Dopamine receptor agonist pramipexole exerts neuroprotection on global cerebral ischemia/reperfusion injury by inhibiting ferroptosis

Objective: To explore the mechanism of dopamine receptor agonist pramipexole in exerting neuroprotection on global cerebral ischemia/reperfusion injury (GCI/R).

Material and method: Male Sprague-Dawley rats were randomly divided into four groups (n = 36 in each group), and the Pulsinelli's four-vessel occlusion method was used to establish the rat model of GCI/R injury. Pramipexole administration group was intraperitoneally injected with pramipexole 0.5 mg/kg once a day for 14 days. Pramipexole combined with levodopa administration group was intraperitoneally injected with pramipexole 0.5 mg/kg and levodopa 50 mg/kg once a day for 14 days. The mNSS scores and Y maze test were used to evaluate neurological behaviors. Nissl staining and transmission electron microscopy were used to respectively observe hippocampal neurons and mitochondrial ultrastructure. Molecular biological tests including tissue iron concentration, GSH, MDA were used to detect the degree of ferroptosis. Western blotting was used to detect the expression levels of Nrf2, GPX4, X-CT and p53 proteins at 3 days, 7 days and 14 days after GCI/R injury.

Results: Pramipexole alone or combined with levodopa for 14 days improved neurological behaviors, improved the morphology of neurons, increased the number of surviving neurons in the hippocampal CA1 region of GCI/R rats, which showed similar neuroprotective effects. Pramipexole alone or combined with levodopa for 14 days restored mitochondrial ultrastructure, decreased malondialdehyde concentration and increased glutathione concentration in the brain of GCI/R rats, which also induced the relative expressions of Nrf2, GPX4 and X-CT proteins and reduced p53 protein.

Conclusion: Pramipexole alone or combined with levodopa exert neuroprotection by inhibiting ferroptosis after GCI/R injury via Nrf2/GPX4/SLC7A11 pathway, and long-term intervention could be applied as an effective therapeutic strategy for neuroprotection against GCI/R injury.