3-aminopropanal. Spermine oxidase is highly expressed in the mouse brain and plays a key role in regulating the levels of spermine, which is involved in protein synthesis, cell division and cell growth. Spermine is normally released by neurons at synaptic sites where it exerts a neuromodulatory function, by specifically interacting with different types of ion channels, and with ionotropic glutamate receptors. In order to get an insight into the neurobiological roles of spermine oxidase and spermine, we have deregulated spermine oxidase gene expression producing and characterizing the transgenic mouse model JoSMOrec, conditionally overexpressing the enzyme in the neocortex. We have investigated the effects of spermine oxidase overexpression in the mouse neocortex by transcript accumulation, immunohistochemical analysis, enzymatic assays and polyamine content in young and aged animals. Transgenic JoSMOrec mice showed in the neocortex a higher H2O2 production in respect to Wild-Type controls, indicating an increase of oxidative stress due to SMO overexpression. Moreover, the response of transgenic mice to excitotoxic brain injury, induced by kainic acid injection, was evaluated by analysing the behavioural phenotype, the immunodistribution of neural cell populations, and the ultrastructural features of neocortical neurons. Spermine oxidase overexpression and the consequently altered polyamine levels in the neocortex affects the cytoarchitecture in the adult and aging brain, as well as after neurotoxic insult. It resulted that the transgenic JoSMOrec mouse line is more sensitive to KA than Wild-Type mice, indicating an important role of spermine oxidase during excitotoxicity. These results provide novel evidences of the complex and critical functions carried out by spermine oxidase and spermine in the mammalian brain.

Pharmacological Inhibition of Spermine Oxidase Reduces Neurodegeneration and Improves Retinal Function in Diabetic Mice

“…SMOX is reported as a crucial enzyme in the polyamine catabolic pathway which plays a significant role in maintaining the polyamine homeostasis [27,51]. The involvement of SMOX in neurodegenerative diseases has been reported by other laboratories [52,53]. Elevated SMOX/APAO levels represent elevated oxidative stress resulting from elevated polyamine oxidation.…”

HIV-Tat Induces the Nrf2/ARE Pathway through NMDA Receptor-Elicited Spermine Oxidase Activation in Human Neuroblastoma Cells

“…A growing body of evidence links the polyamine spermine (Spm) catabolism to neurodegeneration, as observed in various in vitro and in vivo models [ 8 – 11 ]. Endogenous Spm is a ubiquitous cell component that is essential for normal cellular functions and growth [ 12 , 13 ].…”

Treatment with polyamine oxidase inhibitor reduces microglial activation and limits vascular injury in ischemic retinopathy

“…This was associated with increases in spermidine and H 2 O 2 and decreases in spermine, suggesting a significant role for SMO in the neuronal injury [36]. Studies in transgenic mice overexpressing SMO in neonatal cortex have shown increased levels of H 2 O 2 and increased sensitivity to excitotoxic brain injury [38]. Studies using a rat model of cerebral ischemia have shown that inhibition of PAOs using MDL 72527 significantly reduced brain edema, ischemic injury volume and polyamine levels [39].…”