**2. Animal models for PD**

Cellular processes associated with PD such as oxidative stress, neurodegeneration, neuroinflammation and cell death, has been successfully evaluated in rat and mice. Till date, there exist two general types of experimental murine models: genetically manipulated and chemically induced.

#### **2.1. Genetically manipulated**

The induction of gene mutations, alterations in protein functionality and sub- or overexpression of proteins have generated models for PD. These innovative genetic engineering strategies have been developing for PARK2, alpha-synuclein, PINK1, and oxDJ-1. The results are diverse. For example, the genetic deletion of exon 3 of PARK2 in mice increases extracellular striatal dopamine contents but the DAT levels are decreased [4, 5]. These facts do not alter the nigrostriatal pathway because the number of dopaminergic neurons remains normal. A key factor for Parkinson's disease progression is the formation of Lewy bodies [6], due to which, α-synuclein has been incorporated as a gene or peptide to produce amyloid-like composed fibrils. Other strategy involves the incorporation of drugs to modify alpha synuclein aggregation in mice and in *in vitro* models [7, 8]. In mice, it causes dopaminergic neuronal death [2]. But the deleterious effect is dependent on the site of administration, type of particle (gene, peptides, and oligomers), dose, and molecular vector used.

#### **2.2. Chemically induced**

The most commonly used neurotoxins are: (a) 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) [9], which is converted to 1-methyl-4-phenylpyridinium (MPP+) by monoamine oxidase (MAO-B), (b) 6-hydroxydopamine (6-OHDA) [6, 10], (c) herbicides such as paraquat or rotenone [11] and (d) metals (manganese, iron) [12]. MPTP crosses the blood-brain barrier (BBB) [13], which in addition to cause damage to the nigrostriatal pathway, causes neuronal loss of the GABAergic neurons [14], catecholaminergic neurons (VTA, *locus coeruleus*, retrorubral nuclei) [15], reduction of serotonine receptor in the cortical and subcortical regions and reactive gliosis [16]. The toxicity of herbicides and metals is characterized by mitochondrial dysfunction due to peripheral and brain cellular stress [6, 17]. The neurotoxin 6-hydroxydopamine is more selective for the dopaminergic neurons of the SNpc [18, 19] because it causes specific degeneration of dopaminergic neurons in the SNpc [19–21] and does not cross the BBB. The advantages and limitations of 6-hydroxydopamine model are showed in **Table 1**.

**3. Vulnerability of dopaminergic neurons to 6-OHDA**

**Feature Advantages Limitations**

(uncommon)

performed in rats (most common), mice, cats, guinea pigs, dogs and monkeys

intracranial injection by stereotaxis needs precise administrations on nigrostriatal

progressive. Dose and site dependent

Selective entry into the target using Dopamine transporter (DAT), can cause selective destruction of brain

More in SNpc, nucleus specific to dopaminergic neuronal population, than in VTA, nucleus containing glutamatergic neuronal populations, representing a

of methamphetamine or apomorphine injected and severity of the lesion; correlates with the magnitude of

Survival rate [27] High survival 5 in 100 die due to lack of proper

Oxidative/nitrosative stress, apoptosis, autophagy, necrosis, neuroinflammation

dopaminergic neurons

good model for PD

nigrostriatal lesions

Circling motor behavior [12, 20] Quantifiable depending on the dosage

common) or bilateral (uncommon) injection into the nigrostriatal pathway None

Animal Model of Parkinson Disease: Neuroinflammation and Apoptosis in the…

None

equipment

neurons

neurons

None

None Causes cognitive, psychiatric and

None Absent due to acute

pathophysiology

Stereotaxis procedure needs special

http://dx.doi.org/10.5772/intechopen.71271

377

Cannot reproduce complete

Noradrenaline transporter (NAT) mediated entry causes damage and destruction of brain noradrenergic

Toxic for other catecholaminergic

neurodegenerative property of

gastrointestinal disorders

No Lewy body formation

post-surgery recovery

6-OHDA injection

Animal(s) used [6, 22] The injection of 6-OHDA can be

Usage of the model [1, 20, 23, 24] Unilateral (standardized and most

Mode of administration [20, 25] As the 6-OHDA does not cross BBB,

Type of lesion [20, 26] Reproducible; retrograde; relatively

Transporter mediated entry

Dopaminergic neuronal loss

Progressive and age-dependent

effects of PD [6, 22]

Non-motor behavioral phenotypes [3, 6]

Cellular process associated to the cytotoxicity [3, 13, 29–31]

**Table 1.** Characteristics of 6-OHDA model.

[13, 27]

[6, 28]

pathway

6-Hydroxydopamine (6-OHDA) is a highly oxidizable dopamine analog, which can be captured through the dopamine transporter (DAT) [25]. Till date, three mechanisms have been proposed to explain the cytotoxic effect of 6-OHDA: (1) intra- or extracellular auto-oxidation,


**Table 1.** Characteristics of 6-OHDA model.

progressive degeneration of the dopaminergic neurons of the nigrostriatal pathway, neuroinflammation, the presence of Lewy bodies and generalized damage of the neuronal circuits

Cellular processes associated with PD such as oxidative stress, neurodegeneration, neuroinflammation and cell death, has been successfully evaluated in rat and mice. Till date, there exist two general types of experimental murine models: genetically manipulated and chemi-

The induction of gene mutations, alterations in protein functionality and sub- or overexpression of proteins have generated models for PD. These innovative genetic engineering strategies have been developing for PARK2, alpha-synuclein, PINK1, and oxDJ-1. The results are diverse. For example, the genetic deletion of exon 3 of PARK2 in mice increases extracellular striatal dopamine contents but the DAT levels are decreased [4, 5]. These facts do not alter the nigrostriatal pathway because the number of dopaminergic neurons remains normal. A key factor for Parkinson's disease progression is the formation of Lewy bodies [6], due to which, α-synuclein has been incorporated as a gene or peptide to produce amyloid-like composed fibrils. Other strategy involves the incorporation of drugs to modify alpha synuclein aggregation in mice and in *in vitro* models [7, 8]. In mice, it causes dopaminergic neuronal death [2]. But the deleterious effect is dependent on the site of administration, type of particle (gene, peptides, and oligomers), dose, and

The most commonly used neurotoxins are: (a) 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) [9], which is converted to 1-methyl-4-phenylpyridinium (MPP+) by monoamine oxidase (MAO-B), (b) 6-hydroxydopamine (6-OHDA) [6, 10], (c) herbicides such as paraquat or rotenone [11] and (d) metals (manganese, iron) [12]. MPTP crosses the blood-brain barrier (BBB) [13], which in addition to cause damage to the nigrostriatal pathway, causes neuronal loss of the GABAergic neurons [14], catecholaminergic neurons (VTA, *locus coeruleus*, retrorubral nuclei) [15], reduction of serotonine receptor in the cortical and subcortical regions and reactive gliosis [16]. The toxicity of herbicides and metals is characterized by mitochondrial dysfunction due to peripheral and brain cellular stress [6, 17]. The neurotoxin 6-hydroxydopamine is more selective for the dopaminergic neurons of the SNpc [18, 19] because it causes specific degeneration of dopaminergic neurons in the SNpc [19–21] and does not cross the BBB. The advantages and limitations of 6-hydroxydopamine model are

that control the movement [3].

376 Experimental Animal Models of Human Diseases - An Effective Therapeutic Strategy

**2. Animal models for PD**

**2.1. Genetically manipulated**

molecular vector used.

**2.2. Chemically induced**

showed in **Table 1**.

cally induced.
