Objective To investigate the effect of adenosine A2A receptor antagonist on a rat model of lithium-pilocarpine status epilepticus (SE).Methods A total of 50 WD rats were randomly divided into control group, model group, and A2A receptor antagonist group. The rats in the model group were given intraperitoneal injection of chloride lithium-pilocarpine to establish a rat model of epilepsy, those in the A2A receptor antagonist group were given intraperitoneal administration of SCH58261 at a dose of 0.05 mg/kg before chloride lithium-pilocarpine injection, and those in the control group were given normal saline at the same dose. All rats were given diazepam and chloride aldehyde to terminate seizures at 40 minutes after successful induction of seizures, and samples were collected at 24 hours after termination of seizures. Nissl staining was used to observe hippocampal neuronal damage in the three groups, and Western blot was used to measure the changes in the expression of mitogen-activated protein kinases (JNK/p-JNK, P38/p-P38, and ERK/p-ERK).Results The number of normal neurons in the bilateral hippocampal CA3 region was 158.6±8.4 in the control group, 59.8±7.4 in the model group, and 123.4±5.0 in the A2A receptor antagonist group; the model group had a significantly lower number than the control group (P<0.05), and the A2A receptor antagonist group had a significantly higher number than the model group (P<0.05). Western blot showed that the model group had significant increases in the expression of p-JNK, p-P38, and p-ERK, while the A2A receptor antagonist group had significant reductions in the expression of p-JNK and p-P38.Conclusions In the lithium-pilocarpine model, adenosine A2A receptor antagonist has a protective effect against neuronal damage, possibly by inhibiting the expression of p-JNK and p-p38.