Therapeutic Hypothermia Increases the Expression of RNA-binding Protein Motif 3 and Attenuates Cognitive Deficits Following Cardiac Arrest in Rats.

Cardiac arrest (CA) remains a leading cause of mortality and morbidity worldwide. Cognitive deficits are common neurological sequelae among CA survivors. Preclinical and clinical studies have confirmed that therapeutic hypothermia (TH) is an effective intervention for mitigating brain injury following CA. Hypothermia induces the expression of specific small proteins, including RNA-binding motif protein 3 (RBM3), which provides neuroprotection under stress conditions. However, the role of RBM3 in TH after CA has not been fully elucidated. In this study, we investigated the role of RBM3 in attenuating cognitive deficits following hypothermic brain resuscitation. We constructed a rat model of CA and resuscitation, and used shRNA transfection to interfere with RBM3 expression to explore the underlying mechanisms of TH's effects on cognitive alterations. Rats were randomly assigned to one of five groups: sham group (Sham), CA group (CA), TH group (TH), adeno-associated virus (AAV)-shRNA-RBM3 transfection group (shRNA-RBM3), and AAV-shRNA-negative control transfection group (shRNA-control). Key synaptic regulatory proteins, dendritic spines, and synaptic ultrastructures were examined. The rats exhibited spatial learning and memory impairments in the Morris water maze test and novel object recognition task. Hypothermia increased RBM3 expression in hippocampal neurons, mitigated early brain injury, preserved dendritic spine integrity and synaptic ultrastructure, upregulated key synaptic regulatory proteins, and ameliorated cognitive impairment following resuscitation. When RBM3 expression in the hippocampus was inhibited, the beneficial effects of therapeutic hypothermia were partially reversed. Overall, our findings provide new insights into the mechanisms of hypothermia-induced neuroprotection, demonstrating that neuroplasticity and rehabilitation can be achieved following global cerebral ischemia-reperfusion injury after CA. Therefore, the RBM3-mediated cold shock pathway represents a potential target for enhancing neuroprotection and neurorehabilitation through hypothermia.