No abstract

Ketamine, a dissociative anesthetic most commonly used in many pediatric procedures, has been reported in many animal studies to cause widespread neuroapoptosis in the neonatal brain after exposure in high doses and/or for prolonged period. This neurodegenerative change occurs most severely in the forebrain including the anterior cingulated cortex (ACC) that is an important brain structure for mediating a variety of cognitive functions. However, it is still unknown whether such apoptotic neurodegeneration early in life would subsequently impair the synaptic plasticity of the ACC later in life. In this study, we performed whole-cell patch-clamp recordings from the ACC brain slices of young adult rats to examine any alterations in long-term synaptic plasticity caused by neonatal ketamine exposure. Ketamine was administered at postnatal day 4–7 (subcutaneous injections, 20 mg/kg given six times, once every 2 h). At 3–4 weeks of age, long-term potentiation (LTP) was induced and recorded by monitoring excitatory postsynaptic currents from ACC slices. We found that the induction of LTP in the ACC was significantly reduced when compared to the control group. The LTP impairment was accompanied by an increase in the α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptor-mediated excitatory synaptic transmission and a decrease in GABA inhibitory synaptic transmission in neurons of the ACC. Thus, our present findings show that neonatal ketamine exposure causes a significant LTP impairment in the ACC. We suggest that the imbalanced synaptic transmission is likely to contribute to ketamine-induced LTP impairment in the ACC.

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.

No abstract

The capacity of SARS-CoV-2 to evolve poses challenges to conventional prevention and treatment options such as vaccination and monoclonal antibodies, as they rely on viral receptor binding domain (RBD) sequences from previous strains. Additionally, animal CoVs, especially those of the SARS family, are now appreciated as a constant pandemic threat. We present here a new antiviral approach featuring inhalation delivery of a recombinant viral trap composed of ten copies of angiotensin-converting enzyme 2 (ACE2) fused to the IgM Fc. This ACE2 decamer viral trap is designed to inhibit SARS-CoV-2 entry function, regardless of viral RBD sequence variations as shown by its high neutralization potency against all known SARS-CoV-2 variants, including Omicron BQ.1, BQ.1.1, XBB.1 and XBB.1.5. In addition, it demonstrates potency against SARS-CoV-1, human NL63, as well as bat and pangolin CoVs. The multivalent trap is effective in both prophylactic and therapeutic settings since a single intranasal dosing confers protection in human ACE2 transgenic mice against viral challenges. Lastly, this molecule is stable at ambient temperature for more than twelve weeks and can sustain physical stress from aerosolization. These results demonstrate the potential of a decameric ACE2 viral trap as an inhalation solution for ACE2-dependent coronaviruses of current and future pandemic concerns.