parkinson s disease ( pd ) is an age - related degenerative disorder of the central nervous system .
it is often characterized by muscle rigidity , tremor , slowing of physical movement ( bradykinesia ) and , in extreme cases , loss of physical movement ( akinesia ) .
the symptoms of pd are attributed to the loss of pigmented dopamine - secreting ( dopaminergic ) neurons in the pars compacta region of the substantia nigra ( sn ) and a subsequent striatal deficiency of dopamine .
idiopathic pd is also pathologically characterized by the presence of cytoplasmic neuronal inclusions , called lewy bodies , in the affected region of the brain .
the etiology of the disease has been poorly understood , and development of novel non - dopaminergic therapeutic strategies has remmained challenging since initial description of the disease by james parkinson in 1817 .
although pharmacological dopamine replacement strategies provide temporary symptomatic relief , there are at present no therapeutic methods for halting progressive neuronal cell loss .   
mptp neurotoxicity develops only after metabolization to mpdp+ by mao - b in glial cells and then to mpp+ , the active toxic compound .
animal models are an important tool in elucidating mechanisms involved in the pathological process and in investigating new therapeutic strategies for pd .
currently , both genetic and toxic models of pd are available , but use of neurotoxins , such as 6-hydroxydopamine ( 6-ohda ) , paraquat , 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine ( mptp ) and rotenone , is still the most popular means of modeling destruction of the nigrostriatal dopaminergic neurons seen in pd . among these neurotoxins ,
6-ohda and mptp have been more extensively used by investigators to produce pd models despite their limitations .
the neurotoxin 6-ohda is a structural analogue of catecholamines , dopamine and noradrenaline , and exerts its toxic effects on catecholaminergic neurons .
since 6-ohda does not penetrate the blood brain barrier in adult rats , it must be administrated stereotactically into the substantia nigra or striatum to damage the dopaminergic nigrostriatal system .
recognition of mptp as a neurotoxin occurred early in 1982 , when several young drug addicts mysteriously developed a profound parkinsonian syndrome after intravenous use of street preparations of meperidine analogs that , unknown to anyone , were contaminated with mptp , an incidental byproduct during the chemical synthesis of a meperidine analog ( fig .
it is also well known that mptp depletes striatal dopamine and causes damage to the substantia nigra pars compacta ( snpc ) dopaminergic neurons in non - human primates and several species of rodents .
recently , a great deal of interest has been focused on stem cell therapies for pd .
in addition to fetal nigral transplantation , the capability of self - repair in the central nervous system ( cns ) in the adult mammalian has also given a new perspective in the cell - based approach for treatment of neurodegenerative disorders .
in pd or its animal models , much attention has been attracted to whether the depletion of dopaminergic neurons triggers activation of neural stem cells and their subsequent migration into the damaged area , finally resulting in repopulation of dopaminergic neurons in the sn .
this review will provide the body of evidence available for endogenous neurogenesis in response to neurotoxin damage in animal models of pd .
   schematic representations of the migratory pattern of newly generated a cells in the svz ( up ) and the cell populations in the sgz of the dg ( bottom left ) and svz ( bottom right ) in the adult rodent brain ( adapted from ref .
neurogenesis continues into adult life in the brains of rodents , nonhuman primates , and humans .
it is confined largely to two discrete areas , the subventricular zone ( svz ) and the subgranular zone ( sgz ) of dentate gyrus ( dg ) ( fig .
the svz , located throughout the inner wall of the lateral ventricle , is the largest germinal region and harbors neural stem cells that retain the capacity to generate multiple cell types .
the svz is composed of neural progenitor cells ( migrating neuroblasts , a cells ) , neural stem cells ( astrocytes , b cells ) , neural precursor cells ( rapidly dividing transit amplifying cells , c cells ) and ependymal cells ( fig .
