Objective: This study established a 6-OHDA-lesioned adult zebrafish-based PD model and investigated the neuroregenerative processes of diencephalic dopaminergic neurons (DpN).

Background: Studies on endogenous neuroregeneration as a potential curative measure for Parkinson’s disease utilizing conventional mammalian-based PD models are often hampered with futile axogenesis. The emergence of zebrafish, a non-mammalian model with impressive neuroregeneration capacity and highly homologous genome to humans may address these limitations.

Method: 25mg/kg of 6-OHDA were intracerebroventricularly administered specifically into the diencephalon of adult zebrafish (Danio rerio). Immnunoflurorescence protocols was conducted to quantify tyrosine hydroxylase immunoreactive (TH-ir; indicating DpN) and Bromodeoxyuridine-immunoreactive (BrdU-ir; indicating proliferative cells) at brain regions of interest [olfactory bulb (OB), telencephalon, diencephalon]. To elucidate neurodifferentiation activity of lesioned fish, Foxa2 and Nurr1 differential gene expressions at different regions were enumerated using qPCR.

Results: At day 3 post-lesion, diencephalic TH-ir cell count revealed >85% DpN significantly (p<0.05) ablated when compared to intact fish. Whereas, at day-30 post-lesion Th-ir cell count increased significantly (p<0.05) than day-3 post-lesion but exhibited no significant difference with intact. Cellular proliferation demonstrated a transient yet significant (p<0.05) decrease and then increase in OB (-55%; +114%) and telencephalon (-73%; +194%) at day 5 and 7 post-lesion, but BrdU-ir cell count in diencephalon remained unchanged at all time points. Conversely, significant (p<0.05) decline and gradual increase of Foxa2 (-44% at day 3 and 9 post-lesion) and Nurr1 (-46% at day 3, 9 and -65% at day 14 post-lesion) were observed in the diencephalon; whilst no significant changes (p>0.05) of both differential markers were discerned in OB and telencephalon.

Conclusion: The present study had successfully established a stable 6-OHDA-lesioned adult zebrafish-based PD model and validated the model’s DpN regenerative capability. Further investigation to harness the regenerative potentials of this vertebrate and it’s application towards future human DpN regeneration studies is therefore now warranted.

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MDS Abstracts - https://www.mdsabstracts.org/abstract/dopaminergic-neuroregeneration-in-the-diencephalon-of-6-ohda-lesioned-adult-zebrafish-based-parkinsons-disease-model/