Abstract WP309: UDP-Glucose Exacerbates Neuronal Apoptosis via Its Receptor P2y14 After Subarachnoid Hemorrhage in Rats

Abstract

Introduction: Subarachnoid hemorrhage (SAH) is a severe subtype of stroke that can lead to poor outcomes. Recent studies reported that uridine diphosphate glucose (UDP-G), one of the intermediates in glucose/glycogen metabolism, can be released from damaged cells and proceed with pathologic conditions by activating the purinergic P2Y14 receptor. This study aimed to elucidate the role of brain UDP-G/P2Y14 signaling after SAH. Hypothesis: The inhibition of the brain UDP-G/P2Y14 signaling pathway would attenuate neuronal apoptosis and neurological deficits after SAH in rats. Methods: A total of 200 adult male Sprague Dawley rats were used. Endovascular perforation method was used to induce SAH. The time course changes of CSF UDP-G, brain protein levels of UDP-G converting enzyme UDP-G pyrophosphorylase-2 (UGP2) and P2Y14 receptors, as well as the brain cell types expressing P2Y14 were examined. A selective P2Y14 receptor inhibitor PPTN hydrochloride or exogenous UDP-G was administered intranasally 1 hour after SAH. SAH grading, neurological evaluation, immunofluorescence, TUNEL staining, Nissl staining, western blot, and liquid chromatography-mass spectrometry were performed. Results: Endogenous CSF UDP-G and brain UGP2 were increased at 3 hours and 6 hours after SAH. The protein level of the brain P2Y14 receptor was not changed temporally and was mainly expressed in neurons 24 hours after SAH. PPTN hydrochloride decreased but exogenous UDP-G aggravated the number of TUNEL-positive neurons, brain protein levels of proapoptotic molecules such as cleaved caspase 3, and modified Garcia neurological score at 24 hours after SAH. Early inhibition of P2Y14 receptor signaling by PPTN hydrochloride preserved the numbers of Nissl staining identified surviving neurons in the hippocampus, amygdala, and cortex with improved water maze learning performance and depressive-like behavior at 1-month post-SAH. Conclusion: Brain UDP-G/P2Y14 receptor signaling activation plays a detrimental role after SAH, as a part of glucose metabolic pathology at the tissue level. P2Y14 receptor inhibitor reduced neuronal apoptosis and improved neurological deficits after SAH, which may serve as potential therapeutics in treating patients with SAH.