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It is estimated that abnormal accumulation of all-trans-retinal (atRAL) is a leading cause of photoreceptor degeneration in retinal degenerative diseases. Deficiency of interphotoreceptor retinoid-binding protein (IRBP), a retinoid transporter in the visual cycle, is responsible for the impaired clearance of atRAL and results in atRAL toxicity in retina. Therefore, IRBP has been proposed to be a potent target in preventing atRAL-induced photoreceptor degeneration. In this study, the neuroprotective effect of tetramethylpyrazine (TMP) against atRAL toxicity in the differentiated Y-79 cells, a in vitro model of photoreceptor, was first investigated. Our findings showed that atRAL could induce cytotoxicity, oxidative/nitrosative stresses, apoptosis and leukostasis in the differentiated Y-79 cells; however, the pre-treatment of TMP significantly attenuated such effects in a dose-dependent manner. Furthermore, our results indicated that TMP exerted its neuroprotective effect mainly through upregulating IRBP expression. The present study significantly contributes to better understanding the important role of IRBP in retinal degenerative diseases and forms the basis of the therapeutic development of TMP in such diseases in the future.TMP attenuates atRAL-induced cytotoxicity in the differentiated Y-79 cells.TMP attenuates atRAL toxicity through suppressing oxidative/nitrosative stresses, apoptosis and leukostasis.The neuroprotective effect of TMP against atRAL toxicity is mediated through upregulating IRBP expression.