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• PPZM exhibited significant scavenging activity of DPPH and OH free radicals in vitro. • PPZM effectively against H 2 O 2 -induced cell damage by decreasing LDH and MDA release, and increasing SOD activity. • The neuroprotective effects of PPZM may be involved in the inhibition of mitochondria-dependent apoptosis. • PPZM can be used as the source of natural antioxidants and neuroprotective agents. The pericarp of Zanthoxylum bungeanum Maxim (PZM) is one of eight fascinating condiments and also used as a traditional herbal medicine to treat a variety of diseases. In this study, ultrasound-assisted extraction (UAE) was applied for the extraction of polysaccharides from PZM (PPZM) and the extraction conditions were optimized by response surface methodology (RSM). The obtained PPZM yield (2.60 ± 0.06%) was closely agreed with the predicted value (2.58%), and the optimal extraction conditions obtained were: liquid to solid ratio of 32 mL/g, extraction time of 42 min, and extraction temperature of 61 °C. PPZM was determined to be composed of mannose (Man), rhamnose (Rha), galacturonic acid (GalA), glucose (Glu), galactose (Gal), arabinose (Ara) with a molar ratio of 4.93: 5.03: 71.01: 16.01: 24.87: 18.79, and the average molecular weight (Mw) of PPZM was 1.72 × 105 Da. Typical polysaccharide characteristics were determined by fourier transform infrared spectroscopy (FT-IR). PPZM exhibited remarkable antioxidant activities in vitro. More importantly, PPZM effectively protected adrenal phaeochromocytoma PC12 cells against H 2 O 2 -induced damage by inhibiting the release of lactate dehydrogenase (LDH) and malondialdehyde (MDA), increasing the level of superoxide dismutase (SOD), and inhibiting abnormal apoptosis. Further experiments indicated that the anti-apoptotic effects of PPZM were closely related to down-regulating the expressions of Bax and Caspase-3, and up-regulating the expression of Bcl-2. Therefore, PPZM can be used as the source of natural antioxidants and neuroprotective agents. [ABSTRACT FROM AUTHOR]