6-OHDA Rats

Disease Simulated: Parkinson's disease (PD)

Strain Description

Parkinson's disease (PD) is a progressive neurodegenerative disorder that primarily affects motor function. It is characterized by the degeneration of dopamine-producing neurons in the brain, which leads to symptoms such as tremors, bradykinesia, rigidity, and postural instability. Non-motor symptoms can also manifest, including cognitive impairment, mood disorders, and sleep disturbances. Globally, it affects approximately 8.5 million individuals, predominantly within the elderly population ^[1-2].

6-Hydroxydopamine (6-OHDA) is one of the most widely used neurotoxins for modeling the degeneration of dopaminergic (DA) neurons in Parkinson’s disease research. This model involves injecting the neurotoxin 6-OHDA into specific regions of the brain to selectively destroy dopaminergic neurons, resulting in PD-like motor symptoms such as bradykinesia, rigidity, and tremor. The model is commonly employed to investigate disease pathophysiology, evaluate neuroprotective strategies, and assess potential therapeutic interventions ^[3-4]. Among the various models developed, the 6-OHDA-lesioned rodent model is considered a gold standard for replicating PD motor symptoms and L-DOPA-induced dyskinesia (LID), due to its reproducibility and translational relevance ^[5].

Modeling Protocol

• Model Construction: A 6-OHDA solution was injected into the left brain medial forebrain bundle and substantia nigra. Two weeks later, apomorphine was administered intraperitoneally to the rats, and rightward rotations were counted.
• Treatments and Behavioral Assessments: L-DOPA (20 mg/kg) was injected intraperitoneally daily. At specified time points, gait analysis, grip strength, and rotarod performance were measured.
  
  

Validation Data

1. Behavior Test

Figure 1. The flow charts of 6-OHDA PD rats. After 2 weeks of brain stereotaxic injection, apomorphine (APO, 0.5 mg/kg) was administered intraperitoneally to the rats, and rightward rotations were counted. The gait analysis, grip strip strength and rotarod were measured at specific time points. The significance analyzed with one-way ANOVA, ns represents not significant, *p < 0.05, **p < 0.01, ***p < 0.001, ****p < 0.001.

Behavior Phenotype Summary

• The WT group did not exhibit rightward rotation following APO administration.
• In 6-OHDA PD rats, there was an increase in walking time, along with a decrease in average speed and stride length. However, these impairments were reversed after 20 days of L-DOPA administration.
• Compared to WT, the 6-OHDA PD rats showed reduced grip strength, which was mitigated after 25 days of L-DOPA treatment.
• 6-OHDA PD rats displayed decreased latency compared to WT, with L-DOPA administration reversing this reduction after 30 days.

2. Pathology Assessment

Figure 2. Immunofluorescence images of tyrosine hydroxylase expression three weeks after 6-OHDA injection.

Pathology Phenotype Summary

• Tyrosine hydroxylase (TH) is a crucial marker of dopaminergic neurons, and the reduction in TH expression is a hallmark of the disease's progression.
• The 6-OHDA was injected into the left side of the brain. As a result, no TH fluorescence (red fluorescence) was detected in the left substantia nigra and striatum, while the right substantia nigra and striatum still exhibited TH fluorescence. These findings confirm the successful establishment of the 6-OHDA PD rat model.

References
[1]Ascherio A, Schwarzschild MA. The epidemiology of Parkinson's disease: risk factors and prevention. Lancet Neurol. 2016 Nov;15(12):1257-1272.
[2]Vijiaratnam N, Simuni T, Bandmann O, Morris HR, Foltynie T. Progress towards therapies for disease modification in Parkinson's disease. Lancet Neurol. 2021 Jul;20(7):559-572.
[3]Guimarães RP, Ribeiro DL, Dos Santos KB, Godoy LD, Corrêa MR, Padovan-Neto FE. The 6-hydroxydopamine Rat Model of Parkinson's Disease. J Vis Exp. 2021 Oct 27;(176).
[4]Lu X, Kim-Han JS, Harmon S, Sakiyama-Elbert SE, O'Malley KL. The Parkinsonian mimetic, 6-OHDA, impairs axonal transport in dopaminergic axons. Mol Neurodegener. 2014 May 3;9:17.
[5]Tronci E, Francardo V. Animal models of L-DOPA-induced dyskinesia: the 6-OHDA-lesioned rat and mouse. J Neural Transm (Vienna). 2018 Aug;125(8):1137-1144.