Abstract
Administration of subanesthetic doses of ketamine during brain maturation represents a tool to mimic an early insult to the central nervous system (CNS). The cerebellum is a key player in psychosis pathogenesis, to which oxidative stress also contributes. Here, we investigated the impact of early celastrol administration on behavioral dysfunctions in adult mice that had received ketamine (30 mg/kg i.p.) at postnatal days (PNDs) 7, 9, and 11. Cerebellar levels of 8-hydroxydeoxyguanosine (8-OHdG), NADPH oxidase (NOX) 1 and NOX2, as well as of the calcium-binding protein parvalbumin (PV), were also assessed. Furthermore, celastrol effects on ketamine-induced alterations of proinflammatory (TNF-α, IL-6 and IL-1β) and anti-inflammatory (IL-10) cytokines in this brain region were evaluated. Early celastrol administration prevented ketamine-induced discrimination index decrease at adulthood. The same was found for locomotor activity elevations and increased close following and allogrooming, whereas no beneficial effects on sniffing impairment were detected. Ketamine increased 8-OHdG in the cerebellum of adult mice, which was also prevented by early celastrol injection. Cerebellar NOX1 levels were enhanced at adulthood following postnatal ketamine exposure. Celastrol per se induced NOX1 decrease in the cerebellum. This effect was more significant in animals that were early administered with ketamine. NOX2 levels did not change. Ketamine administration did not affect PV amount in the cerebellum. TNF-α levels were enhanced in ketamine-treated animals; however, this was not prevented by early celastrol administration. While no changes were observed for IL-6 and IL-1β levels, ketamine determined a reduction of cerebellar IL-10 expression, which was prevented by early celastrol treatment. Our results suggest that NOX inhibition during brain maturation prevents the development of psychotic-like behavioral dysfunctions, as well as the increased cerebellar oxidative stress and the reduction of IL-10 in the same brain region following ketamine exposure in postnatal life. This opens novel neuroprotective opportunities against early detrimental insults occurring during brain development.
Highlights
The recreational use of the N-methyl-D-aspartate receptor (NMDA-R) antagonist ketamine, at subanesthetic doses, has been widely reported to cause psychedelic effects in humans [1].the development of a psychotic-like state has been described following prolonged assumption of this psychoactive compound [2,3]
To the possible effects of early celastrol administration on cognitive dysfunctions induced by ketamine exposuretheinpossible postnatal life,ofwe performed
While no differences were detected in the discrimination index among saline, dimethyl sulfoxide (DMSO) and celastrol-treated mice, a significant decrease of this parameter was dimethyl sulfoxide (DMSO)
Summary
The recreational use of the N-methyl-D-aspartate receptor (NMDA-R) antagonist ketamine, at subanesthetic doses, has been widely reported to cause psychedelic effects in humans [1]. Enhanced levels of NOX1 enzyme have been reported in neuropsychiatric diseases characterized by psychotic symptoms [29,30], and increased NOX2 expression was observed in specific brain regions, such as the prefrontal cortex and nucleus accumbens of environmental [19,31,32] and pharmacologic rodent models of psychosis, including the one obtained by ketamine administration in adult mice [33,34,35]. We evaluated early of this compound on ketamine-induced oxidative stress, as well as on NADPH oxidase expression celastrol effects on possible ketamine-induced changes of proinflammatory Alpha (TNF-ɑ), interleukin-6 interleukin-1 beta (IL-1β)), as well as anti-inflammatory [interleukin-10 (IL-10)] cytokines in the same brain region
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