Zebrafish Parkinson's Disease Research Articles

Neuro-Restorative Effect of Nimodipine and Calcitriol in 1-Methyl 4-Phenyl 1,2,3,6 Tetrahydropyridine-Induced Zebrafish Parkinson's Disease Model.

Parkinson's disease (PD) is one of the most prevalent neurodegenerative diseases, characterized by the loss of dopaminergic neurons in the substantia nigra pars compacta. The treatment of PD aims to alleviate motor symptoms by replacing the reduced endogenous dopamine. Currently, there are no disease-modifying agents for the treatment of PD. Zebrafish (Danio rerio) have emerged as an effective tool for new drug discovery and screening in the age of translational research. The neurotoxin 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) is known to cause a similar loss of dopaminergic neurons in the human midbrain, with corresponding Parkinsonian symptoms. L-type calcium channels (LTCCs) have been implicated in the generation of mitochondrial oxidative stress, which underlies the pathogenesis of PD. Therefore, we investigated the neuro-restorative effect of LTCC inhibition in an MPTP-induced zebrafish PD model and suggested a possible drug candidate that might modify the progression of PD. All experiments were conducted using a line of transgenic zebrafish, Tg(dat:EGFP), in which green fluorescent protein (GFP) is expressed in dopaminergic neurons. The experimental groups were exposed to 500 μmol MPTP from 1 to 3 days post fertilization (dpf). The drug candidates : levodopa 1 mmol, nifedipine 10 μmol, nimodipine 3.5 μmol, diethylstilbestrol 0.3 μmol, luteolin 100 μmol, and calcitriol 0.25 μmol were exposed from 3 to 5 dpf. Locomotor activity was assessed by automated tracking and dopaminergic neurons were visualized in vivo by confocal microscopy. Levodopa, nimodipine, diethylstilbestrol, and calcitriol had significant positive effects on the restoration of motor behavior, which was damaged by MPTP. Nimodipine and calcitriol have significant positive effects on the restoration of dopaminergic neurons, which were reduced by MPTP. Through locomotor analysis and dopaminergic neuron quantification, we identified the neuro-restorative effects of nimodipine and calcitriol in zebrafish MPTP-induced PD model. The present study identified the neuro-restorative effects of nimodipine and calcitriol in an MPTP-induced zebrafish model of PD. They restored dopaminergic neurons which were damaged due to the effects of MPTP and normalized the locomotor activity. LTCCs have potential pathological roles in neurodevelopmental and neurodegenerative disorders. Zebrafish are highly amenable to high-throughput drug screening and might, therefore, be a useful tool to work towards the identification of diseasemodifying treatment for PD. Further studies including zebrafish genetic models to elucidate the mechanism of action of the diseasemodifying candidate by investigating Ca2+ influx and mitochondrial function in dopaminergic neurons, are needed to reveal the pathogenesis of PD and develop disease-modifying treatments for PD.

The Neuroprotective Effect of Isotetrandrine on Parkinson's Disease via Anti-Inflammation and Antiapoptosis In Vitro and In Vivo.

Parkinson's disease (PD) is one of the most influential diseases in the world, and the current medication only can relieve the clinical symptoms but not slow the progression of PD. Therefore, we intend to examine the neuroprotective activity of plant-derived compound isotetrandrine (ITD) in vitro and in vivo. In vitro, cells were cotreated with ITD and LPS to detect the inflammatory-related protein and mRNA. In vivo, zebrafish were pretreated with ITD and inhibitors prior to 6-OHDA treatment. Then, the behavior was monitored at 5 dpf. Our result showed ITD inhibited LPS-induced upregulation of iNOS, COX-2 protein expression, and iL-6, inos, cox-2, and cd11b mRNA expression in BV2 cells. The data in zebrafish also demonstrated a significant improvement of ITD on the 6-OHDA-induced locomotor deficiency. ITD also improved 6-OHDA-induced apoptosis in zebrafish PD. We also pharmacologically validated the mechanism with three inhibitors, including LY294002, PI3K inhibitor; LY32141996, ERK inhibitor, SnPP, and HO-1 inhibitors. All of these inhibitors could abolish the neuroprotective effect of ITD partially in locomotor activity. Besides, the molecular level also showed the same trend. Treatment of these inhibitors could significantly abolish ITD-induced antineuroinflammatory and antioxidative stress effects in zebrafish PD. Our study showed ITD possessed a neuroprotective activity in zebrafish PD. The mRNA level also supported our arguments. The neuroprotection of ITD might be through antineuroinflammation and antiapoptosis pathways via PI3K, ERK, and HO-1.

