Open access peer-reviewed chapter

Animal Model of Parkinson Disease: Neuroinflammation and Apoptosis in the 6-Hydroxydopamine-Induced Model

Written By

Daniel Hernandez-Baltazar, Rasajna Nadella, Maria de Jesus Rovirosa-Hernandez, Laura Mireya Zavala-Flores and Christian de Jesus Rosas Jarquin

Submitted: 01 August 2017 Reviewed: 26 September 2017 Published: 20 December 2017

DOI: 10.5772/intechopen.71271

From the Edited Volume

Experimental Animal Models of Human Diseases - An Effective Therapeutic Strategy

Edited by Ibeh Bartholomew

Chapter metrics overview

1,622 Chapter Downloads

View Full Metrics

Abstract

6-Hydroxydopamine (6-OHDA), a synthetic neurotoxin, has been used to generate animal models of Parkinson’s disease (PD). Even though 6-OHDA induced neurodegenerative model in rat, it does not reproduce all the symptoms of the disease, but it does replicate most of the cellular processes such as oxidative stress, neurodegeneration, neuroinflammation and apoptotic neuronal death. The knowledge of the mechanisms involved in neurodegeneration is relevant to define possible therapeutic targets for PD.

Keywords

  • neurodegeneration
  • substantia nigra pars compacta
  • cellular stress
  • Parkinson’s disease
  • therapy

1. Introduction

Parkinson’s disease (PD) is a chronic-neurodegenerative disorder that presents motor and non-motor symptoms. The bradykinesia, resting tremor, rigidity and postural instability are caused by neurobiological defects [1]. PD affects a wide variety of nuclei in the central nervous system (CNS), including the dorsal motor nucleus of the vagus, nuclei of the Rafe, locus coeruleus, pontine peduncle nucleus, retrorubral nucleus, parabrachial nucleus, ventral tegmental area (VTA) and the substantia nigra pars compacta (SNpc) [2]. PD could be sporadic or due to genetic alterations (alpha-synuclein, parkin, PINK1, dardarin, and oxDJ-1). Despite the fact that PD is multifactorial; an indisputable sign of the disease is the progressive degeneration of the dopaminergic neurons of the nigrostriatal pathway, neuroinflammation, the presence of Lewy bodies and generalized damage of the neuronal circuits that control the movement [3].

Advertisement

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 over-expression 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, 20, 21] and does not cross the BBB. The advantages and limitations of 6-hydroxydopamine model are showed in Table 1.

FeatureAdvantagesLimitations
Animal(s) used [6, 22]The injection of 6-OHDA can be performed in rats (most common), mice, cats, guinea pigs, dogs and monkeys (uncommon)None
Usage of the model [1, 20, 23, 24]Unilateral (standardized and most common) or bilateral (uncommon) injection into the nigrostriatal pathwayNone
Mode of administration [20, 25]As the 6-OHDA does not cross BBB, intracranial injection by stereotaxis needs precise administrations on nigrostriatal pathwayStereotaxis procedure needs special equipment
Type of lesion [20, 26]Reproducible; retrograde; relatively progressive. Dose and site dependentCannot reproduce complete pathophysiology
Transporter mediated entry [13, 27]Selective entry into the target using Dopamine transporter (DAT), can cause selective destruction of brain dopaminergic neuronsNoradrenaline transporter (NAT) mediated entry causes damage and destruction of brain noradrenergic neurons
Dopaminergic neuronal loss [6, 28]More in SNpc, nucleus specific to dopaminergic neuronal population, than in VTA, nucleus containing glutamatergic neuronal populations, representing a good model for PDToxic for other catecholaminergic neurons
Progressive and age-dependent effects of PD [6, 22]NoneAbsent due to acute neurodegenerative property of 6-OHDA injection
Circling motor behavior [12, 20]Quantifiable depending on the dosage of methamphetamine or apomorphine injected and severity of the lesion; correlates with the magnitude of nigrostriatal lesionsNone
Non-motor behavioral phenotypes [3, 6]NoneCauses cognitive, psychiatric and gastrointestinal disorders
Survival rate [27]High survival5 in 100 die due to lack of proper post-surgery recovery
Cellular process associated to the cytotoxicity [3, 13, 29, 30, 31]Oxidative/nitrosative stress, apoptosis, autophagy, necrosis, neuroinflammationNo Lewy body formation

Table 1.

Characteristics of 6-OHDA model.

Advertisement

3. Vulnerability of dopaminergic neurons to 6-OHDA

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, which favors the production of hydrogen peroxide, superoxide and hydroxyl radicals [13]; (2) formation of hydrogen peroxide by the effect of monoamine oxidase [32]; and (3) direct inhibition of the mitochondrial respiratory chain I complex [33].

These mechanisms can act independently or in combination to generate reactive oxygen species (ROS) [30]. Injection of 6-OHDA increases iron levels in the SNpc, which further induces the generation of ROS and cytochrome c release [13]. ROS and quinones derived from 6-OHDA diminishes the antioxidant capacity of the cell, resulting in oxidative damage to proteins, lipids and DNA [34]. Miyama and colleagues observed that 6-OHDA treatment decreased cellular glutathione content in a time-dependent manner before the oxidation of DJ-1 (oxDJ-1), a PD-related endogenous protein [35]. The oxidative stress generated can be amplified by the increase of free calcium in the cytoplasm, which is the product of glutamate excitotoxicity or by the loss of mitochondrial membrane permeability [36].

The dopaminergic neurons of the SNpc are vulnerable to oxidative stress induced by 6-OHDA, because they have increased basal levels of ROS, as well as low levels of glutathione peroxidase, an enzyme that reduces hydrogen peroxide to water [37]. The dopamine neurotransmitter has a high susceptibility to auto-oxidize and to become neuromelanin, which promotes the formation of hydroxyl radicals. This when combined with iron accumulated normally at high concentrations in dopaminergic neurons [3, 38], affects its elimination capacity. Also, during the oxidation of dopamine, several transient metabolites are formed such as dopamine o-quinone, aminochrome and 5,6-indolequinone [39]. These metabolites induce the formation of superoxide and adducts with several proteins like parkin [40, 41], tyrosine hydroxylase (TH) [42], glutathione peroxidase 4 [43] and several others. Indeed, it has been proposed that 5,6-indolequinone is the most reactive species that could form adducts with alpha-synuclein generating neurotoxic oligomers [7].

