Key Event Title
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Key Event Components
Key Event Overview
AOPs Including This Key Event
|AOP Name||Role of event in AOP|
|Mitochondrial dysfunction and Neurotoxicity||AdverseOutcome|
Key Event Description
A large number of neurological disorders are characterized by a clinical syndrome with motor symptoms of bradykinesia, tremor, rigidity and postural instability. As these clinical features are common to multiple disorders, the clinical syndrome is referred as “parkinsonism” and when parkinsonism is representing the prevalent part of the syndrome, these are referred as “parkinsonian disorders”. Parkinson’s Disease (PD) is one of parkinsonian disorders and can have an idiopathic, genetic or toxic (i.e. MPTP induced parkinsonism) cause (Dickson 2012). All these disorders include a deregulation of the extrapyramidal system.
The pyramidal motor system comprises bundles of neurons originating in the motor centers of the cerebral cortex to terminate in the brainstem or in the spinal cord where they are responsible for voluntary control of motor functions (Brooks 1971). The extrapyramidal system, which is the anatomical organization of the AO, is the part of the motor system primarily involved in the control and regulation of involuntary motor control, and in fine tuning (Barnes et al., 1983). Especially the initiation and maintenance of complex movement patterns or of neuronal regulatory pathways involved in postural control of the body are regulated by the nigrostriatal system that is affected in parkinsonian states. The CNS input is modulated by extrapyramidal circuits before the execution of complex motor movements. The modulated information from the basal ganglia is looped back through the thalamus to the cortex, from where final motor signals are sent via the pyramidal system; i.e. the basal ganglia system is not involved in the control of motor neurons and striatal muscles, but it modulates the signals from the cortex to these systems. Thus, an impaired input of dopamine into the striatum leads to an impairment of this modulation loop, and a disturbance of basal ganglia feedback to the thalamus and cortex. This ultimately manifests in key parkinsonian symptoms such as tremor, rigidity, or bradykinesia (Bernheimer et al., 1973). These conditions can be generated experimentally by dopamine depletion with reserpine, by inhibition of dopamine receptors, by mechanical or chemical ablation of nigrostriatal dopamine neurons (cut of the median forebrain bundle or injection of the toxicant 6-OH-dopamine) or the application of toxicants that leading to a relatively selective death of dopaminergic neurons in the substantia nigra (e.g. MPTP) and therefore a reduction of dopamine in the striatum (Kolata et al., 1983).
The basal ganglia include the ventral striatum, the neostriatum composed of the putamen and the caudate nucleus, the globus pallidus pars externa (GPe), the globus pallidus pars interna (GPi), the subthalamic nucleus (STN), the substantia nigra pars reticulata (SNpr) and the substantia nigra pars compacta (SNpc) (Obeso et al., 2008). The main input sites into basal ganglia are the striatum and the STN where cortical (glutamatergic) innervations terminate in a topographically organized manner that largely reflects the organization in the cortex (Fallon et al., 1978; Takada et al., 1998). Both the GPi and the SNpr represent the main output nuclei projecting into the thalamus (Parent et al., 1999; Alexander et al., 1990). The connection between input and output nuclei is functionally organized into a “direct” and an “indirect” pathway (Silverdale et al., 2003). These two pathways in parallel regulate the activity of the basal ganglia output neurons of the GPi and STN and are modulated by dopamine in the striatum. The dopaminergic terminals in teh striatum originate from dopaminergic projections from the SNpc. Striatal dopamine modulates the activity of inhibitory GABAergic medium spiny neurons that make up 90% of all neurons in the striatum (Smith et al., 1994). Medium spiny neurons that preferentially express the D1 dopamine receptor are involved in the direct pathway and directly project into the two main output nuclei (GPi and SNpr). Activation of the D1 medium spiny neuronal direct pathway results in a reduction of the inhibitory basal ganglia output (GPi and SNpr) leading to a dis-inhibition of thalamic target neurons (Bolam et al., 2000). These events ultimately lead to an elevated activity in the respective cortical neurons, i.e. D1 signalling in the striatum leads to an increase in motor activity.
Medium spiny neurons predominantly expressing the D2 dopamine receptor mostly project to the GPe (Gerfen et al., 1990). Activation of D2 expressing neurons leads to an inhibition of their activity. D2 neurons of the indirect pathway connect the striatum with GPi/SNpr via synaptic connections in the GPe and the STN. Activating neurons originating in the STN project into the GPi/SNpr are glutamatergic. From the STN, activating glutamatergic neuronal projections into the GPi/SNpr lead to a basal, low activation. Activation of the indirect pathway by striatal dopamine from the substantia nigra hence leads to a low basal inhibitory GABAergic output into thalamic structures, and thus allows a strong motor cortex activation of the thalamus.