The effect of acetic acid-induced pain in Parkinson’s disease model in zebrafish

Parkinson's disease (PD) is the second most common neurodegenerative disease caused by the degeneration of dopaminergic neurons and the accumulation of Lewy bodies. Pain is one of the most common non-motor symptoms in PD, but the molecular mechanism of pain in PD is not fully understood, which prevents early diagnosis of PD. We aimed to determine the changes in opioidergic pathways when external pain is inflicted by inducing pain intraperitoneally in zebrafish, for which we generated a rotenone-induced PD model. After behavioural analyses in control(C), acetic acid (AA), rotenone (ROT), and rotenone+ acetic acid (ROT+AA) groups, catecholamine levels in brain tissue were determined by LC-MS/MS, expression of opioid peptides and their receptors by RT-PCR, expression of tyrosine hydroxylase by immunohistochemical method, and analyses of oxidant-antioxidant parameters by spectrophotometric methods. In the ROT group, distance travelled, average speed, and brain dopamine levels decreased, while LPO (lipid peroxidation) and NO (nitric oxide) increased as indicators of oxidative damage, and the SOD activity decreased. The mRNA expression of lrrk, pink1, and park7 genes associated with PD increased, while the mRNA expression of park2 decreased. This indicates that rotenone exposure is a suitable means to induce PD in zebrafish. The fact that body curvature was higher in the AA group than in the ROT and ROT+AA groups, as well as the decreased expression of penka, pdyn, and ion channels associated with the perception of peripheral pain in the ROT+AA group, suggest that mechanisms associated with pain are impaired in the rotenone-induced PD model in zebrafish.

Anti-Parkinson's Disease Activity of Sanghuangprous vaninii Extracts in the MPTP-Induced Zebrafish Model.

Parkinson's disease (PD) is a devastating disease of the central nervous system that occurs mainly in the elderly age group, affecting their quality of life. The PD pathogenesis is not yet fully understood and lacks the disease-modifying treatment strategies. Sanghuangprous vaninii (S. vaninii) is a perennial fungus with a plethora of pharmacological activities including anti-cancer and antioxidant activity and so on. However, no study till date has reported its neuroprotective effect against symptoms that are similar to PD in pre-clinical investigation. In the current study, we investigated anti-PD-like effects of S. vaninii mycelium extracts (SvMEs) on MPTP-induced PD in zebrafish. We observed that the loss of dopaminergic neurons and neurovascular reduction were reversed by using SvMEs in the zebrafish brain in a concentration-independent manner. Moreover, it also relieved locomotor impairments in MPTP-induced PD zebrafish. In addition, SvMEs exerted significant antioxidant activity in vitro, which was also demonstrated in vivo on ktr4:NTR-hKikGR zebrafish. Upon investigating the underlying mechanism, we found that SvMEs may alleviate oxidant stress and accelerate α-synuclein degradation and then alleviate PD-like symptoms. Antioxidant-related genes (sod1, gss, gpx4a, gclm, and cat) implied that the SvMEs exhibited anti-PD activity due to the antioxidation mechanism. Finally, upon analysis of chemical composition of SvMEs by liquid chromatography-mass spectrometry, we identified 10 compounds that are plausibly responsible for the anti-PD-like effect of SvMEs. On the limiting part, the finding of the study would have been more robust had we investigated the protein expression of genes related to PD and oxidative stress and compared the effects of SvMEs with any standard anti-PD therapy. Despite this, our results indicated that SvMEs possess anti-PD effects, indicating SvMEs as a potential candidate that is worth exploring further in this avenue.