Parkinson's disease (PD) is a neurodegenerative disorder that affects about 1.5% of the global population over 65 years of age. Robust, well-validated pre-clinical models of PD are valuable tools for understanding the biology and possible treatment of this complex disease. As a CRO specializing in PD preclinical research, Creative Biolabs offers a commonly used 6-hydroxydopamine (6-OHDA) unilateral lesion rat model to our clients for the assessment of both protective and restorative treatments.
Mechanisms of Action
6-OHDA is a selective catecholaminergic neurotoxin that is used, mainly, to generate lesions in the nigrostriatal dopamine (DA) neurons in rats. This neurotoxin for PD model was first introduced in 1968 by Ungerstedt when he noticed that a unilateral application of 6-OHDA into the nucleus caudatus putamen or the substantia nigra caused the loss of monoaminergic terminals and dopaminergic cell bodies, respectively, with a marked motor asymmetry known as hemiparkinsonism, typically characterized by a rotational behavior to the impaired side. 6-OHDA application can give rise to oxidative stress to form reactive oxygen species (ROS) and reactive nitrogen species (RNS). Moreover, it can also inhibit mitochondrial respiratory chain by interacting directly with complexes I and IV. These events are thought to induce death in catecholaminergic neurons.
Fig. 1 Graphical illustration of the site of stereotaxic injection in the median forebrain bundle (MFB) shows dopaminergic fibers connecting the striatum and the SNc. (De et al. 2015)
Model Description
Since 6-OHDA cannot cross the blood-brain barrier, systemic administration fails to induce parkinsonism. So, the induction of this model requires that 6-OHDA be injected (typically as a unilateral injection) into the SNc, medial forebrain bundle or striatum. Intraventricular administration has also been achieved. Unilateral injection produces DA neuron loss on the injected side while sparing the contralateral DA neurons. It also requires pretreatment with an inhibitor for noradrenaline transporters (NATs) such as desipramine when selective loss of dopaminergic neurons is desired, because 6-OHDA is effectively incorporated into catecholamine neurons through NAT in addition to DA transporter (DAT). Furthermore, 6-OHDA can easily be degraded by monoamine oxidase(MAO-B), so pretreatment with an MAO-B inhibitor, such as pargyline, is also required to protect 6-OHDA from oxidative breakdown.
Features of 6-OHDA Model
Fig.2 Histological analysis of 6-OHDA lesioned rats using tyrosine hydroxylase (TH) immunohistochemistry following striatal lesion using 10 μg (A) or 20 μg (B) 6-OHDA or following 6-OHDA lesioning of the medial forebrain bundle (C). (D) Cavalieri quantification of the proportion of TH immunoreactivity retained in the caudate putamen. (Vandeputte et al. 2010)
Assessments
Traditionally, behavioral assessments of motor impairments in the unilateral 6-OHDA model are done by drug-induced rotation tests. However, drug-free sensorimotor behavioral tests have been developed including the cylinder test, in which the animal balances itself while rearing in a confined environment; the stepping test, which is used to assess forelimb akinesia; and the corridor task, a sensitive test of lateralized sensorimotor response selection. Once behavioral analysis is complete, rats can be sacrificed and brain tissues are harvested for histological and immunohistochemical analysis. Briefly, Creative Biolabs is capable of providing assessments including but not limited to:
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The portfolio of rodent preclinical neurological disease models at Creative Biolabs is placed below for your review:
If you are interested in our 6-OHDA PD model, please contact us to discuss your specific requirements. We are willing to share our expertise with our clients to facilitate their brilliant studies.
References
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