Functional anatomy of basal ganglia. A) Normal conditions. Striatal (STR) dopamine mainly originates from projections originating in the substantia nigra pars compacta (SNc). The STR is mainly composed of inhibitory GABAergic medium spiny neurons (MSN). MSN involved in the direct pathway directly project to the globus pallidus pars interna (GPi) and the sunstantia nigra pars reticulata (SNpr) leading to a basal inhibition of these output nuclei. MSN involved in the indirect pathway send inhibitory projections to the globus pallidus pars externa (GPe). Their activity is dampened by dopamine binding to D2 receptor expressing MSN in the striatum. B) Lack of striatal dopamine. Under conditions of a lack of striatal dopamine, inhibitory GABAergic neurons, originating in the striatum, receive less activation, resulting in a declined inhibition of GPi and SNpr inhibitory output. In the indirect pathway, the lack of dopamine causes a lack of its inhibitory influence on inhibitory GABAergic projections into the GPe. This accelerated inhibition of the GPe results in a decline in its inhibitory output into the STN. The decline in STN inhibition allows its overactivation, resulting in an excessive activation of stimulatory glutamatergic projections into the GPi and SNpr (according to Silverdale 2003).
Parkinson’s Disease is characterized by a decline in striatal dopamine input from the substantia nigra pars compacta (Smith t al., 1994). Under normal conditions, ganglial output via GPi/SNpr nuclei causes a moderate inhibitory influence on cortical and brainstem motor neurons. A reduction in striatal dopamine leads to an underactivation of D1 receptor-expressing medium spiny neurons of the direct pathway. This insufficient activation of the inhibitory GABAergic medium spiny neurons results in a reduction of its normal inhibitory influence on GPi and SNpr output nuclei. As a consequence, dopamine depletion leads to the overactivation of the inhibitory GABAergic GPi/SNpr output via the direct pathway (Mitchell et al., 1989).
In the indirect pathway, the reduced activation of D2 receptors expressing neurons leads to an overactivation of inhibitory output nuclei projecting into the GPe. The resulting inhibitory output of the GPe is hence reduced, thus leading to a declined inhibition of the STN. Overactivation of the stimulatory glutamatergic projections originating in the STN leads to the hyperactivation of the output GPi/SNpr nuclei. As a consequence of striatal dopamine depletion, the direct pathway becomes underactivated and the indirect pathway becomes overactivated. This leads to an overactivation of the basal ganglia output nuclei. Due to their inhibitory influence on thalamocortical motor centers, the resulting reduced cortical activation leads to the prominent impairment of motor functions in parkinsonian states (Silverdale et al., 2003).
The model of direct and indirect pathways linking striatal dopamine content with the basal ganglia output nuclei has been criticized in recent years as it ignores the influence of extrastriatal dopamine (Smith et al., 2000), or the fact that some medium spiny neurons express dopamine receptors of both the D1 and of the D2 type (Surmeier et al., 1996). Principal validity of the model and the central role of striatal dopamine was e.g. demonstrated by L-DOPA-mediated supplementation of striatal dopamine content in unprimed PD patients that causes a partial reduction in the overactivation of GPi/SNpr output (Yuan et al., 2010; Heimer et al., 2006). As an alternative way for symptomatic treatment of parkinsonian conditions, deep brain stimulation of either the STN or the GPi was shown to relieve from parkinsonian motor features (Mazzone 2003, Odekerken 2013).
How It Is Measured or Detected
For the analysis of striatal dopamine content and its correlation with motor control, both biochemical analysis methods on the cellular and tissue level as well as behavioral tests are required. Available test models are mice and rats on the one hand and non-human primates and humans on the other. Motor impairment features associated with parkinsonian states in man serve as reference standard. Monkey models have the advantage to largely reflect complex motor impairment patterns observed in humans which are rather difficult to assess in rodents. Rodent models in contrast are cost-efficient and allow both biochemical analysis that require major invasive methods as well as basic behavioral tests. Due to the limitations in the assessment of moderate motor impairment in rodents and the well-established correlation between striatal dopamine content and impaired motor output, analysis of striatal dopamine is often applied as surrogate readout for the assessment of motor deficits.
Detection of striatal dopamine (total or extracellular).