However, not all dopaminergic neurons of SNpc are vulnerable to 6-OHDA toxicity because there are subpopulations of dopaminergic neurons in SNpc expressing calcium-binding proteins such as calretinin and calbindin-D28k, which prevent the accumulation of intracellular calcium, avoiding the consequent excitotoxicity due to glutamate, and the cytotoxic action of 6-OHDA [44, 45]. The redox system plays an important role in protecting the dopaminergic neurons against oxidative stress. The thioredoxin and glutaredoxin systems directly mediate reduction of the 6-OHDA-quinone in vitro and protect neurons against dopamine-induced cell death [46].

Advertisement

4. 6-OHDA model

Ungerstedt and colleagues demonstrated that intracerebral stereotaxic injection of 6-OHDA causes degeneration of the nigrostriatal pathway [10]. To evaluate the 6-OHDA toxicity in vivo, three models of injury have been developed: (1) the medial forebrain bundle injection [47, 48], (2) the intranigral lesion [21, 49] and (3) the intra-striatal injury [20, 50, 51, 52]. Although injury to the medial forebrain bundle and the intranigral lesion is useful to demonstrate the immediate neurotoxic effects, it has the disadvantage of causing rapid and generalized degeneration of the injured nucleus [53], being unfavorable models to study the cell death type generated by long-term oxidative stress. However, the unilateral or bilateral intra-striatal model does cause the progressive loss of dopaminergic neurons of the SNpc, emulating the nigrostriatal damage observed in PD (Figure 1) [23, 24, 54, 55, 56].

Figure 1.

Overview of cellular processes promoted by 6-OHDA in rat.

4.1. Intra-striatal model

Kirik and colleagues [20] described that the ventrolateral region of striatum in the rat that receives afferents from the motor and the sensorimotor areas of the cortex and exclusive innervations of the SNpc. The dorsomedial region of the striatum has a mixture of innervations of the SNpc, the VTA, the frontal cortical area and the limbic system. Therefore, 6-OHDA lesions involving the dorsomedial region have general effects on locomotion and drug-induced (such as amphetamine and apomorphine) rotational behavior, while lesions affecting the ventrolateral region show effects pronounced at the beginning of the movement, sensorimotor orientation and fine motor behavior [20]. In addition, they observed that a single dose given at one striatal site causes 80% reduction in striatal innervation, and a loss of about 90% of the nigral dopaminergic population; while the dose administered at several sites of the striatum generates damage in extra-striatal innervation [20]. The effect of intra-striatal injection depends on the site of injury and dose.

The intra-striatal injection of 6-OHDA mainly affects dopaminergic neurons of the SNpc, and it also generates a reduction of dopaminergic neurons in the VTA, which form the mesolimbic pathway and innervate to the nucleus accumbens [28, 57]. The loss of dopaminergic neurons in the VTA does not exceed 20% of the population, and the damage does not progress over time, as observed in the SNpc. The 6-OHDA model does not replicate the presence of Lewy bodies [8], and for this reason, murine models with alpha-synuclein have been established. These approaches are based on gene knockout models [58], or gene overexpression [59] and intracerebral injection of alpha-synuclein [60]. These approaches might be the relevant in understanding the degeneration of the nigrostriatal pathway and its impact on other brain nuclei, but further research is still needed.

Advertisement

5. Neuroinflammation

Neuroinflammation in PD is characterized by microgliosis and astrogliosis increased around the dopaminergic neurons in SNpc [61]. These cellular process promotes high levels of expression of major histocompatibility complex type II (MHC-II) [62], chemokine receptors, integrins, neurotrophins and several other markers [63]. Elevated levels of pro-inflammatory cytokines, inducible nitric oxide synthase (iNOS), cyclooxygenase 2 (COX2), nitric oxide and reactive oxygen or nitrogen species (ROS/RNS) by NADPH oxidase system or by mitochondria are also observed in PD patients [31, 64]. Recently it has been demonstrated that copper-zinc superoxide dismutase (SOD1) released by microglial cells, or a TNF receptor 2 selective agonist, could confer neuroprotection against 6-OHDA toxicity in vivo [65, 66].

Injury of CNS leads to cell death, cellular swelling, excitotoxicity and the release of free radicals and nitric oxide, which triggers a strong glial response [67, 68] referred as reactive gliosis, involving the activation of microglia, astrocytes, oligodendrocytes and Neuron/glial 2 (NG2) cells [69, 70]. After injury, mature astrocytes proliferate and acquire stem cell properties suggesting their capacity to promote regeneration [71]. Depending on the stimulus and intensity of the lesion, all the three types of glia directs the cell either toward the neuroprotection by producing neurotrophic factors or toward the neurodegeneration by producing apoptotic mediators and ROS/RNS. However, NG2 cells, with their neurogenic [72], oligodendrogenic [73], astrogenic [74] and microgliogenic properties play indirect role in directing the cell toward apoptosis or protection. The presence of NG2-positive cells has been identified in SNpc but not in the striatum of the rat [75]. A recent study in a murine paradigm showed that conversion of NG2 cells to astrocytes to produce cerebral dopamine neurotrophic factor (CDNF) is anti-inflammatory in 6-OHDA-induced rat PD model [76]. However, studying the role, mode of activation and conversion of NG2 cells could give further clues to the field of neuroinflammation.

The neuroinflammatory process has been evaluated through glial cell markers such as glial fibrillary acidic protein (GFAP) for astrocytes [77, 78] and OX-42 or Iba-1 antibodies to microglia [79, 80]. The temporal course of activation of these glial populations has been determined by the neurotoxic effect, from day 3 post-injury [51], and even its activation was observed up to 3 weeks after injury with 6-OHDA [78]. The neuroinflammatory process to that precedes the death of nigral dopaminergic neurons (2 weeks post-injury) is probably a mechanism indicating cell damage. Another body of evidence suggests that the increase in the activation of glial cells, and the consequent release of pro- and anti-inflammatory cytokines at the site of damage, could increase the cytotoxicity of 6-OHDA [26]. Overexpression of human alpha-synuclein in a mouse model of PD showed enhanced expression of proinflammatory cytokines and microglial activation [81]. Recently, the studies focused on NG2 cells, mitochondrial dysfunction or Lewy body accumulation (trend topic based in alpha-synuclein model) has been relevant to understand neuroinflammatory process and define alternative therapeutic targets for PD.

