Continuous Pyruvate Supplementation Enhances Neuroprotective Resilience Against Kainate-Induced Status Epilepticus Through Metabolic Preconditioning.

Refractory status epilepticus refers to persistent and recurrent seizures unresponsive to medication, often leading to neuronal injury and neurobehavioral deficits. Studies have demonstrated that intraperitoneal bolus administration of pyruvate attenuates neuronal damage in rodent models of chemically induced status epilepticus (SE), while the precise neuroprotective mechanism remains to be further explored. This study investigated the neuroprotective effects of long-term supplementation with exogenous pyruvate against SE. When male C57BL/6 mice received 3% sodium pyruvate (SP) in the drinking water ad libitum for 20 weeks, they exhibited elevated levels of essential neurochemicals and energy metabolites in the brain compared to the control mice that received the equimolar saline solution. Following the intraperitoneal administration of kainate (KA) to induce severe SE, the SP-fed mice showed enhanced resistance to seizure activity, reduced neuronal injury, and improved neurobehavioral performance compared to the saline-fed mice. Regarding the molecular mechanisms underlying their neuroprotective properties, the levels of pyruvate metabolism-mediating proteins, neuronal and synaptic proteins, and neuroprotective proteins remained upregulated in the brains of the SP-fed mice following KA-induced SE. Conversely, the levels of pro-apoptotic and oxidative stress markers were suppressed. Collectively, this study indicates that long-term pyruvate supplementation may sustainably augment neurochemical and energy metabolism in the normal brain, thereby eliciting intrinsic neuroprotective properties. These effects contribute to preventing or ameliorating seizure activity, neuronal damage, and neurobehavioral deficits in mice following KA-induced SE, suggesting its prophylactic or therapeutic potential against epileptic seizures and SE through metabolic preconditioning.