Neutral Sphingomyelinase Modulation in the Protective/Preventive Role of rMnSOD from Radiation-Induced Damage in the Brain

Abstract

Studies on the relationship between reactive oxygen species (ROS)/manganese superoxide dismutase (MnSOD) and sphingomyelinase (SMase) are controversial. It has been demonstrated that SMase increases the intracellular ROS level and induces gene expression for MnSOD protein. On the other hand, some authors showed that ROS modulate the activation of SMase. The human recombinant manganese superoxide dismutase (rMnSOD) exerting a radioprotective effect on normal cells, qualifies as a possible pharmaceutical tool to prevent and/or cure damages derived from accidental exposure to ionizing radiation. This study aimed to identify neutral SMase (nSMase) as novel molecule connecting rMnSOD to its radiation protective effects. We used a new, and to this date, unique, experimental model to assess the effect of both radiation and rMnSOD in the brain of mice, within a collaborative project among Italian research groups and the Joint Institute for Nuclear Research, Dubna (Russia). Mice were exposed to a set of minor γ radiation and neutrons and a spectrum of neutrons, simulating the radiation levels to which cosmonauts will be exposed during deep-space, long-term missions. Groups of mice were treated or not-treated (controls) with daily subcutaneous injections of rMnSOD during a period of 10 days. An additional group of mice was also pretreated with rMnSOD for three days before irradiation, as a model for preventive measures. We demonstrate that rMnSOD significantly protects the midbrain cells from radiation-induced damage, inducing a strong upregulation of nSMase gene and protein expression. Pretreatment with rMnSOD before irradiation protects the brain with a value of very high nSMase activity, indicating that high levels of activity might be sufficient to exert the rMnSOD preventive role. In conclusion, the protective effect of rMnSOD from radiation-induced brain damage may require nSMase enzyme.

Facts about Fats: New Insights into the Role of Lipids in Metabolism, Disease and Therapy

“…Importantly, rMnSOD counteracts the radiation-induced liver damage exerting a protective role via acid sphingomyelinase (aSMase), and a preventive role via neutral sphingomyelinase (nSMase) [16]. Cataldi et al also demonstrated that nSMase is responsible for the preventive and protective effect elicited by rMnSOD against radiation-induced damage in the brain [17].…”

Acid and Neutral Sphingomyelinase Behavior in Radiation-Induced Liver Pyroptosis and in the Protective/Preventive Role of rMnSOD

“…The specific experimental model used for the present study permitted us to simultaneously investigate the effect of ionizing radiation and the protective/preventive effect of rMnSOD against radiation-induced liver damage. This was a unique opportunity under a collaborative project among Italian research groups and the Joint Institute for Nuclear Research, Dubna (Russia) [22]. Our results provide evidence that both prominent signs of pyroptosis (i.e., the loss of cell membrane integrity and the overexpression of Caspase-1) are induced by radiation treatment in a dose-dependent manner.…”

“…Our previous studies indicated that radiation targets SMase in the thyroid [20,21] and brain [22]. As there are two SMases involved in the apoptotic process (lysosomal aSMase and endoplasmic reticulum/nucleus nSMase1), we defined their behavior in the liver, where radiation upregulated Caspase-1, thereby triggering pyroptosis.…”

“…Thus, the apoptotic process requires the action of both aSMase and nSMase (especially nSMase1 [9]), but whether there is cooperation between the two enzymes and whether they behave differently in relation to the same apoptotic stimulus has not yet been investigated. To study what happens to the metabolism of hepatic SM via both the lysosomal and endoplasmic reticulum/nucleus SMase during irradiation, and to ascertain if this process can be modulated by protective molecules, we used the same experimental model previously applied to evaluate the effects of both ionizing radiation and a specific protective molecule in the brain [22]. This research originated from a collaborative project among Italian research groups and the Joint Institute for Nuclear Research, Dubna (Russia), in which mice were exposed to a set of minor γ radiation, neutrons, and a spectrum of neutrons, simulating the radiation levels that cosmonauts are exposed to during deep-space long-term missions.…”

“…In the brain, radiation was shown to deconstruct neurofilaments in a dose-dependent manner with an increase of the nSMase3 gene and protein expression. Human recombinant manganese superoxide dismutase (rMnSOD), which has a protective and preventive role on brain damage, strongly increased nSMase expression and activity [22]. Since ionizing radiation induces oxidative stress, and rMnSOD has specific antioxidant and anti-free radical activity, in the previous study, we analyzed the behavior of the nSMase3 that is stimulated in the cellular stress response [12].…”