Advertisement

6. Apoptosis

The majority of studies indicated that apoptosis is the main type of cell death produced by 6-OHDA, but necrosis and autophagy contribute on neurodegenerative process also [29, 82, 83]. Given the variety of experimental models, it is not still possible to determine the proportion of dopaminergic neurons of the SNpc affected by one or other types of cell death. However, the convergence of several types of cell death could explain the time course of degeneration and the activation of the neuroinflammatory process [84].

Cell death has been highlighted as the final effect of 6-OHDA cytotoxicity. Several techniques are used to determine cell death type in dopaminergic neurons in rats (TUNEL, silver staining, and immunostaining to caspase-3, GSK-3β, Bax, Bad) [85, 86, 87]. Interestingly TUNEL technique is unspecific to identify apoptosis because on in vitro studies the 6-OHDA induces necrosis at same dose used in vivo [88, 89]. So the use of other apoptotic markers is recommended to show the loss of cellular integrity or specific chromatin condensation on the dopaminergic neurons of the SNpc [51].

Caspase-3 is the major effector caspase in neurons and its activation has been demonstrated by applying neurotoxins in vitro and in vivo. This cysteine protease is enrolled both in intrinsic and in extrinsic apoptotic pathway [90, 91, 92]. In in vivo studies, its presence has been evidenced 1 week after intra-striatal injection of 6-OHDA in rats [78, 93]. Most in vivo studies have demonstrated the expression of caspase-3 in different cell death models, suggesting that caspase-3 activation is involved in programmed cell death of the SNpc [92, 94, 95]. However, some recent studies are unable to confirm the presence of active caspase-3 or caspase-9 and, based on this, state that these caspases are not involved in the apoptosis of dopaminergic neurons of the SNpC [96, 97]. This controversy is further exacerbated by recent findings demonstrating the involvement of caspase-3 in non-apoptotic functions, such as the activation of microglia [98, 99]. Although most authors agree with the involvement of caspase-3 in the 6-OHDA-induced neurodegeneration, the doubt still remains if caspase-3 expression only leads to neuronal death. It has therefore been necessary to explore other markers of the apoptotic process and in this regard, scientists have highlighted the study and role of glycogen synthase kinase 3β (GSK-3β).

GSK-3β is involved in the signaling pathway of neuronal apoptosis activated by oxidative stress [100], a central factor in the neuropathological process of PD [101]. GSK-3β is activated by phosphorylation of the tyrosine residue 216 (Y216), located in the kinase domain and inactivated by the phosphorylation of serine 9 (S9) [100]. It was observed that a single dose of 6-OHDA administered in the neostriatum of the rat causes caspase-3 and GSK-3β expression, loss of cytoskeletal integrity, TH levels decreased and activation of apoptotic process in dopaminergic neurons of SNpc [51, 85, 92].

Other authors demonstrated atrophy and progressive death of dopaminergic neurons dependent on translocation to the nucleus of the inducing factor of Apoptosis-inducing factor (AIF), in which there was no activation of caspase-3 or release of cytochrome C or signs of apoptosis. These researchers further demonstrate that death induced by 6-OHDA in dopaminergic neurons is mediated by activation of AIF-dependent Bax [97]. In this work, AIF activation suggests the involvement of regulated necrosis. The controversy between dependent or independent death of caspase-3 could be explained by the dose, study model and site of injury employed. However, since most evidence includes the involvement of caspase-3 in the 6-OHDA-induced apoptotic process, studies that contradict this fact suggest that 6-OHDA could also lead to neuronal death by apoptosis (independent of caspase-3) or other cell death processes (necrosis and autophagy) in vivo.

All the toxin-induced PD models had scant attention when it comes to the neuroprotective or regenerative strategies. Neuropathology and studies related to the correlation between inflammation and immune cells need to pay much more attention. It is of great interest to know the stimulus by which glial cells respond to the microenvironment and how do they decide whether to release neuroprotective or apoptotic mediators. It would be of interest to know if all the activated glial cells arise from a limited number of precursor cells or if all glia have equal potential to proliferate. It is also most important to study in detail about the types of receptors which are present on glial cells that play a major role in the field of neuroinflammation.

Advertisement

7. Relevance of 6-OHDA model in gene therapy

The 6-OHDA injury model has been used to demonstrate the benefits of neurotrophic therapy (NT) [102]. NT consists of directed delivery of genes encoding neurotrophic factors such as brain derived neurotrophic factor (BDNF) [103], glial cell line-derived neurotrophic factor (GDNF) [104, 105, 106, 107, 108, 109], cerebral dopamine neurotrophic factor (CDNF) [76, 110], mesencephalic astrocyte-derived neurotrophic factor (MANF) [111], vascular endothelial growth factor (VEGF) [112] through nanoparticles [113, 114], or through viral or non-viral gene vectors [76, 104, 105, 106, 107, 115]. The purpose of NT assessed in the 6-OHDA model is to prevent the progression of neurodegeneration and to stimulate the functional regeneration of the nigrostriatal system [116, 117]. The recovery of dopaminergic populations could improve motor function. It is therefore important to identify further underlying mechanisms of oxidative stress, neuroinflammation, neurodegeneration and neuronal death caused by 6-OHDA. This knowledge is the key to discovery novel therapies to treat PD.

Advertisement

8. Conclusion

The 6-OHDA model reproduces several cellular processes identified in the PD, therefore it is a key model to explore the molecular bases of cytotoxicity, as well as to study the cellular processes activated by oxidative stress (neuroinflammation and neuronal death), and consequently a useful model to understand the mechanisms of novel therapies for PD.

Advertisement

Acknowledgments

This work was supported by Consejo Nacional de Ciencia y Tecnología (Cátedra CONACyT # 1840 for DHB) and the Instituto de Neuroetología from Universidad Veracruzana (DGI-174332015137 to MJRH). Special thanks to Nancy Gabriela Vazquez Ixtepan, Cesar Augusto Sandoval Vargas and Erick Hernandez Baltazar for the illustration resources.