2 ) . neural stem b cells divide to give rise to clusters of precursor c cells , which in turn generate neuroblast a cells . newly generated
a cells in the svz migrate through a network of tangential pathways in the lateral wall of the lateral ventricle and then converge onto the rostral migratory stream ( rms ) to enter the olfactory bulb ( ob ) via a  chain migration  behavior , in which they differentiate into granule cells and interneurons ( fig .
it has been suggested that prokineticin 2 ( pk2 ) serves as a chemoattractant for svz - derived neuroblast a cells , which appears to guide the migration of a cells from the svz through the rms to their final layers in the ob .
the multipotential a cells residing in the svz and rms are eliminated through apoptosis to maintain a balance for proper development of the mammalian nervous system .
metalloproteinases ( mmps ) may also play a crucial role in the migration of individual a cells since their migration rates are reduced by the presence of inhibitors of mmps .
the architecture and function of the adult human svz differs significantly from that described in other mammals .
there are four layers of varying thicknesses and cell densities throughout the lateral ventricular wall : a monolayer of ependymal cells ( layer i ) , a hypocellular gap ( layer ii ) , a ribbon of cells ( layer iii ) composed of astrocytes and a transitional zone ( layer iv ) into the brain parenchyma .
neuronal progenitors in the adult mammalian hippocampal dg reside in the sgz , which is located in the hilus immediately beneath the granular layer of the dg .
neurogenesis in the dg was first demonstrated 40 years ago by autoradiography in rodents and thereafter was further demonstrated in all mammalian species including human and nonhuman primates .
two types of neural progenitors can be identified in the sgz according to their specific morphologies and expression of unique sets of molecular markers ( fig.2 ) .
the primary progenitors ( type-1 cells ) have the appearance of radial glia , which also express glial fibrillary acidic protein ( gfap ) .
they share similar features with type the b cells residing in the adult svz and are suggested to be a putative stem cell population .
type-2 cells ( intermediate progenitors ) are gfap - negative and highly proliferative , sharing similar features with the neuroblast a cells residing in the adult svz .
type-2 cells may arise from type 1 cells , but direct evidence delineating this lineage relationship is still lacking .
newborn type-2 cells disperse and migrate a short distance into the granule cell layer where they differentiate , extend axons and express neuronal marker proteins .
the migration of newborn neurons in the dentate gyrus may also be controlled by guidance cues , as these cells only migrate to the hilus or molecular layer under pathological conditions , such as in animal models of temporal lobe epilepsy .
dopamine plays important roles in many physiological functions , including motor control , mood and the reward pathway , and as a neurotransmitter , it binds to the five types of dopamine receptor , d1 , d2 , d3 , d4 and d5 , and their variants .
the d1 and d5 receptors are members of the d1-like family ( d1l ) , whereas the d2 , d3 and d4 receptors are members of the d2-like family ( d2l ) .
it is known that both pd and neurotoxin - induced pd animal models are mainly characterized by a hallmark of dopamine depletion .
neurogenesis is a key event during both physiological and pathological processes and is regulated by a variety of stimuli , such as hormones , intrinsic growth factors , neurotransmitters , exogenously applied agents , environmental factors , exercise and age .
the activation of dopamine receptors influences cell proliferation in the lateral ganglionic eminence ( lge ) and the neuroepithelium of the frontal cortex in embryonic mice .
dopamine has attracted a lot of attention concerning the role it plays in adult neurogenesis in recent years . in pd animal models , the first thing that needs to be clarified
is whether decreased / increased neurogenesis is associated with the dopamine - involved signaling pathway or is a response to destruction of the nigrostriatal system . by using immunohistochemical and ultrastrctural analyses , hglinger et al .
have provided anatomical evidence that d2l receptors in the svz are expressed predominately on c cells , whereas a cells express both d1l and d2l receptors in the mouse brain .
dopaminergic fiber has also been confirmed to contact precursor cells in the svzs of adult humans and primates .
