Intracerebral ifenprodil enhances autophagy function in 6-OHDA-lesioned rats to provide synaptic plasticity.

Progressive degeneration of dopamine neurons in the substantia nigra is the primary pathological abnormality in Parkinson's disease (PD). It has been demonstrated that overactivation of glutamatergic neurons leads to excessive accumulation of intracellular calcium and impairs autophagy. To assess the neuroprotective effects of ifenprodil, rats with 6-hydroxydopamine (6-OHDA)-induced injuries were administered ifenprodil either intraperitoneally (I.P.) or directly into the caudate-putamen (CPU) and substantia nigra pars reticulata (SNr). The results indicate that ifenprodil increases motor function in 6-OHDA-lesioned rats. Furthermore, ifenprodil enhances tyrosine hydroxylase (TH) neuron expression and promotes neuronal autophagy by upregulating beclin-1 and LC3-2 while downregulating P62 and PARP expression. Additionally, ifenprodil may enhance synaptic plasticity by downregulating NR2B-CaMKII and PSD95 expression. A notable improvement was observed in the CPU group. Our study showed that direct delivery of ifenprodil to specific brain regions produced superior therapeutic effects compared to systemic administration in 6-OHDA-lesioned rat models.