Phlorizin Inhibits Glutamate Release from Cortical Synaptosomes and Protects against Kainic Acid-Induced Excitotoxicity in Rats

This research investigates how phlorizin, a plant-derived dihydrochalcone, modulates glutamate release in synaptosomes and exerts neuroprotective effects in a rat model of kainic acid (KA)-induced excitotoxicity. In rat cortical synaptosomes, phlorizin concentration-dependently inhibited evoked glutamate release (IC₅₀ = 14.4 μM). This effect was abolished under calcium-free conditions or by blockade of P/Q type but not N type Ca²⁺ channels. In vivo, oral phlorizin pretreatment (100 mg/kg/day, 7 days) attenuated KA-induced seizures and neurodegeneration, restored NeuN and GAP-43 expression, and normalized cortical glutamate homeostasis by regulating GLT-1, glutamine synthetase, SNAT1/3, glutaminase, and VGLUT1. It shifted NMDA receptor subunit composition toward a neuroprotective profile (increasing GluN2A/GluN2B ratio) and suppressed astrocytic IL-1β/IL-1R1/Src signaling. Furthermore, phlorizin preserved blood brain barrier integrity by increasing ZO-1 and reducing albumin extravasation and MMP-9. These results demonstrate that phlorizin exerts multifaceted neuroprotection by inhibiting synaptic glutamate release, modulating glutamate homeostasis, and suppressing neuroinflammation and barrier disruption.