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1.
Neurosci Lett ; 823: 137654, 2024 Feb 16.
Artigo em Inglês | MEDLINE | ID: mdl-38281695

RESUMO

The α7 neuronal nicotinic acetylcholine receptor (α7 nAChR) is a potential target for the development of Parkinson's disease (PD) therapeutics. α-Synuclein (α-Syn), a principal component of Lewy bodies (cytoplasmic inclusions), is a major contributor to PD pathophysiology. Previous studies have demonstrated that activating α7 nAChR protects against nigrostriatal dopamine degeneration in acute and chronic PD animal models induced by 6-hydroxydopamine and rotenone, respectively. In the present study, we investigated the effects of PNU282987, a selective α7 nAChR agonist, against α-Syn-induced neurotoxicity in α-SynWT-, α-SynA30P-, and α-SynE46K-N2a cells. PNU282987 exhibited substantial neuroprotection against both wild-type and mutant-type α-Syn-induced toxicity. Furthermore, PNU282987 promoted transcription factor EB activity and reduced intracellular α-Syn protein levels through autophagy induction. These results highlight the therapeutic potential of α7 nAChR activation in diseases characterized by α-Syn aggregation, such as PD.


Assuntos
Compostos Bicíclicos com Pontes , Síndromes Neurotóxicas , Doença de Parkinson , Receptores Nicotínicos , Animais , alfa-Sinucleína/metabolismo , Receptor Nicotínico de Acetilcolina alfa7 , Doença de Parkinson/tratamento farmacológico , Doença de Parkinson/metabolismo , Benzamidas/farmacologia , Agonistas Nicotínicos/toxicidade , Receptores Nicotínicos/metabolismo
2.
Sci Rep ; 13(1): 15629, 2023 09 20.
Artigo em Inglês | MEDLINE | ID: mdl-37731009

RESUMO

Parkinson's disease (PD) is a neurodegenerative disorder characterized by the loss of dopaminergic neurons in the substantia nigra. The pathological hallmark of PD is the appearance of intraneuronal cytoplasmic α-synuclein (α-Syn) aggregation, called Lewy bodies. α-Syn aggregation is deeply involved in the pathogenesis of PD. Oxidative stress is also associated with the progression of PD. In the present study, to investigate whether a hypoxia-inducible factor (HIF)-prolyl hydroxylase (PH) inhibitor, FG-4592 (also called roxadustat), has neuroprotective effects against α-Syn-induced neurotoxicity, we employed a novel α-Syn stably expressing cell line (named α-Syn-N2a cells) utilizing a piggyBac transposon system. In α-Syn-N2a cells, oxidative stress and cell death were induced by α-Syn, and FG-4592 showed significant protection against this neurotoxicity. However, FG-4592 did not affect α-Syn protein levels. FG-4592 triggered heme oxygenase-1 (HO-1) expression downstream of HIF-1α in a concentration-dependent manner. In addition, FG-4592 decreased the production of reactive oxygen species possibly via the activation of HO-1 and subsequently suppressed α-Syn-induced neurotoxicity. Moreover, FG-4592 regulated mitochondrial biogenesis and respiration via the induction of the peroxisome proliferator-activated receptor-γ coactivator-1α. As FG-4592 has various neuroprotective effects against α-Syn and is involved in drug repositioning, it may have novel therapeutic potential for PD.


Assuntos
Fármacos Neuroprotetores , Doença de Parkinson , Inibidores de Prolil-Hidrolase , Humanos , Prolil Hidroxilases , alfa-Sinucleína , Fármacos Neuroprotetores/farmacologia , Pró-Colágeno-Prolina Dioxigenase , Doença de Parkinson/tratamento farmacológico , Estresse Oxidativo , Glicina , Hipóxia
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