Advertisement

Abbreviations

6-OHDA6-hydroxydopamine
AIFapoptosis-inducing factor
BBBblood–brain barrier
BDNFbrain derived neurotrophic factor
CDNFcerebral dopamine neurotrophic factor
CNScentral nervous system
COX2cyclooxygenase 2
DATdopamine transporter
GDNFglial cell line-derived neurotrophic factor
GFAPglial fibrillary acidic protein
GSK-3glycogen synthase kinase-3
Iba-1ionized calcium binding adaptor molecule 1
iNOSinducible nitric oxide synthase
MANFmesencephalic astrocyte-derived neurotrophic factor
MHC-IImajor histocompatibility complex type II
MPP+1-methyl-4-phenylpyridinium
MPTP1-methyl-4-phenyl-1, 2, 3, 6-tetrahydropyridine
NADPHnicotinamide adenine dinucleotide phosphate
NATnoradrenaline transporter
NG2neuron/glial 2
NTneurotrophic therapy
OX-42CD11b antibody (integrin, alpha M)
oxDJ-1oxidized DJ-1 protein
PDParkinson’s disease
PINK1PTEN-induced putative kinase 1
ROSreactive oxygen species
ROS/RNSreactive oxygen or nitrogen species
S9serine 9
SNsubstantia nigra
SNpcsubstantia nigra pars compacta
SOD1superoxide dismutase 1
TNFtumor necrosis factor
TUNELterminal deoxynucleotidyl transferase mediated X-dUTP nick end labeling
VEGFvascular endothelial growth factor
VTAventral tegmental area
Y216tyrosine residue 216