thus , dopamine seems to play a key role in the regulation of adult mammalian neurogenesis .
findings from in vitro experiments show that activation of the d2l receptor directly stimulates proliferation of svz precursor cells .
this is supported by a recent study , in which stimulation of dopamine d2 receptors increased the proliferation of neural progenitor cells both in vivo and in vitro .
the depletion of nigrostriatal dopamine reduces precursor cell production in the svzs of mice and aged primates and further leads to impaired neurogenesis in the ob .
based on the finding that acute administration of sch23390 , a d1 receptor antagonist , reduces the number of 5-bromodeoxyuridine ( brdu)-positive cells in the sgz of the dg , suzuki et al .
suggest that adult neurogenesis in the dg may be regulated naturally by dopamine via d1-like receptors .
a very recent report demonstrated that dopamine regulates adult neurogenesis by a mechanism of modulating ciliary neurotrophic factor ( cntf ) expression in svz astrocytes .
the findings of van kampen et al . indicate that administration of the dopamine d3 receptor agonist , 7-hydroxy - n , n - di - n - propyl-2-aminotetralin ( 7-oh - dpat ) , significantly increases the proliferation of neural stem cells ( nscs ) in the adult rat brain but not in the adult mouse brain .
furthermore , chronic intraventricular administration of 7-oh - dpat triggers a profound induction of cell proliferation in the rat sn and promotes adoption of a neuronal phenotype in some of these newly generated cells . on the other hand
, it has been suggested that treatment with 7-oh - dpat does not affect the proliferation , survival or neurogenesis of murine and human neural progenitor cells derived from the fetal midbrain in vitro .
moreover , chronic treatment with the antipsychotic drug haloperidol leads to increased nsc numbers , resulting in more progenitors and more new neurons and glia in the adult rat brain due to a mechanism of antagonizing dopamine at the d2 receptors on nscs .
mptp neurotoxicity develops only after metabolization to 1-methyl-4-phenyl-2,3-dihydropyridinium ( mpdp+ ) by an enzyme , monoamine oxidase ( mao)-b , and further to 1-methyl-4-phenylpyridinium ( mpp+ ) , the active toxic compound ( fig .
since mpp+ is selectively transported into presynaptic dopaminergic nerve terminals through the dopamine transporter ( dat ) and the absence of the dat on dopaminergic neurons confers complete protection against mptp toxicity , the neurotoxicity of mptp is suggested to be selective to dopaminergic neurons in the sn .
mptp is mainly used in non - human primates and rodents , and the latter are less sensitive to mptp neurotoxicity . in rodents ,
c57bl/6 mice have been used in a great deal of reports for creation of a pd animal model for understanding the disease pathogenesis , despite their limitions .
first provided morphological evidence that administration of mptp leads to a 2-fold increase of brdu incorporation in nigral dopaminergic neurons .
newly generated dopaminergic neurons has been demonstrated to be derived from the cells lining the ventricular system . by using the nestin second intron enhancer - controlled lacz reporter transgenic mouse model coupled with the mptp lesion system , shan et al . demonstrated that there is increased dopaminergic neurogenesis in the sn , supporting the findings of zhao et al . as described above . in rat and macaque monkey hemi - parkinsonian models
treated stereotatically with mpp+ , the dopamine - depleted hemisphere showed more polysialic acid ( psa)-positive cells , candidates for newly differentiated young neurons , than the intact side , and a small number of tyrosine hydroxylase ( th)-positive cells were demonstrated to be psa - positive . in the striatum of the mptp - treated aged macaque , although there is an increase in the number of th - immunoreactive neurons , the increase has been suggested to be derived from pre - existing gabaergic interneurons ( phenotype shift ) , not neurogenesis .
performed a retroviral vector - based method to evaluate neurogenesis in the obs of mptp - treated mice , and the results showed that dopaminergic neurogenesis can be enhanced in the ob after dopaminergic neuron loss .
