MPEP ameliorates sepsis-associated delirium by modulating hippocampal mGluR5 signaling and pyramidal neuron excitability in mice.

Background: Delirium is a cerebral manifestation commonly seen in sepsis, known as sepsis-associated delirium (SAD), and is thought to be closely related to excitatory nervous system disorders. Metabotropic glutamate receptor 5 (mGluR5) is one of the important receptors in the central glutamatergic nervous system, which is widely involved in the regulation of synaptic transmission, synaptic plasticity and excitatory/inhibitory balance. The inhibition of mGluR5 is considered as a potential drug target for reversing excitatory nervous system disorders. However, whether blocking mGluR5 signaling can be used as a treatment for SAD is still unknown.

Purpose: This study aimed to investigate the potential mechanisms of mGluR5 antagonist 2-methyl-6-(phenylethynyl)-pyridine (MPEP) in treating SAD by modulating hippocampal mGluR5 signaling and pyramidal neuron excitability.

Methods: LPS-induced sepsis mouse model and HT22 cells were established to evaluate the preventive effect of MPEP on SAD. Behavioral tests such as the buried food test (BFT), open field test (OFT) and Y-maze test, combined with cortical electroencephalogram (EEG) detection, were used to assess SAD. Magnetic resonance imaging (MRI) was used to assess changes in hippocampal Glu metabolism and perfusion. The hippocampus was extracted for assays, including ELISA for glutamate (Glu) level, RT-qPCR for mGluR5 mRNA expression, WB for mGluR5 protein expression, IF for mGluR5 intensity, and TUNEL staining for apoptosis of pyramidal cells, as well as Nissl and Golgi staining for neuronal damage. In addition, fiber-optic Ca imaging, microelectrode array (MEA), and whole-cell patch clamp in hippocampal CA1 region were used to assess changes in pyramidal neuron activity and synaptic transmission.

Results: 10 mg/kg MPEP alleviated LPS-induced delirium-like behaviors, such as a 41 % reduction in the latency to eat food in the BFT, a 97 % increase in the time spent in the central area in the OFT, and 195 % and 267 % increase in the entries into the novel arm and the duration in the novel arm in the Y-maze test, respectively. MPEP with 10 mg/kg reduced the high expression of mGluR5 and the increase in Ca activity in pyramidal neurons in the hippocampal CA1 region, repaired neuronal damage, and decreased excitatory synaptic transmission in LPS-induced sepsis mice.

Conclusion: This study suggests that MPEP alleviates SAD by blocking the mGluR5 signaling, thereby reducing excitotoxic damage to hippocampal CA1 pyramidal neurons. These findings support further exploration of MPEP as a candidate drug for the clinical treatment of SAD from the preclinical level.