References

  1. 1. Dexter DT, Jenner P. Parkinson disease: From pathology to molecular disease mechanisms. Free Radical Biology & Medicine. 2013;62:132-144
  2. 2. Sulzer D, Surmeier DJ. Neuronal vulnerability, pathogenesis, and Parkinson's disease. Movement Disorders. 2013;28(1):41-50
  3. 3. Double KL. Neuronal vulnerability in Parkinson's disease. Parkinsonism & Related Disorders. 2012;18(Suppl 1):S52-S54
  4. 4. Goldberg MS, Fleming SM, Palacino JJ, Cepeda C, Lam HA, Bhatnagar A, et al. Parkin-deficient mice exhibit nigrostriatal deficits but not loss of dopaminergic neurons. The Journal of Biological Chemistry. 2003;278(44):43628-43635 Epub 22-08-2003
  5. 5. Shaltouki A, Sivapatham R, Pei Y, Gerencser AA, Momcilovic O, Rao MS, et al. Mitochondrial alterations by PARKIN in dopaminergic neurons using PARK2 patient-specific and PARK2 knockout isogenic iPSC lines. Stem Cell Reports. 2015;4(5):847-859 Epub 07-04-2015
  6. 6. Blesa J, Przedborski S. Parkinson's disease: Animal models and dopaminergic cell vulnerability. Frontiers in Neuroanatomy. 2014;8:155
  7. 7. Bendor JT, Logan TP, Edwards RH. The function of alpha-synuclein. Neuron. 2013;79(6):1044-1066
  8. 8. Lindgren HS, Lelos MJ, Dunnett SB. Do alpha-synuclein vector injections provide a better model of Parkinson's disease than the classic 6-hydroxydopamine model? Experimental Neurology. 2012;237(1):36-42
  9. 9. Huang D, Xu J, Wang J, Tong J, Bai X, Li H, et al. Dynamic changes in the nigrostriatal pathway in the MPTP mouse model of Parkinson's disease. Parkinson's Disease. 2017;2017:9349487 Epub 24-08-2017
  10. 10. Ungerstedt U. 6-Hydroxy-dopamine induced degeneration of central monoamine neurons. European Journal of Pharmacology. 1968;5(1):107-110
  11. 11. Nistico R, Mehdawy B, Piccirilli S, Mercuri N. Paraquat- and rotenone-induced models of Parkinson's disease. International Journal of Immunopathology and Pharmacology. 2011;24(2):313-322 Epub 11-06-2011
  12. 12. Tieu K. A guide to neurotoxic animal models of Parkinson's disease. Cold Spring Harbor Perspectives in Medicine. 2011;1(1):a009316
  13. 13. Blum D, Torch S, Lambeng N, Nissou M, Benabid AL, Sadoul R, et al. Molecular pathways involved in the neurotoxicity of 6-OHDA, dopamine and MPTP: Contribution to the apoptotic theory in Parkinson's disease. Progress in Neurobiology. 2001;65(2):135-172
  14. 14. Altar CA, Heikkila RE, Manzino L, Marien MR. 1-Methyl-4-phenylpyridine (MPP+): Regional dopamine neuron uptake, toxicity, and novel rotational behavior following dopamine receptor proliferation. European Journal of Pharmacology. 1986;131(2-3):199-209
  15. 15. Oliveira LM, Tuppy M, Moreira TS, Takakura AC. Role of the locus coeruleus catecholaminergic neurons in the chemosensory control of breathing in a Parkinson's disease model. Experimental Neurology. 2017;293:172-180 Epub 23-04-2017
  16. 16. Kanazawa M, Ohba H, Nishiyama S, Kakiuchi T, Tsukada H. Effect of MPTP on serotonergic neuronal systems and mitochondrial complex I activity in the living brain: A PET study on conscious rhesus monkeys. Journal of Nuclear Medicine. 2017;58(7):1111-1116
  17. 17. Ter Horst GJ, Knigge MF, Van der Wal A. Neurochemical lesioning in the rat brain with iontophoretic injection of the 1-methyl-4-phenylpyridinium ion (MPP+). Neuroscience Letters. 1992;141(2):203-207
  18. 18. Javoy F, Sotelo C, Herbet A, Agid Y. Specificity of dopaminergic neuronal degeneration induced by intracerebral injection of 6-hydroxydopamine in the nigrostriatal dopamine system. Brain Research. 1976;102(2):201-215 Epub 06-02-1976
  19. 19. Sauer H, Oertel WH. Progressive degeneration of nigrostriatal dopamine neurons following intrastriatal terminal lesions with 6-hydroxydopamine: A combined retrograde tracing and immunocytochemical study in the rat. Neuroscience. 1994;59(2):401-415
  20. 20. Kirik D, Rosenblad C, Bjorklund A. Characterization of behavioral and neurodegenerative changes following partial lesions of the nigrostriatal dopamine system induced by intrastriatal 6-hydroxydopamine in the rat. Experimental Neurology. 1998;152(2):259-277
  21. 21. Stanic D, Finkelstein DI, Bourke DW, Drago J, Horne MK. Timecourse of striatal re-innervation following lesions of dopaminergic SNpc neurons of the rat. The European Journal of Neuroscience. 2003;18(5):1175-1188
  22. 22. Bezard E, Yue Z, Kirik D, Spillantini MG. Animal models of Parkinson's disease: Limits and relevance to neuroprotection studies. Movement Disorders. 2013;28(1):61-70 Epub 04-07-2012
  23. 23. Roedter A, Winkler C, Samii M, Walter GF, Brandis A, Nikkhah G. Comparison of unilateral and bilateral intrastriatal 6-hydroxydopamine-induced axon terminal lesions: Evidence for interhemispheric functional coupling of the two nigrostriatal pathways. The Journal of Comparative Neurology. 2001;432(2):217-229
  24. 24. Heuer A, Smith GA, Lelos MJ, Lane EL, Dunnett SB. Unilateral nigrostriatal 6-hydroxydopamine lesions in mice I: Motor impairments identify extent of dopamine depletion at three different lesion sites. Behavioural Brain Research. 2012;228(1):30-43
  25. 25. Blandini F, Armentero MT. Animal models of Parkinson's disease. The FEBS Journal. 2012;279(7):1156-1166
  26. 26. Stott SR, Barker RA. Time course of dopamine neuron loss and glial response in the 6-OHDA striatal mouse model of Parkinson's disease. The European Journal of Neuroscience. 2014;39(6):1042-1056
  27. 27. Jagmag SA, Tripathi N, Shukla SD, Maiti S, Khurana S. Evaluation of models of Parkinson's disease. Frontiers in Neuroscience. 2015;9:503 Epub 03-02-2016
  28. 28. Brichta L, Greengard P. Molecular determinants of selective dopaminergic vulnerability in Parkinson's disease: An update. Frontiers in Neuroanatomy. 2014;8:152
  29. 29. Giordano S, Darley-Usmar V, Zhang J. Autophagy as an essential cellular antioxidant pathway in neurodegenerative disease. Redox Biology. 2014;2:82-90
  30. 30. Harrison JF, Hollensworth SB, Spitz DR, Copeland WC, Wilson GL, LeDoux SP. Oxidative stress-induced apoptosis in neurons correlates with mitochondrial DNA base excision repair pathway imbalance. Nucleic Acids Research. 2005;33(14):4660-4671
  31. 31. Lull ME, Block ML. Microglial activation and chronic neurodegeneration. Neurotherapeutics. 2010;7(4):354-365
  32. 32. Chiba K, Trevor A, Castagnoli N, Jr. Metabolism of the neurotoxic tertiary amine, MPTP, by brain monoamine oxidase. Biochemical and Biophysical Research Communications. 1984;120(2):574-578