increased neurogenesis has also been confirmed in a very recent paper , in which mptp lesions increased the incorporation of brdu as well as the number of cells that co - expressed brdu and the immature neuronal marker doublecortin ( dcx ) in the dg , svz and striatum , but not in the sn of the mptp - treated mouse , although the differentiation of newly generated cells into dopaminergic neurons was not investigated . on the other hand ,
demonstrated that proliferation of transit amplifying cells ( c cells ) is impaired in the svz and sgz in the mptp mouse model for pd .
c cells are the target of a dopaminergic innervations , and impaired neurogenesis in the svz is thus suggested to be mediated by mptp administration - induced dopamine depletion .
furthermore , reduced c cells lead to a subsequent decrease in a cells . in adult macaques
, mptp - induced dopamine depletion also results in decreases in the number of proliferating cell nuclear antigen - positive ( pcna ) cells and a cells in the svz , suggesting that intact dopaminergic nigro - subventricular innervation is crucial for sustained neurogenesis in aged primates .   
the majority of brdu - positive cells in the svz are rapidly depleted at 2 days , and only few brdu - positive cells migrate into the ob at 7 days after mptp administration . in recent years
, the selective neurotoxicity of mptp in the dopaminergic system of the adult brain has been challenged .
a number of studies have demonstrated that mptp also destroys forebrain migrating neuroblasts and nigrostriatal glial cells ( astrocytes ) in the adult mouse brain . in our previous studies ,
the number of apoptotic cells in the svz and rms peaked at 24 hours after mptp injections and decreased thereafter , paralleling the changes in number of cleaved caspase-3-positive cells .
the cells undergoing apoptosis in the svz , rms and ob were identified as a cells using immunohistochemistry and ultrastructural analyses , while a few were astrocytes ( b cells ) , and none were transit - amplifying procursors ( c cells ) .
the decrease in a cell numbers was most marked on day 2 and lasted to day 8 after administration .
we also demonstrated that mao - b inhibitors , such as deprenyl or n-(2-aminoethyl)-4-chlorobenzamide ( ro 16 - 6491 ) completely protected a cells against mptp neurotoxicity , suggesting that mptp neurotoxicity in a cells is also mediated by the conversion of mptp into mpp+ by mao - b .
a cells are main populations in the svz and rms of the adult brain , and proliferation of a cells may contribute to dult endogenous neurogenesis . using brdu labeling ,
we provided evidence that mptp injury leads to transiently impaired neurogenesis in the adult mouse svz and ob . the majority of brdu - positive cells in the svz are rapidly depleted by mptp , and only a few brdu - positive cells migrate into the ob thereafter ( fig .
3 ) . thus , impaired neurogenesis is more likely to be due to an mptp - induced decrease in a cells rather than a mechanism through dopamine depletion as reported in previous studies .
impaired neurogenesis persists for about two weeks in the mptp - injured mouse brain and is followed by recruitment of cells in the svz ( he et al . , unpublished data ) .
the self - repairing process for the damaged germinal region is evidenced by regeneration of a cells ( he et al . , unpublished data ) .
thus , neurogenesis in the nigrostriatal system in response to mptp damage , if it does occur , may be a later event in the self - repairing process of the injured svz .
in a recent study , increases in brdu - positive cells and brdu - dcx double - labeled cells in the svz were observed 14 d after acute mptp treatment .
this , however , may have been due to an activated self - repairing process in the svz rather than a response to nigrostriatal damage .
since 6-ohda does not penetrate the blood brain barrier in adults , it must be administrated stereotactically into the substantia nigra or striatum to damage the dopaminergic nigrostriatal system .
although administration of 6-ohda produces a decreased striatal dopamine level and loss of dopaminergic neurons in the sn in the adult brain , the 6-ohda model does not mimic any clinical or pathological features of pd . in adult rats , when the right mesencephalic dopaminergic neurons are ablated by stereotactical injection of 6-ohda into the right nigrostriatal pathway , the number of pcna - positive cells in the svz ipsilateral to the lesion decreases .
