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Advanced Neurology Alzheimer’s and Parkinson’s disease rodent models

3.1.2. α-Syn preformed fibrils the potential effects of drugs on motor symptoms and

α-Syn is a small protein predominantly found in the nervous progressive dopaminergic neuronal death. In addition,
system, mainly localized within pre-synaptic terminals. because the toxin can be injected unilaterally, one
While its physiological function remains largely elusive, hemisphere can serve as an internal control. However, this
evidence suggests a role in vesicle dynamics. α-Syn is a model does not replicate certain aspects of human PD,
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principal component of Lewy bodies, which are abnormal such as the abnormal aggregations of α-Syn.
protein aggregations that typically form inside neurons 3.1.4. Rotenone and paraquat
of PD and several other neurodegenerative conditions
in humans. In PD, the accumulation of Lewy bodies is Many epidemiological studies indicate that exposure to
associated with non-motor symptoms, such as dementia, pesticides and residing in rural areas is significant risk
and can also contribute to motor pathology when found factors for sporadic PD. Among pesticides, paraquat and
in the SNc. In one experimental model, monomeric α-Syn rotenone have been associated with PD and are used in
is converted to PFF and injected into the animal’s brain, research to induce animal models of the disease. Paraquat,
usually targeting the dorsal striatum, in doses ranging from an herbicide, shares structural similarities with MPP+.
4 to 8 µg. 21-23 The α-Syn PFFs trigger pathological changes Rotenone, the most potent member of the rotenoids – a
in endogenous α-Syn in a prion-like manner, dysregulating group of natural cytotoxic compounds derived from
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striatal dopamine release, leading to neurodegeneration tropical plants – is used as an insecticide and fish poison.
in the SNc, and resulting in motor deficits. This model In rodent models, paraquat has been shown to induce
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generates more progressive neurodegeneration, closely damage to the SNc, suggesting a potential link between its
resembling the human form of PD. Nonetheless, this fact exposure and the development of PD, despite its limited
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also enables a bilateral pathology in the animal’s brain, ability to penetrate the blood–brain barrier. Systemic
even when α-Syn PFFs are injected unilaterally, meaning administration of 10 mg/kg of paraquat dichloride hydrate
there may be no unaffected brain hemisphere to use as once a week for 3 consecutive weeks leads to dopaminergic
an internal control. In addition, this model requires more neuron degeneration and the formation of α-Syn inclusions
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time to produce significant neurodegenerative changes in in mice. The effects of paraquat appear to be mediated by
mice brains compared to other models. 25 the formation of superoxide radicals. However, it remains
uncertain whether the dopaminergic toxicity is selective
3.1.3. 6-OHDA or whether other cell types are also affected. Paraquat’s
6-OHDA is a neurotoxin first described in 1959 and is capability to consistently induce dopaminergic neuronal
widely used in pre-clinical studies of PD. Since 6-OHDA loss and the presence of α-Syn is valuable for research
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cannot cross the blood–brain barrier, it is usually injected exploring the role of α-Syn in PD’s neurodegeneration.
directly into the nigrostriatal pathway, targeting the SNc, Rotenone is a high lipophilic molecule capable of
medial forebrain bundle (MFB), or striatum. This injection easily crossing the blood–brain barrier and biological
induces motor symptoms such as akinesia, deficits in membranes. Unlike some other neurotoxins, it does not
motor control and movement initiation, and drug- depend on DAT to enter the cells. Rotenone inhibits
induced-rotational behavior. 26 6-OHDA promotes the mitochondrial complex I, ultimately leading to nigrostriatal
depletion of dopamine neurons in the SNc and decreases dopaminergic degeneration. Despite its non-specificity to
dopamine levels in the striatum. It can be administered dopaminergic neurons, complex I inhibition by rotenone
unilaterally or bilaterally, promoting varying degrees of occurs throughout the brain. This suggests that the selective
dopamine depletion. Unilateral injection of the toxin degeneration of nigrostriatal dopaminergic neurons is
produces a clear, progressive pattern of neuronal death, associated with their higher sensitivity. In the rotenone
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similar to that observed in PD patients. Structurally model, α-Syn-positive and Lewy bodies-like inclusions, as
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analogous to dopamine, 6-OHDA is taken up by DAT well as motor impairment, have been reported. Rotenone
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into the intracellular space of dopaminergic neurons, administration in rodents is achieved through intravenous
where it impairs mitochondrial function by inhibiting injections, requiring cannulation of the jugular vein, or
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mitochondrial complex I. This disruption of cellular by gavage, intraperitoneally, or subcutaneous injections,
respiration leads to cell damage. Another mechanism usually necessitating long-term administration protocols.
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of 6-OHDA neurotoxicity involves the generation of In addition, some studies have reported a diffuse pattern of
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free radicals following its degradation within neuronal degeneration in animals treated with rotenone. Another
intracellular space, resulting in the production of ROS limitation is that rotenone exposure can cause multiple
that causes further cellular damage to these neurons. 28,29 organ damage and high mortality in animals, especially at
This 6-OHDA model is extremely useful for evaluating higher doses and with prolonged treatment. 35,36 While lower

Volume 3 Issue 3 (2024) 5 doi: 10.36922/an.2903