  33. 33. Glinka Y, Tipton KF, Youdim MB. Nature of inhibition of mitochondrial respiratory complex I by 6-hydroxydopamine. Journal of Neurochemistry. 1996;66(5):2004-2010
  34. 34. Schober A. Classic toxin-induced animal models of Parkinson's disease: 6-OHDA and MPTP. Cell and Tissue Research. 2004;318(1):215-224
  35. 35. Miyama A, Saito Y, Yamanaka K, Hayashi K, Hamakubo T, Noguchi N. Oxidation of DJ-1 induced by 6-hydroxydopamine decreasing intracellular glutathione. PLoS One. 2011;6(11):e27883
  36. 36. Singh S, Kumar S, Dikshit M. Involvement of the mitochondrial apoptotic pathway and nitric oxide synthase in dopaminergic neuronal death induced by 6-hydroxydopamine and lipopolysaccharide. Redox Report. 2010;15(3):115-122
  37. 37. Hirsch EC, Faucheux B, Damier P, Mouatt-Prigent A, Agid Y. Neuronal vulnerability in Parkinson's disease. Journal of Neural Transmission. Supplementum. 1997;50:79-88
  38. 38. Gerlach M, Riederer P, Double KL. Neuromelanin-bound ferric iron as an experimental model of dopaminergic neurodegeneration in Parkinson's disease. Parkinsonism & Related Disorders. 2008;14(Suppl 2):S185-S188
  39. 39. Segura-Aguilar J, Paris I, Munoz P, Ferrari E, Zecca L, Zucca FA. Protective and toxic roles of dopamine in Parkinson's disease. Journal of Neurochemistry. 2014;129(6):898-915
  40. 40. Rial D, Castro AA, Machado N, Garcao P, Goncalves FQ, Silva HB, et al. Behavioral phenotyping of Parkin-deficient mice: Looking for early preclinical features of Parkinson's disease. PLoS One. 2014;9(12):e114216 Epub 09-12-2014
  41. 41. LaVoie MJ, Ostaszewski BL, Weihofen A, Schlossmacher MG, Selkoe DJ. Dopamine covalently modifies and functionally inactivates parkin. Nature Medicine. 2005;11(11):1214-1221
  42. 42. Xu Y, Stokes AH, Roskoski R, Jr., Vrana KE. Dopamine, in the presence of tyrosinase, covalently modifies and inactivates tyrosine hydroxylase. Journal of Neuroscience Research. 1998;54(5):691-697
  43. 43. Hauser DN, Dukes AA, Mortimer AD, Hastings TG. Dopamine quinone modifies and decreases the abundance of the mitochondrial selenoprotein glutathione peroxidase 4. Free Radical Biology & Medicine. 2013;65:419-427
  44. 44. Nemoto C, Hida T, Arai R. Calretinin and calbindin-D28k in dopaminergic neurons of the rat midbrain: A triple-labeling immunohistochemical study. Brain Research. 1999;846(1):129-136
  45. 45. Tsuboi K, Kimber TA, Shults CW. Calretinin-containing axons and neurons are resistant to an intrastriatal 6-hydroxydopamine lesion. Brain Research. 2000;866(1-2):55-64
  46. 46. Arodin L, Miranda-Vizuete A, Swoboda P, Fernandes AP. Protective effects of the thioredoxin and glutaredoxin systems in dopamine-induced cell death. Free Radical Biology & Medicine. 2014;73:328-336
  47. 47. Perese DA, Ulman J, Viola J, Ewing SE, Bankiewicz KS. A 6-hydroxydopamine-induced selective parkinsonian rat model. Brain Research. 1989;494(2):285-293
  48. 48. Venero JL, Revuelta M, Cano J, Machado A. Time course changes in the dopaminergic nigrostriatal system following transection of the medial forebrain bundle: Detection of oxidatively modified proteins in substantia nigra. Journal of Neurochemistry. 1997;68(6):2458-2468
  49. 49. Stanic D, Parish CL, Zhu WM, Krstew EV, Lawrence AJ, Drago J, et al. Changes in function and ultrastructure of striatal dopaminergic terminals that regenerate following partial lesions of the SNpc. Journal of Neurochemistry. 2003;86(2):329-343
  50. 50. Decressac M, Mattsson B, Bjorklund A. Comparison of the behavioural and histological characteristics of the 6-OHDA and alpha-synuclein rat models of Parkinson's disease. Experimental Neurology. 2012;235(1):306-315
  51. 51. Hernandez-Baltazar D, Mendoza-Garrido ME, Martinez-Fong D. Activation of GSK-3beta and caspase-3 occurs in nigral dopamine neurons during the development of apoptosis activated by a striatal injection of 6-hydroxydopamine. PLoS One. 2013;8(8):e70951
  52. 52. Mercanti G, Bazzu G, Giusti P. A 6-hydroxydopamine in vivo model of Parkinson's disease. Methods in Molecular Biology. 2012;846:355-364
  53. 53. Blesa J, Phani S, Jackson-Lewis V, Przedborski S. Classic and new animal models of Parkinson's disease. Journal of Biomedicine & Biotechnology. 2012;2012:845618
  54. 54. da Rocha JT, Pinton S, Gai BM, Nogueira CW. Diphenyl diselenide reduces mechanical and thermal nociceptive behavioral responses after unilateral intrastriatal administration of 6-hydroxydopamine in rats. Biological Trace Element Research 2013;154(3):372-378
  55. 55. Kelsey JE, Langelier NA, Oriel BS, Reedy C. The effects of systemic, intrastriatal, and intrapallidal injections of caffeine and systemic injections of A2A and A1 antagonists on forepaw stepping in the unilateral 6-OHDA-lesioned rat. Psychopharmacology. 2009;201(4):529-539
  56. 56. Amalric M, Moukhles H, Nieoullon A, Daszuta A. Complex deficits on reaction time performance following bilateral intrastriatal 6-OHDA infusion in the rat. The European Journal of Neuroscience. 1995;7(5):972-980
  57. 57. Walsh JJ, Han MH. The heterogeneity of ventral tegmental area neurons: Projection functions in a mood-related context. Neuroscience. 2014;282:101-108
  58. 58. Tai Y, Chen L, Huang E, Liu C, Yang X, Qiu P, et al. Protective effect of alpha-synuclein knockdown on methamphetamine-induced neurotoxicity in dopaminergic neurons. Neural Regeneration Research. 2014;9(9):951-958
  59. 59. He Q, Koprich JB, Wang Y, WB Y, Xiao BG, Brotchie JM, et al. Treatment with trehalose prevents behavioral and neurochemical deficits produced in an AAV alpha-synuclein rat model of Parkinson's disease. Molecular Neurobiology. 2016;53(4):2258-2268
  60. 60. Roostaee A, Beaudoin S, Staskevicius A, Roucou X. Aggregation and neurotoxicity of recombinant alpha-synuclein aggregates initiated by dimerization. Molecular Neurodegeneration. 2013;8:5
  61. 61. Teismann P, Schulz JB. Cellular pathology of Parkinson's disease: Astrocytes, microglia and inflammation. Cell and Tissue Research. 2004;318(1):149-161
  62. 62. Sabol SL, Nirenberg M. Regulation of adenylate cyclase of neuroblastoma×glioma hybrid cells by alpha-adrenergic receptors. II. Long lived increase of adenylate cyclase activity mediated by alpha receptors. The Journal of Biological Chemistry. 1979;254(6):1921-1926 Epub 25-03-1979
