Impact of Ketamine on Learning and Memory Function, Neuronal Apoptosis and Its Potential Association with miR-214 and PTEN in Adolescent Rats

Abstract

Ketamine, an N-methyl-D-aspartate (NMDA) receptor antagonist, is used as a general pediatric anesthetic and anti-depressive drug. Recent studies suggest that ketamine enhances neuronal apoptosis in developing rats. The goal of this study is to explore whether ketamine could result in learning and memory impairment and neurodegeneration in adolescent rats, and if so, whether the effects of ketamine are associated with miR-214 and PTEN expression. Fifty-day-old SD rats were randomly divided into three groups receiving ketamine at 30, or 80 mg/kg, i.p. or saline for seven consecutive days. Twenty-four hours after the last treatment, learning and memory function were tested by the Morris water maze. The rats were then decapitated, and the brains were isolated for detection of neuronal apoptosis and protein PTEN expression by TUNEL and immunohistochemistry respectively. Expression levels of the miR-214 and PTEN in the hippocampus were measured by qRT-PCR and western blot analysis respectively. Ketamine administered to the adolescent rats at a dose of 80 mg/kg rather than the lower dose of 30 mg/kg caused learning and memory impairment, increased the number of apoptotic cells in the hippocampal CA1 region, cerebral cortex and subcortical region, decreased the miR-214 levels and increased PTEN protein expression in hippocampus. The results suggest that ketamine at a dose of 80 mg/kg in the adolescent rats is able to induce the learning and memory impairment and neurodegeneration, in which the down-regulation of miR-214 and high expression of PTEN protein may be involved.

A systematic review of methodology applied during preclinical anesthetic neurotoxicity studies: important issues and lessons relevant to the design of future clinical research

“…Consistent with the above findings, isoflurane and sevoflurane exposure at PD7 and PD14 (but not at PD60) were shown to be associated with decreases in the hippocampal stem cell pool and a reduced number of dentate gyrus granule neurons (28,29). In particular, exposure of adolescent rats (PD50) to ketamine lead to apoptosis only in case of high-dose regimen administration of 80 mgÁkg À1 for 7 days (30). Likewise exposure at PD7 to propofol anesthesia was associated with reduced levels of excitatory neurotransmitters in both the cortex and the hippocampus (31), with increased caspase-3 levels in the hippocampal CA1 region suggesting that these changes were the result of apoptosis (31).…”

MicroRNA‐21 and microRNA‐214 play important role in reproduction regulation during porcine estrous

“…miR‐21 has been identified as an antiapoptotic LH‐induced factor in preovulatory GCs, and it ensures both the survival and differentiation of these cells (Carletti et al., ). The role of miR‐214 in the regulation of cell apoptosis and gonad steroidogenesis (such as progesterone) has been reported previously (Tian, Zeng, Li, Wu, & Wang, ; Wang et al., ). Here, we showed that the miR‐21 expression level increased at the same time as the LH concentration increases before, during, and 3–4 days after ovulation.…”

Changes in hippocampal AMPA receptors and cognitive impairments in chronic ketamine addiction models: another understanding of ketamine CNS toxicity

“…However, according to another study, mice exposed to the same dosing paradigm showed no deficits in learning and memory15. We hypothesized that adult mice may express learning and memory deficits with a higher concentration of long term ketamine administration, as a previous study found that adolescent rats exposed to ketamine 80 mg/kg exhibited learning and memory impairments in Morris water maze tests, rather than at the lower dose of 30 mg/kg, in a seven day administration paradigm38. Consistent with our hypothesis, the higher ketamine concentration used in this study did result in a significant spatial learning and memory impairment after six months administration instead of the three month paradigm.…”

“…did not may be due to the fact that we used adult animals (2 months old) instead of adolescent mice (1 month old); since adult mice have more well-established brain structure and defenses against neurotoxic substances than the developing or immature brain. In fact, several studies have found acute or chronic ketamine administration induced learning and memory impairment in developing or adolescent rodents more than in adulthood12131538. To exclude the effect of age in our behavioral tests results, we analyzed two control groups (Control 1 with physiological saline administration for three months and Control 2 with that for six months) and found no significant difference between the two groups.…”