Inhibition of Calcium-Sensing Receptor Alleviates Chronic Intermittent Hypoxia-Induced Cognitive Dysfunction via CaSR-PKC-ERK1/2 Pathway.

Obstructive sleep apnea-hypopnea syndrome (OSAHS) is typically characterized by chronic intermittent hypoxia (CIH), associated with cognitive dysfunction in children. Calcium-sensing receptor (CaSR) mediates the apoptosis of hippocampal neurons in various diseases. However, the effect of CaSR on OSAHS remains elusive. In the present study, we investigated the role of CaSR in CIH-induced memory dysfunction and underlying mechanisms on regulation of PKC-ERK1/2 signaling pathway in vivo and in vitro. CIH exposures for 4 weeks in mice, modeling OSAHS, contributed to cognitive dysfunction. CIH accelerated apoptosis of hippocampal neurons and resulted in the synaptic plasticity deficit via downregulated synaptophysin (Syn) protein level. The mice were intraperitoneally injected with CaSR inhibitor (NPS2143) 30 min before CIH exposure and the results demonstrated CaSR inhibitor alleviated the apoptosis and synaptic plasticity deficit in the hippocampus of CIH mice. We established intermittent hypoxia PC12 cell model and found that the activation of CaSR accelerated CIH-induced PC12 apoptosis and synaptic plasticity deficit by upregulated p-ERK1/2 and PKC. Overall, our findings revealed that CaSR held a critical function on CIH-induced cognitive dysfunction in mice by accelerating hippocampal neuronal apoptosis and reducing synaptic plasticity via augmenting CaSR-PKC-ERK1/2 pathway; otherwise, inhibition of CaSR alleviated CIH-induced cognitive dysfunction.

Caffeine excites medial parabrachial nucleus neurons of mice by blocking adenosine A1 receptor.

Caffeine has been used as a first-line drug for treatment of apnea neonatorum for decades due to its high safety and effectiveness. Studies report that caffeine mainly acts as a blocker of Adenosine Receptors (ARs). However, the mechanism of caffeine in reducing apnea neonatorum in the central nervous system has not been fully explored. Medial parabrachial nucleus (MPB) is part of the respiratory center of the pons that may be related to the activity of caffeine. Previous studies have not explored the effect and mechanism of caffeine on MPB neurons. To elucidate this, the current study used antagonists of A1 and A2a receptors to mimic the effect of caffeine in MPB of mice in vitro using the patch-clamp technique. The firing rates and spontaneous post-synaptic currents were recorded. The findings of the study showed that caffeine excited MPB neurons. Notably, the adenosine A1R antagonist 8-cyclopentyl-1,3-dimethyl-xanthine (CPT) but not the adenosine A2aR antagonist Istradefylline (KW6002) mimicked the exciting effect of caffeine, implying that caffeine excited MPB neurons in mice by blocking A1Rs. Further, the results indicated that caffeine could increase efficiency of synaptic transmission to excite MPB neurons. These findings suggest that A1Rs in MPB may be potential targets for caffeine in reducing apnea neonatorum.

Prediction of drug capturing by lipid emulsions in vivo for the treatment of a drug overdose.

Despite the successful treatment of drug intoxications, little information is available to quantitively predict the effect of lipid emulsions on pharmacokinetic features of overdosed drug molecules. We defined two new parameters, drug accommodation capacity and drug capture kinetics, to characterize the drug capture capability of lipid emulsions. By precisely characterizing their drug capture capability, the effect of lipid emulsions on pharmacokinetic features of overdosed drug molecules was quantitively described. This quantitative description enabled an accurate prediction of the reducing extent on the half-life and area under drug concentration-time curve, which was verified by the successful treatment of overdosed propafenone. Moreover, the capture effect prediction using drug capture capability was more accurate than that of directly using logP. Overall, the developed capture capability accurately described the effect of lipid emulsions on drug pharmacokinetic features, which can guide the clinical application of lipid emulsions for the treatment of drug overdose.

Blockade of adenosine A2A receptor alleviates cognitive dysfunction after chronic exposure to intermittent hypoxia in mice.

Obstructive sleep apnea-hypopnea syndrome (OSAHS) is widely known for its multiple systems damage, especially neurocognitive deficits in children. Since their discovery, adenosine A2A receptors (A2ARs) have been considered as key elements in signaling pathways mediating neurodegenerative diseases such as Huntington's and Alzheimer's, as well as cognitive function regulation. Herein, we investigated A2AR role in cognitive impairment induced by chronic intermittent hypoxia (CIH). Mice were exposed to CIH 7 h every day for 4 weeks, and intraperitoneally injected with A2AR agonist CGS21680 or A2AR antagonist SCH58261 half an hour before IH exposure daily. The 8-arm radial arm maze was utilized to assess spatial memory after CIH exposures.To validate findings using pharmacology, the impact of intermittent hypoxia was investigated in A2AR knockout mice. CIH-induced memory dysfunction was manifested by increased error rates in the radial arm maze test. The behavioral changes were associated with hippocampal pathology, neuronal apoptosis, and synaptic plasticity impairment. The stimulation of adenosine A2AR exacerbated memory impairment with more serious neuropathological damage, attenuated long-term potentiation (LTP), syntaxin down-regulation, and increased BDNF protein. Moreover, apoptosis-promoting protein cleaved caspase-3 was upregulated while anti-apoptotic protein Bcl-2 was downregulated. Consistent with these findings, A2AR inhibition with SCH58261 and A2AR deletion exhibited the opposite result. Overall, these findings suggest that A2AR plays a critical role in CIH-induced impairment of learning and memory by accelerating hippocampal neuronal apoptosis and reducing synaptic plasticity. Blockade of adenosine A2A receptor alleviates cognitive dysfunction after chronic exposure to intermittent hypoxia in mice.