Ceftriaxone affects ferroptosis and alleviates glial cell activation in Parkinson's disease

Parkinson's disease (PD) is the second most common neurodegenerative disorder, which is characterized by the death of dopaminergic neurons. It has been reported that ceftriaxone (CEF) exerts promising effects on alleviating dopaminergic neuron death in PD models. However, the neuroprotective mechanisms of CEF in PD have not been well understood. In the present study, to investigate the neuroprotective effects of CEF through western blot and immunofluorescence assays, two in vivo models were established, namely the 1‑methyl‑4‑phenyl‑1,2,3,6‑tetrahydropyridine (MPTP)‑ and lipopolysaccharide (LPS)‑induced models. Additionally, three in vitro models were used to explore the neuroprotective mechanisms of CEF, namely the 1‑methyl‑4‑phenylpyridinium ion (MPP+)‑induced dopaminergic neuron injury, LPS‑induced microglia activation and TNFα‑induced astrocyte activation models, with key insights derived from western blot and qPCR experiments. The in vivo studies demonstrated that CEF exerted neuroprotective effects and reduced glial cell activation. Additionally, CEF reversed the reduction of Tyrosine Hydroxylase and suppressed the activation of microglia and astrocytes. Furthermore, the in vitro experiments revealed that CEF could display both direct and indirect neuroprotective effects and could directly alleviate MPP+‑induced neuronal toxicity and suppress the activation of microglia and astrocytes. In addition, CEF indirectly reduced neuronal injury caused by conditioned medium from activated microglia and astrocytes. Mechanistic studies revealed that CEF inhibited the Ferroptosis pathway via regulating the expression of solute carrier family 7 member 11 and Glutathione Peroxidase 4 in a non‑cell‑specific manner. Via inhibiting Ferroptosis, CEF could directly protect dopaminergic neurons and prevent glial cell activation, and indirectly impair neurons. In conclusion, the results of the current study highlighted the potential research and therapeutic value of CEF in regulating Ferroptosis in PD.

Parkinson's disease; astrocyte; ceftriaxone; ferroptosis; glutathione peroxidase 4; microglia; neuroinflammation; solute carrier family 7 member 11.