  63. 63. Kettenmann H, Hanisch UK, Noda M, Verkhratsky A. Physiology of microglia. Physiological Reviews. 2011;91(2):461-553
  64. 64. Milligan ED, Watkins LR. Pathological and protective roles of glia in chronic pain. Nature Reviews. Neuroscience. 2009;10(1):23-36
  65. 65. Polazzi E, Mengoni I, Caprini M, Pena-Altamira E, Kurtys E, Monti B. Copper-zinc superoxide dismutase (SOD1) is released by microglial cells and confers neuroprotection against 6-OHDA neurotoxicity. Neuro-Signals. 2013;21(1-2):112-128 Epub 11-05-2012
  66. 66. Fischer R, Maier O, Siegemund M, Wajant H, Scheurich P, Pfizenmaier K. A TNF receptor 2 selective agonist rescues human neurons from oxidative stress-induced cell death. PLoS One. 2011;6(11):e27621 Epub 24-11-2011
  67. 67. Back T, Schuler OG. The natural course of lesion development in brain ischemia. Acta Neurochirurgica. Supplement. 2004;89:55-61
  68. 68. Bonfoco E, Krainc D, Ankarcrona M, Nicotera P, Lipton SA. Apoptosis and necrosis: Two distinct events induced, respectively, by mild and intense insults with N-methyl-D-aspartate or nitric oxide/superoxide in cortical cell cultures. Proceedings of the National Academy of Sciences of the United States of America. 1995;92(16):7162-7166
  69. 69. Bradl M, Lassmann H. Oligodendrocytes: Biology and pathology. Acta Neuropathologica. 2010;119(1):37-53 Epub 23-10-2009
  70. 70. Fitch MT, Silver J. CNS injury, glial scars, and inflammation: Inhibitory extracellular matrices and regeneration failure. Experimental Neurology. 2008;209(2):294-301
  71. 71. Buffo A, Rite I, Tripathi P, Lepier A, Colak D, Horn AP, et al. Origin and progeny of reactive gliosis: A source of multipotent cells in the injured brain. Proceedings of the National Academy of Sciences of the United States of America. 2008;105(9):3581-3586
  72. 72. Belachew S, Chittajallu R, Aguirre AA, Yuan X, Kirby M, Anderson S, et al. Postnatal NG2 proteoglycan-expressing progenitor cells are intrinsically multipotent and generate functional neurons. The Journal of Cell Biology. 2003;161(1):169-186
  73. 73. Tripathi RB, Rivers LE, Young KM, Jamen F, Richardson WD. NG2 glia generate new oligodendrocytes but few astrocytes in a murine experimental autoimmune encephalomyelitis model of demyelinating disease. The Journal of Neuroscience. 2010;30(48):16383-16390
  74. 74. Leoni G, Rattray M, Butt AM. NG2 cells differentiate into astrocytes in cerebellar slices. Molecular and Cellular Neurosciences. 2009;42(3):208-218
  75. 75. Kitamura Y, Inden M, Minamino H, Abe M, Takata K, Taniguchi T. The 6-hydroxydopamine-induced nigrostriatal neurodegeneration produces microglia-like NG2 glial cells in the rat substantia nigra. Glia. 2010;58(14):1686-1700
  76. 76. Nadella R, Voutilainen MH, Saarma M, Gonzalez-Barrios JA, Leon-Chavez BA, Jimenez JM, et al. Transient transfection of human CDNF gene reduces the 6-hydroxydopamine-induced neuroinflammation in the rat substantia nigra. Journal of Neuroinflammation. 2014;11:209
  77. 77. Middeldorp J, Hol EM. GFAP in health and disease. Progress in Neurobiology. 2011;93(3):421-443
  78. 78. Walsh S, Finn DP, Dowd E. Time-course of nigrostriatal neurodegeneration and neuroinflammation in the 6-hydroxydopamine-induced axonal and terminal lesion models of Parkinson's disease in the rat. Neuroscience. 2011;175:251-261
  79. 79. Aguzzi A, Barres BA, Bennett ML. Microglia: Scapegoat, saboteur, or something else? Science. 2013;339(6116):156-161
  80. 80. Rodrigues RW, Gomide VC, Chadi G. Astroglial and microglial activation in the wistar rat ventral tegmental area after a single striatal injection of 6-hydroxydopamine. The International Journal of Neuroscience. 2004;114(2):197-216
  81. 81. Theodore S, Cao S, McLean PJ, Standaert DG. Targeted overexpression of human alpha-synuclein triggers microglial activation and an adaptive immune response in a mouse model of Parkinson disease. Journal of Neuropathology and Experimental Neurology. 2008;67(12):1149-1158
  82. 82. In S, Hong CW, Choi B, Jang BG, Kim MJ. Inhibition of mitochondrial clearance and Cu/Zn-SOD activity enhance 6-hydroxydopamine-induced neuronal apoptosis. Molecular Neurobiology. 2016;53(1):777-791
  83. 83. Marin C, Aguilar E. In vivo 6-OHDA-induced neurodegeneration and nigral autophagic markers expression. Neurochemistry International. 2011;58(4):521-526
  84. 84. Jellinger KA. Cell death mechanisms in neurodegeneration. Journal of Cellular and Molecular Medicine. 2001;5(1):1-17
  85. 85. Marti MJ, Saura J, Burke RE, Jackson-Lewis V, Jimenez A, Bonastre M, et al. Striatal 6-hydroxydopamine induces apoptosis of nigral neurons in the adult rat. Brain Research. 2002;958(1):185-191
  86. 86. Blandini F, Levandis G, Bazzini E, Nappi G, Armentero MT. Time-course of nigrostriatal damage, basal ganglia metabolic changes and behavioural alterations following intrastriatal injection of 6-hydroxydopamine in the rat: New clues from an old model. The European Journal of Neuroscience. 2007;25(2):397-405
  87. 87. Zuch CL, Nordstroem VK, Briedrick LA, Hoernig GR, Granholm AC, Bickford PC.Time course of degenerative alterations in nigral dopaminergic neurons following a 6-hydroxydopamine lesion. The Journal of Comparative Neurology. 2000;427(3):440-454
  88. 88. Charriaut-Marlangue C, Ben-Ari Y. A cautionary note on the use of the TUNEL stain to determine apoptosis. Neuroreport. 1995;7(1):61-64
  89. 89. Ito Y, Shibata MA, Kusakabe K, Otsuki Y. Method of specific detection of apoptosis using formamide-induced DNA denaturation assay. The Journal of Histochemistry and Cytochemistry. 2006;54(6):683-692
  90. 90. Cutillas B, Espejo M, Gil J, Ferrer I, Ambrosio S. Caspase inhibition protects nigral neurons against 6-OHDA-induced retrograde degeneration. Neuroreport. 1999;10(12):2605-2608
  91. 91. D'Amelio M, Sheng M, Cecconi F. Caspase-3 in the central nervous system: Beyond apoptosis. Trends in Neurosciences. 2012;35(11):700-709
  92. 92. Oo TF, Siman R, Burke RE. Distinct nuclear and cytoplasmic localization of caspase cleavage products in two models of induced apoptotic death in dopamine neurons of the substantia nigra. Experimental Neurology. 2002;175(1):1-9
  93. 93. Sanchez-Iglesias S, Rey P, Mendez-Alvarez E, Labandeira-Garcia JL, Soto-Otero R. Time-course of brain oxidative damage caused by intrastriatal administration of 6-hydroxydopamine in a rat model of Parkinson's disease. Neurochemical Research. 2007;32(1):99-105
