Neurokinin-1 Receptor Antagonist Reverses Functional CNS Alteration Caused by Combined γ-rays and Carbon Nuclei Irradiation

Abstract

Background: Ionizing Radiation (IR) is one of the major limiting factors for human deep-space missions. Preventing IR-induced cognitive alterations in astronauts is a critical success factor. It has been shown that cognitive alterations in rodents can be inferred by alterations of a psycho- emotional balance, primarily an anxiogenic effect of IR. In our recent work, we hypothesized that the neurokinin-1 (NK1) receptor might be instrumental for such alterations. Objective: The NK1 receptor antagonist rolapitant and the classic anxiolytic diazepam (as a comparison drug) were selected to test this hypothesis on Wistar rats. Method: Pharmacological substances were administered through intragastric probes. We used a battery of tests for a comprehensive ethological analysis. High-performance liquid chromatography was applied to quantify monoamines content. An analysis of mRNA expression was performed by real-time PCR. Protein content was studied by the Western blotting technique. Results: Our salient finding includes no substantial changes in anxiety, locomotor activity and cognitive abilities of treated rats under irradiation. No differences were found in the content of monoamines. We discovered a synchronous effect on mRNA expression and protein content of 5- HT2a and 5-HT4 receptors in the prefrontal cortex, as well as decreased content of serotonin transporter and increased content of tryptophan hydroxylase in the hypothalamus of irradiated rats. Rolapitant affected the protein amount of a number of serotonin receptors in the amygdala of irradiated rats. Conclusion : Rolapitant may be the first atypical radioprotector, providing symptomatic treatment of CNS functional disorders in astronauts caused by IR.

The Effects of Galactic Cosmic Rays on the Central Nervous System: From Negative to Unexpectedly Positive Effects That Astronauts May Encounter

“…On the one hand, rapid habituation correlates positively with OEB [ 91 , 92 ] and adaptive, nonpathological anxiety [ 93 ], which fully corresponds to the emotional status of animals irradiated at space-related doses. The direction of this correlation is also confirmed in the study, which showed the absence of irradiation effects on habituation against the background of anxiolytic therapy [ 82 ]. On the other hand, in both humans and animals, the disruption of habituation is strongly correlated with cognitive impairments [ 94 , 95 ] and vice versa [ 93 , 96 ].…”

“…Recently, the involvement of the neurokinin-1 receptor in the IR-induced anxiogenic effect has been confirmed pharmacologically. At the same time, downregulation of 5-HT 2c serotonin receptor expression in the amygdala as well 5-HT 4 in the hypothalamus can be considered as a neuro-adaptive anxiolytically-orientated response of nerve tissue [ 82 ]. Thereby, due to the anti-anxiety molecular changes, the anxiogenic effect of irradiation is probably not persistent.…”

“…Irradiation by H + leads to neutral or even enhancing recognition memory in doses of 0.5 or 1 Gy (0.2 or 0.5 keV/µm) [ 97 , 119 ]. More space-related combined irradiation ( 12 C, 0.14 Gy, 10.3 keV/µm and 0.4 Gy γ-rays) did not affect the recognition memory [ 9 ] or even enhanced it ( 12 C, 0.16 Gy, 10.3 keV/µm, and 0.3 Gy γ-rays) on the anxiolytic therapy background [ 82 ]. Mixed HZE irradiation at space-related dose 0.25 Gy did not affect the recognition memory, but impairment was observed at higher (0.5 or 2 Gy) doses [ 55 ].…”

Neurokinin‐1 receptor antagonist rolapitant suppresses anxiety and alcohol intake produced by repeated withdrawal episodes

“…Since rats exhibit increased anxiety‐like behaviour after exposure to repeated withdrawal episodes we hypothesized that the effectiveness of rolapitant treatment in reducing alcohol intake following withdrawal may be due to its anxiolytic activity. Indeed, NK1r antagonists have been found to exert anxiolytic‐like effects [20], although less pronounced than those reported for benzodiazepines [21]. It is well known that chronic alcohol consumption increases stress reactivity [22,23] and promotes anxiety disorders [24], which, in turn, contributes to the maintenance of and relapse to pathological alcohol use [25].…”

“…However, other mechanisms such as modulation of serotonergic and noradrenergic systems may also be involved in NK1‐mediated anxiolytic effects [32]. It has been found that rolapitant reduces the monoaminergic‐dependent overactivation of the hypothalamic–pituitary–adrenal axis [21]. Another explanation of rolapitant’s effects on alcohol intake comes from a series of studies of NK1r antagonists as a promising medication for neuroinflammatory disease treatment [33].…”