impaired proliferation of cells in the svz has also been suggested to be mediated by a mechanism of dopamine depletion as suggested in mptp animals .
evidence from c57bl/6 mice injected unilaterally with 6-ohda into the midbrain part of the medial forebrain bundle also show impaired neurogenesis , and 6-ohda - induced dopaminergic denervation of the striatum reduces cntf mrna levels in the svz , which further contributes to negative regulation of the proliferation of cells .
although the proliferation of nscs in the svz and dg in the adult brain is an important neurogenesis process and has been demonstrated in some neurodegenerative diseases , it remains controversial whether those proliferated nscs migrate into the damaged area and repopulate the lost functional neurons .
treatment of 6-ohda also leads to a transient decrease in neurogenesis in the olfactory granule cell layer , but , in contrast , an increase of neurogenesis is present in the glomerular layer .
the increased neurogenesis in the glomerular layer is characterized by more newly generated neuronal nuclear antigen ( neun)- and th - expressing neurons , indicating a shift in cell fate decision for newly generated neuronal precursors targeted at the glomerular layer .
detected increases in cell proliferation in the sn in rats injected with 6-ohda into the median forebrain bundle ; however , none of the newly born cells expressed a dopaminergic phenotype , and there is no evidence of neural stem cells emanating from the cerebroventricular system and migrating to the substantia nigra .
growth factors , such as platelet - derived growth factor ( pdgf - bb ) and brain - derived neurotrophic factor ( bdnf ) , can induce striatal neurogenesis in adult rats with 6-ohda lesions , and there are no indications of any newly born cells differentiating into dopaminergic neurons following growth factor treatment both in the striatum and in the sn .
surprisingly , in a salamander 6-ohda model for pd , robust and complete regeneration of the mesencephalic and diencephalic dopamine system occurs after elimination of dopaminergic neurons .
this 6-ohda salamander model gives new insight into the animal models for pd and may be helpful for understanding the molecular mechanism of dopaminergic neurogenesis .
the findings of steiner et al . indicate that the absolute numbers of newborn cells in the sn are not affected by dopamine depletion in the 6-ohda rat model for pd .
instead , 6-ohda lesions induce a specific downregulation of generation of newborn nigral astrocytic cells .
the replacement of lost neurons in a damaged brain area is the best direction for therapeutic development in relation to neurodegenerative diseases .
based on all of the available evidence , neurogenesis is still a most controversial issue in studies of neurodegenerative diseases and their animal models . in mptp animal models for pd , we have demonstrated that mptp destroys a cells in the svz and ob in the adult brain and then transiently impairs neurogenesis ; however , it remains to be investigated whether and how multiple potential neural stem cells migrate into the nigrostriatal system and replace the lost dopaminergic neurons . with increased attention to dopaminergic neurogenesis in neurotoxin - induced animal models for pd , it is expected that the models will become useful as tools for understanding the mechanisms for neurogenesis in pd and that many questions regarding neurogenesis in neurodegenerative diseases will be resolved .
   animal models for parkinson s disease ( pd ) are essential for understanding its pathogenesis and for development and testing of new therapies . 
 discoveries of endogenous neurogenesis in the adult mammalian brain give new insight into the cell - based approach for treatment of neurodegenerative disorders , such as pd . 
 although a great deal of interest has been focused on endogenous neurogenesis in neurotoxin - induced animal models for pd , it still remains controversial whether neural stem cells migrate into the injured area and contribute to repopulation of depleted dopaminergic neurons in neurotoxin - injured adult brains . 
 the purpose of this review is to examine the data available regarding neurogenesis in neurotoxin - induced animal models of pd . 
 it is hoped that data from the animal investigations available in the literature will promote understanding of the neurotoxin - induced animal models for pd . 