Tetramethylpyrazine mitigates ER-stress-driven ATF4/CHOP apoptosis to protect dopaminergic neurons in cellular and MPTP models of Parkinson's disease.

Parkinson's disease (PD) is a prevalent neurodegenerative disorder lacking effective disease-modifying therapies, with neuronal death critically linked to endoplasmic reticulum stress (ERS) and the activation of the activating transcription factor 4/activating transcription factor 3/C/EBP homologous protein (ATF4/ATF3/CHOP) pro-apoptotic pathway. This study investigated whether the alkaloid tetramethylpyrazine (TMP) confers neuroprotection by modulating this pathway. Our approach combined bioinformatics, which suggested ATF4 as a potential regulatory node, with mechanistic experiments in cellular (1-methyl-4-phenylpyridinium [MPP+]) and mouse (1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine [MPTP]) models of PD. In vitro, TMP protected SH-SY5Y cells from apoptosis by downregulating the ATF4 cascade; moreover, the observation that ATF4 silencing phenocopied and occluded TMP's effects confirms that its therapeutic ceiling is dictated by the ATF4 pathway. This mechanism was further explored in vivo, where TMP improved motor function and rescued dopaminergic neurons. Crucially, these therapeutic benefits were largely negated by co-administering Salubrinal (SAL), an inhibitor of eukaryotic initiation factor 2 alpha (eIF2α) dephosphorylation known to sustain ATF4 activation. These findings support a model where TMP's neuroprotective action is associated with the inhibition of the ERS-induced ATF4/CHOP apoptotic axis, highlighting this pathway as a promising therapeutic target for PD.