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

doses may not evoke pathological signs, variability among hours, but no further degeneration is found over longer
animals has been reported with higher doses. In contrast, timelines, which limits its ability to model the progressive
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some studies have shown that long-term administration aspect of the PD. In several studies, LPS was administered
of lower doses can induce PD hallmarks, such as the loss intraperitoneally, resulting in increased inflammation,
of tyrosine hydroxylase (TH)-positive neurons and motor elevated pro-inflammatory factors, microglia activation,
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impairment. The variability, low reproducibility, high and neurodegeneration. However, LPS is also used as a
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toxicity, and non-selectivity are significant limitations of model in other neurodegenerative diseases, including AD,
the rotenone model, as previously reviewed. 34 as discussed below.
3.1.5. Reserpine 3.1.7. Haloperidol

Reserpine is an alkaloid extracted from the plant Rauwolfia Haloperidol is a dopamine type two (D2) receptor
serpentina known for its hypotensive effect. It acts as antagonist used as an antipsychotic drug in schizophrenia
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an irreversible inhibitor of the pre-synaptic VMAT2, patients. The blockade of D2 receptors in the nigrostriatal
leading to monoamine depletion. VMAT2 is responsible pathway results in dysfunction in the basal ganglia circuits,
for transporting dopamine, serotonin, norepinephrine, leading to side effects such as catalepsy and muscle rigidity.
and epinephrine (monoamines) from the cytoplasm into As a mouse model, haloperidol is usually administered
vesicles, where the neurotransmitters are stored until their intraperitoneally or subcutaneously at doses ranging from
released. When reserpine blocks VMAT2, monoamines 0.01 to 30 mg/kg, inducing states of catalepsy, bradykinesia,
remain in the cytoplasm and become accessible to their and rigidity. These conditions can be assessed through
degrading enzyme, MAO, resulting in a reduced release of different behavioral tests, such as the horizontal bar,
monoamines. In addition, metabolized dopamine generates grid, and table tests. Haloperidol mimics the primary
ROS and reactive quinones, contributing to oxidative stress, pathological feature of PD, which is reduced dopamine
lipid peroxidation, and cell damage. 40-42 Patients treated activity in the striatum and the consequent motor deficits
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with reserpine exhibited several side effects, including such as bradykinesia and catalepsy. This model has been
motor lethargy and dyskinesia. Subsequently, reserpine used to assess the effects of potential treatments for these
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was used in animal models to induce Parkinsonian specific motor symptoms of PD, validating the L-dopa
symptoms. 44,45 As one of the first rodent models to mimic treatment and exploring new therapies such as adenosine
PD, reserpine is usually administered subcutaneously in receptor antagonists and allosteric modulators of the
doses varying from 1 to 10 mg/kg, inducing various motor metabotropic glutamate receptor 4. 54-56 However, since this
dysfunctions, such as akinesia, bradykinesia, hypokinesia, model does not mimic the dopaminergic cell loss observed
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catalepsy, and limb rigidity. This model was fundamental in PD patients, models that include neurodegeneration
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in developing the L-dopa treatment used for PD patients. are more accurate for studying the human idiopathic form
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Reserpine-induced monoamine depletion is accompanied of PD.
by oxidative stress and a reduction in TH staining. However, 3.2. Genetic model
this model has several limitations, such as the absence of
dopaminergic neuronal degeneration, lack of selectivity 3.2.1. α-Syn
for dopamine reduction, depletion of both peripheral and The α-Syn protein is encoded by the SNCA gene.
central monoamines, and the fact that motor impairments Mutations in the SNCA gene (PARK1 locus) were reported
and molecular alterations are not sustained after reserpine in autosomal dominant familial PD patients. Among these
treatment is ceased. 47 mutations, A53T, A30P, and E46K point mutations in SNCA
have been recognized in affected families. Subsequently,
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3.1.6. LPS
duplications or triplications in the SNCA gene (PARK4
LPS is known for its capability to evoke an inflammatory locus) of PD families were reported, highlighting that even
response. Neuroinflammation is also an important wild-type α-Syn overexpression is pathogenic. Based
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hallmark in several neurodegenerative diseases, including on these findings, genetic mouse models overexpressing
PD. All this considered, the LPS model was developed mutant forms of α-Syn, such as A53T, A30P, and E46K,
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by injecting it directly into the nigrostriatal pathway, were developed. These mice develop oligomeric and
where it induces a strong inflammatory reaction. 50,51 This fibrillar forms of α-Syn and eventually Lewy bodies. In
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inflammatory response leads, secondarily, to neuronal addition, mice overexpressing wild-type human α-Syn
death. When injected into SNc, LPS induces dopaminergic are used as a model of PD. These animals exhibit both
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degeneration, glial cell activation, and motor behavior non-motor and motor deficits. However, it is important
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deficits. The effects of LPS are observed within a few to note that while Lewy bodies are a hallmark pathology in
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Volume 3 Issue 3 (2024) 6 doi: 10.36922/an.2903