SCAP-derived exosomes restore excitatory-inhibitory balance and attenuate glutamate-induced excitotoxicity via modulation of GABAergic signaling.

Glutamate-induced excitotoxicity is a major pathological mechanism underlying epilepsy and other neurological disorders and is characterized by disruption of the balance between excitatory glutamatergic and inhibitory GABAergic neurotransmission. Although mesenchymal stem cell-derived exosomes have shown neuroprotective potential, the therapeutic effects and mechanisms of stem cell of the apical papilla-derived exosomes (SCAP-exo) remain largely unexplored. Here, SCAP-derived exosomes were isolated and characterized by the expression of the canonical exosomal markers CD63, CD81, Hsp70, and TSG101, and their neuroprotective effects were evaluated in a glutamate-induced PC12 excitotoxicity model. SCAP-exo significantly improved cell viability (48%-80%), reduced lactate dehydrogenase release, intracellular Ca2⁺ accumulation, and tumor necrosis factor-α secretion, and restored GABA and serotonin (5-HT) levels. Mechanistically, SCAP-exo coordinately enhanced inhibitory GABAergic signaling by upregulating GABA_A receptor α1 subunit and glutamate decarboxylase 65 while suppressing GABA transporter 1, and simultaneously attenuated excitatory glutamatergic signaling through downregulation of N-methyl-D-aspartate receptor 1. This coordinated regulation restored excitatory-inhibitory neurotransmitter homeostasis and attenuated downstream inflammatory and calcium-dependent excitotoxic cascades. Collectively, these findings identify SCAP-derived exosomes as a promising cell-free therapeutic strategy for excitotoxicity-related neurological disorders.