Neonatal inhibition of Na + -K + -2Cl − -cotransporter prevents ketamine induced spatial learning and memory impairments

Abstract

Prolonged ketamine exposure in neonates at anesthetic doses is known to cause long-term impairments of learning and memory. A current theoretical mechanism explains this phenomenon as being neuro-excitotoxicity mediated by compensatory upregulation of N-methyl-D-aspartate receptors (NMDARs), which then initiates widespread neuroapoptosis. Additionally, the excitatory behavior of GABAergic synaptic transmission mediated by GABA A receptors (GABA A Rs), occurring during the early neuronal development period, is proposed as contributing to the susceptibility of neonatal neurons to ketamine-induced injury. This is due to differential developmental expression patterns of Na + -K + -2Cl − co-transporter (NKCC1) and K + -Cl − cotransporter. Studies have shown that bumetanide, an NKCC1 inhibitor, allows neurons to become inhibitory rather than excitatory early in development. We thus hypothesized that bumetanide coadministration during ketamine treatment would reduce over excitation and protect the neurons from excitotoxicity. In this initial study, the Morris Water Maze test was used to assess the effects of co-administration of ketamine and bumetanide to neonatal Sprague-Dawley rats on long-term learning and memory changes seen later in life. It was revealed that bumetanide, when co-treated with ketamine neonatally, significantly impeded behavioral deficits typically seen in animals exposed to ketamine alone. Therefore, these findings suggest a new mechanism by which neonatal ketamine induced learning impairments can be prevented.

WNK1 Antagonist Decreased Sevoflurane-induced Neurotoxicity in HT22 Hippocampal Neurons via the WNK1/NKCC1 Signalling Pathway

“…The toxicity of sevo urane was demonstrated more intuitively at the cellular level. These results were similar to the ndings of many studies [19] .…”

“…receptor. Currently, relevant mechanisms have been shown, such as the hypothesis of neurotrophic apoptosis [2,3] , mitochondrial damage and accumulation of ROS [23] , the effect of in ammatory factors [16,24] , the excitatory neurotoxicity hypothesis [3] , the effects on the regeneration of neurons, changes in receptor subtypes [18] , and changes in ion concentration [19][20][21][22][23][24][25] . In our previous study, we found that sevo urane can induce neuroapoptosis in neonatal rats and cause behavioural changes during development, and that GABA A R played a role in sevo urane's neurotoxicity in the developing brain [18] .…”

Ketamine administered pregnant rats impair learning and memory in offspring via the CREB pathway

“…Experimental evidence indicates that the NMDAR antagonist ketamine impairs cognition [19]. Prolonged ketamine exposure in neonates at anesthetic doses has been reported to cause long-term impairments of learning and memory [20]. Furthermore, ketamine decreased p-CREB in the hippocampus [21, 22], and decreased levels of BDNF [23].…”

WNK1 Antagonist Decreased Sevoflurane-induced Neurotoxicity in HT22 Hippocampal Neurons via the WNK1/NKCC1 Signalling Pathway

“…Most general anaesthetics are excitants of GABA A R and inhibitors of the N-methyl-D-aspartate (NMDA) receptor. Currently, many studies demonstrated that neurotrophic apoptosis [2,3] , mitochondrial damage and accumulation of ROS [23] , in ammatory factors [16,24] , the excitatory neurotoxicity [3] , the effects on the regeneration of neurons, changes in receptor subtypes [18] were the possible mechanisms of general anaesthetics' neurotoxicity [19][20][21][22][23][24][25] . In the present study, we found that exposure of sevo urane caused neuron apoptosis and decreased cell vitality, which was consistent with the above conclusions.…”