Xenon Exerts Neuroprotective Effects on Kainic Acid-Induced Acute Generalized Seizures in Rats via Increased Autophagy

Abstract

Xenon has been shown to have neuroprotective effects and is clinically used as a favorable safe inhalation anesthetic. We previously confirmed the neuroprotective effects of xenon treatment in epileptic animals. However, the mechanism underlying these protective effects remains unclear. We aimed to assess the effects of xenon inhalation on autophagy in neuronal injury induced by acute generalized seizures. Kainic acid (KA) was injected into the lateral ventricle of male Sprague–Dawley rats to induce acute generalized seizures. Next, the rats were treated via inhalation of a 70% xenon/21% oxygen/9% nitrogen mixture for 60 min immediately after KA administration. The control group was treated via inhalation of a 79% nitrogen/21% oxygen mixture. Subsequently, two inhibitors (3-methyladenine or bafilomycin A 1 ) or an autophagy inducer (rapamycin) were administered, respectively, before KA and xenon administration to determine the role of autophagy in the protective effects of xenon. The levels of apoptosis, neuronal injury, and autophagy were determined in all the rats. Xenon inhalation significantly attenuated the severity of the seizure-induced neuronal injury. Increased autophagy accompanied this inhibitive effect. Autophagy inhibition eliminated these xenon neuroprotective effects. A simulation of autophagy using rapamycin recapitulated xenon’s protective effects on KA-induced acute generalized seizures in the rats. These findings confirmed that xenon exerts strong neuroprotective effects in KA-induced acute generalized seizures. Further, they indicate that increased autophagy may underlie the protective effects of xenon. Therefore, xenon and autophagy inducers may be useful clinical options for their neuroprotective effects in epileptic seizures.

Xenon attenuates hypoxic-ischemic brain damage by inhibiting autophagy in neonatal rats

“…Our data were consistent with previous reports that neuron autophagy induced by hypoxic-ischemia contributes to acute brain injury [5,24], supporting the notion that inhibition of neuron autophagy protects from HIBD in neonatal rats. Given that aberrant autophagy has been thought to participate in the pathogenesis of human diseases, including neurodegenerative diseases, such as Parkinson’s disease and Alzheimer’s disease [16], infectious and autoimmune diseases and various types of cancers [25] the inhibition of autophagy by Xe suggests that Xe may be valuable for the treatment of these chronic diseases. However, our findings were different from another report that induction of neuron autophagy reduces brain damage [8].…”

“…Mechanistically, Xe can act as an antagonist of N-methyl-D-aspartate (NMDA) receptor, inhibitor of apoptosis, inhibiting potassium channel and others [13][14][15]. A recent study reveals that inhaling 70% Xe for 60 min significantly reduces the severity of neuronal damage caused by epilepsy [16]. However, the effect of Xe on neuroprotection in infants remains controversial [17,18] and whether Xe can modulate aberrant neuron autophagy and protect from HIBD in neonates has not been clarified.…”

Noble gases and neuroprotection: summary of current evidence

“…a current study on xenon and argon using oxygen-glucose deprivation in a hippocampal slice model [10]). Surveying the current literature on neuroprotection by noble gases, more articles on xenon [13 ▪▪ ,15 ▪▪ ,18,21 ▪ ,22,23,25,26] compared with argon [16 ▪ ,17,19 ▪ ,20,24 ▪▪ ] were found and experimental studies dominated the recent output (only one clinical study evaluating xenon was found [15 ▪▪ ]).…”

“…A PubMed search [21 March 2021; search strategy: neuroprotection AND (argon OR xenon OR noble gas)] revealed 23 articles, of which 10 had to be excluded (reviews: n = 6 reviews; technical reports: n = 3, editorial: n = 1). Thus, the results of 10 current original articles on neuroprotection derived by argon and xenon application [13 ▪▪ ,15 ▪▪ ,16 ▪ ,17,18,19 ▪ ,20,21 ▪ ,22,23,24 ▪▪ ,25,26] are summarized and integrated…”

Attenuated iron stress and oxidative stress may participate in anti-seizure and neuroprotective roles of xenon in pentylenetetrazole-induced epileptogenesis

“…Xenon can inhibit synchronous neuronal firing ( Uchida et al, 2012 ) and reduce neuronal damage caused by hyperexcitability by regulating glutamate metabolism ( Lavaur et al, 2016a , b ). Our previous studies demonstrated that xenon can inhibit seizures, neuronal damage, and cognitive deficits in kainic acid-induced status epilepticus and hypoxia-induced seizures ( Zhang et al, 2019 ; Zhang M. et al, 2020 ; Zhu et al, 2020 ). Our previous findings and results of other studies suggest that xenon may exert anti-seizure and neuroprotective effects during epileptogenesis.…”