  94. 94. Hanrott K, Gudmunsen L, O'Neill MJ, Wonnacott S. 6-Hydroxydopamine-induced apoptosis is mediated via extracellular auto-oxidation and caspase 3-dependent activation of protein kinase Cdelta. The Journal of Biological Chemistry. 2006;281(9):5373-5382
  95. 95. Jeon BS, Kholodilov NG, Oo TF, Kim SY, Tomaselli KJ, Srinivasan A, et al. Activation of caspase-3 in developmental models of programmed cell death in neurons of the substantia nigra. Journal of Neurochemistry. 1999;73(1):322-333
  96. 96. Ebert AD, Hann HJ, Bohn MC. Progressive degeneration of dopamine neurons in 6-hydroxydopamine rat model of Parkinson's disease does not involve activation of caspase-9 and caspase-3. Journal of Neuroscience Research. 2008;86(2):317-325
  97. 97. Kim TW, Moon Y, Kim K, Lee JE, Koh HC, Rhyu IJ, et al. Dissociation of progressive dopaminergic neuronal death and behavioral impairments by Bax deletion in a mouse model of Parkinson's diseases. PLoS One. 2011;6(10):e25346
  98. 98. Burguillos MA, Deierborg T, Kavanagh E, Persson A, Hajji N, Garcia-Quintanilla A, et al. Caspase signalling controls microglia activation and neurotoxicity. Nature. 2011;472(7343):319-324
  99. 99. Venero JL, Burguillos MA, Joseph B. Caspases playing in the field of neuroinflammation: Old and new players. Developmental Neuroscience. 2013;35(2-3):88-101
  100. 100. Gomez-Sintes R, Hernandez F, Lucas JJ, Avila J. GSK-3 mouse models to study neuronal apoptosis and neurodegeneration. Frontiers in Molecular Neuroscience. 2011;4:45
  101. 101. Golpich M, Amini E, Hemmati F, Ibrahim NM, Rahmani B, Mohamed Z, et al. Glycogen synthase kinase-3 beta (GSK-3beta) signaling: Implications for Parkinson's disease. Pharmacological Research. 2015;97:16-26
  102. 102. Martinez-Fong D, Bannon MJ, Trudeau LE, Gonzalez-Barrios JA, Arango-Rodriguez ML, Hernandez-Chan NG, et al. NTS-Polyplex: A potential nanocarrier for neurotrophic therapy of Parkinson's disease. Nanomedicine: Nanotechnology, Biology, and Medicine. 2012;8(7):1052-1069 Epub 13-03-2012
  103. 103. Razgado-Hernandez LF, Espadas-Alvarez AJ, Reyna-Velazquez P, Sierra-Sanchez A, Anaya-Martinez V, Jimenez-Estrada I, et al. The transfection of BDNF to dopamine neurons potentiates the effect of dopamine D3 receptor agonist recovering the striatal innervation, dendritic spines and motor behavior in an aged rat model of Parkinson's disease. PLoS One. 2015;10(2):e0117391
  104. 104. Chen SS, Yang C, Hao F, Li C, Lu T, Zhao LR, et al. Intrastriatal GDNF gene transfer by inducible lentivirus vectors protects dopaminergic neurons in a rat model of parkinsonism. Experimental Neurology. 2014;261:87-96
  105. 105. Herran E, Requejo C, Ruiz-Ortega JA, Aristieta A, Igartua M, Bengoetxea H, et al. Increased antiparkinson efficacy of the combined administration of VEGF- and GDNF-loaded nanospheres in a partial lesion model of Parkinson's disease. International Journal of Nanomedicine. 2014;9:2677-2687
  106. 106. Deng X, Liang Y, Lu H, Yang Z, Liu R, Wang J, et al. Co-transplantation of GDNF-overexpressing neural stem cells and fetal dopaminergic neurons mitigates motor symptoms in a rat model of Parkinson's disease. PLoS One. 2013;8(12):e80880
  107. 107. Gonzalez-Barrios JA, Lindahl M, Bannon MJ, Anaya-Martinez V, Flores G, Navarro-Quiroga I, et al. Neurotensin polyplex as an efficient carrier for delivering the human GDNF gene into nigral dopamine neurons of hemiparkinsonian rats. Molecular Therapy. 2006;14(6):857-865
  108. 108. Espadas-Alvarez AJ, Bannon MJ, Orozco-Barrios CE, Escobedo-Sanchez L, Ayala-Davila J, Reyes-Corona D, et al. Regulation of human GDNF gene expression in nigral dopaminergic neurons using a new doxycycline-regulated NTS-polyplex nanoparticle system. Nanomedicine : Nanotechnology, Biology, and Medicine. 2017;13(4):1363-1375 Epub 22-02-2017
  109. 109. Hernandez-Chan NG, Bannon MJ, Orozco-Barrios CE, Escobedo L, Zamudio S, De la Cruz F, et al. Neurotensin-polyplex-mediated brain-derived neurotrophic factor gene delivery into nigral dopamine neurons prevents nigrostriatal degeneration in a rat model of early Parkinson's disease. Journal of Biomedical Science. 2015;22:59 Epub 23-07-2015
  110. 110. Cordero-Llana O, Houghton BC, Rinaldi F, Taylor H, Yanez-Munoz RJ, Uney JB, et al. Enhanced efficacy of the CDNF/MANF family by combined intranigral overexpression in the 6-OHDA rat model of Parkinson's disease. Molecular Therapy. 2015;23(2):244-254
  111. 111. Zhang J, Cai Q, Jiang M, Liu Y, Gu H, Guo J, et al. Mesencephalic astrocyte-derived neurotrophic factor alleviated 6-OHDA-induced cell damage via ROS-AMPK/mTOR mediated autophagic inhibition. Experimental Gerontology. 2017;89:45-56
  112. 112. Sheikh MA, Malik YS, Xing Z, Guo Z, Tian H, Zhu X, et al. Polylysine-modified polyethylenimine (PEI-PLL) mediated VEGF gene delivery protects dopaminergic neurons in cell culture and in rat models of Parkinson's disease (PD). Acta Biomaterialia. 2017;54:58-68 Epub 28-12-2016
  113. 113. Kulkarni AD, Vanjari YH, Sancheti KH, Belgamwar VS, Surana SJ, Pardeshi CV.Nanotechnology-mediated nose to brain drug delivery for Parkinson's disease: A mini review. Journal of Drug Targeting. 2015;23(9):775-788
  114. 114. Iqbal A, Ahmad I, Khalid MH, Nawaz MS, Gan SH, Kamal MA. Nanoneurotoxicity to nanoneuroprotection using biological and computational approaches. Journal of Environmental Science and Health. Part C, Environmental Carcinogenesis & Ecotoxicology Reviews. 2013;31(3):256-284
  115. 115. Wang L, Wang Z, Zhu R, Bi J, Feng X, Liu W, et al. Therapeutic efficacy of AAV8-mediated intrastriatal delivery of human cerebral dopamine neurotrophic factor in 6-OHDA-induced parkinsonian rat models with different disease progression. PLoS One. 2017;12(6):e0179476
  116. 116. Allen PJ, Feigin A. Gene-based therapies in Parkinson's disease. Neurotherapeutics. 2014;11(1):60-67
  117. 117. Pardo J, Morel GR, Astiz M, Schwerdt JI, Leon ML, Rodriguez SS, et al. Gene therapy and cell reprogramming for the aging brain: Achievements and promise. Current Gene Therapy. 2014;14(1):24-34

Written By

Daniel Hernandez-Baltazar, Rasajna Nadella, Maria de Jesus Rovirosa-Hernandez, Laura Mireya Zavala-Flores and Christian de Jesus Rosas Jarquin

Submitted: 01 August 2017 Reviewed: 26 September 2017 Published: 20 December 2017