3‐aminohydantoin derivate as a promising scaffold in dopaminergic neuroprotection and neurorescue in the in vivo and in vitro 6‐hydroxydopamine models of Parkinson's disease

Abstract

Parkinson's disease (PD) is a neurodegenerative disorder characterized by a progressive loss of dopaminergic neurons in the substantia nigra, for which no disease‐modifying treatments are available yet. Thus, developing new neuroprotective drugs with the potential to delay or stop the natural course of the disease is necessary. The aim of the present study was to evaluate the neuroprotective effects of a newly synthesized 3‐aminohydantoin derivative named 3‐amino‐5‐benzylimidazolidine‐2,4‐dione (PHAH). The possible neuroprotective and neurorescue effects of the synthesized compound were tested: (i) in N27 dopaminergic and BV‐2 microglial cell lines treated with 6‐hydroxydopamine (6‐OHDA) and (ii) in the 6‐OHDA rat model of PD. PHAH administration reduced proinflammatory markers, including nitric oxide synthase and interleukin‐1β, in BV‐2 cells activated by lipopolysaccharide. Although PHAH did not restore cell death induced by 6‐OHDA, it was not cytotoxic for dopaminergic cells since cell viability, under the effect of the two concentrations, remained comparable to that of the control cells. Most interestingly, PHAH restored 6‐OHDA‐induced dopaminergic neurodegeneration in the substantia nigra and striatum and ameliorated 6‐OHDA‐induced oxidative stress in the rat brain. In summary, we have proven that in PD models, PHAH has neuroprotective effects in vivo and anti‐inflammatory effects in vitro; however, these effects remain to be confirmed by carrying out certain specific behavioural tests as well as by exploring other neuroinflammatory markers. The present work also suggests that PHAH is a promising scaffold that can serve as the basis for the design and synthesis of other derivatives that can be potent antiparkinsonian agents.