Spermidine, a naturally occurring polyamine, is involved in various internal biological functions, due to its antioxidant and anti-inflammatory properties. A decreased level of polyamines is associated with aging and neurodegenerative disorders including Huntington disease (HD). 3-Nitropropanoic acid (3-NP) induces a spectrum of HD-like neuropathologies in rat striatum and thus serves as a good experimental model of HD. Therefore, the aim of the present study was to investigate whether spermidine confers neuroprotection against 3-NP-induced striatal toxicity and to explore its possible mechanism.Rats were administered 3-NP (10mg/kg/day, i.p.) for 21 days. Spermidine (5 and 10mg/kg/day, p.o.) was administered once a day 1h before 3-NP treatment for 21 days. Body weight and behavioral observations were recorded at weekly intervals after continuous 3-NP treatment. On the 22nd day, the animals were sacrificed, and the rat striatum was isolated for the estimation of biochemical parameters (lipid peroxidation (LPO), glutathione (GSH), and nitrite), determination of pro-inflammatory cytokine levels (tumor necrosis factor (TNF)-α and interleukin (IL)-6 and IL-1β), and neurochemical analysis (gamma-aminobutyric acid (GABA), glutamate, dopamine (DA), norepinephrine (NE), 5-HT, 3,4-dihydroxyphenylacetic acid (DOPAC), homovanillic acid (HVA), 5-hydroxyindoleacetic acid (5-HIAA), adenosine, inosine, and hypoxanthine).The findings of the present study demonstrate significant alterations in motor coordination, oxidative defense, and the levels of pro-inflammatory mediators (TNF-α, IL-6, and IL-1β) and striatal neurotransmitters upon 3-NP treatment. Pretreatment with spermidine significantly attenuated 3-NP-induced alterations in motor coordination, oxidative stress, and the levels of neuroinflammatory markers and striatal neurotransmitters.Our findings suggested that spermidine exerted a potential neuroprotective effect in a 3-NP model of HD, which may provide insight into the therapeutic potential of spermidine for HD.