The standard method used in the majority of experimental work is the determination of total contents of dopamine and its two degradation metabolites HVA and DOPAC. For this purpose, the striatum is quickly removed from experimental animals, homogenized in a suitable acidic buffer, and the dopamine (metabolites) determined by HPLC with electrochemical detector or by HPLC-MS. For live in vivo detection of extracellular dopamine levels, a microdialysis probe is inserted into the striatum. Microdialysis can be performed in anesthetized animals or freely moving animals; basal dopamine levels or stimulated levels (amphetamine, KCl) can be recorded. Dopamine and its metabolites are detected in the dialysate either by HPLC or by HPLC-mass spectrometry analysis (Saraswat 1981, Cui 2009, Gonzalez 2011).
Detection of dopamine neuron terminals in the striatum.
As alternative to the detection of striatal dopamine that is to a large extent limited to live detection setups due to its instability in tissues, the number of remaining dopamine neurons in the substantia nigra pars compacta was suggested as alternative readout (Burns 1983). It allows the analysis of ex vivo samples without the limitations associated with the instability and reactivity of extravesicular dopamine. Although the number of surviving dopamine neurons in the SNpc in PD or in complex-I inhibitor challenged test animals is a valuable parameter on its own, it was discovered that the number of DA neurons in the SNpc not necessarily correlates with the amount of dopamine released in the striatum. Tyrosine hydroxylase (TH) was regularly stained as marker for DA neurons, however it was observed that TH expression was very variable following MPTP intoxication in the absence of cell death and therefore has only limited suitability for the assessment of DA neuronal numbers (Aznavour 2012). Second, many DA neurites and terminals displayed damage or degradation in the absence of death of the corresponding neuronal cell (Ling 2015). Hence, even in the presence of viable DA neurons in the SNpc, their corresponding terminals could no longer be able to release dopamine into the striatum. Staining of DA neuronal terminals in the striatum is therefore used as a more reliable indirect marker for striatal dopamine content. For the analysis of nigrostriatal terminals, the dopamine transporter (DAT) is visualized either by antibody-mediated staining in tissue slices or by the application of radioactively labeled DAT ligands that allow their application both in vivo and in ex vivo samples (Morris 1996).
Behavioral tests: Rodent models.
Rotation: the rotation model of Ungerstedt et al (Ungerstedt 1970) is based on the unilateral lesion of the nigrostriatal dopamine neuron system either in rodents or in non-human primates. The lesion can be produced either surgivally, or by stereotaxic infusion of e.g. 6-OHDA into the nigrostriatal system of one hemisphere, or by infusion of MPTP through one carotid (single sided). After the lesion, animals are left to recover, then the dopamine system is stimulated by injection of amphetamine. The asymmetry of remaining dopamine neurons (only on one side) triggers spontaneous asymmetric motor behaviour, i.e. rotations of the animals. Each full turn of an animal is recorded, the respective numbers of left- and right turns are plotted versus time, respectively. In the standard rotation model, monkeys become hypokinetic in the limbs on the contralateral side of the brain hemisphere treated. Rats preferentially rotate towards the side of the lesion upon treatment with drugs that trigger activation of the remaining dopamine neurons.
Rotarod: assessment of motor coordination. The animals are placed on a rotating rod that is subjected to linear acceleration. The latency to fall from the rod is detected (Jones 1968). Hang test: Detection of neuromuscular strength. Mice are placed on a horizontal grid. When the animals grabbed the grid with their fore- and hindpaws, the grid is inverted with the animal hanging upside down. In a typical setup, mice are required to remain on the grid for at least 30 s (Tillerson 2002).
Forepaw Stride length during walking. Ink is applied to the forepaws and the mice walk across a blank sheet of paper. Training of the animals to walk across the white paper in a straight line without stopping is performed before the respective treatment. The distance between single steps on each side are measured (Klapdor 1997).
Grid test: Mice hang upside down for 30 s on the grid that is also used for the Hang test and are recorded on video for closer analysis. With this method, the average forepaw distance is measured by assessing the distance covered, divided by the number of successful forepaw steps. In the course of the analysis, the number of unsuccessful forepaw steps are detected and displayed as percentage of the total number of steps performed (Crawley 1999).
Akinesia: the animal is placed on a flat surface and the latency until it has moved all of its four limbs is assessed.
Open field test: Infrared beams detect the animals activity for the determination of parameters such as the time spent locomoting, the distance travelled, or the number of rearings.
Pole test: the animal is placed on a gauze-taped pole with the head upwards below the top of the pole. Two parameters are detected: 1) time until animals turn by 180°; 2) time until the animals reach the floor.
Non-invasive imaging of DA neuron terminals
Positron emission tomography (PET): Based on its appropriate half life time of ca. 2 h for clinical investigations, fluorine-18 labeled L-[18F]-fluorodopa is routinely used in trace amounts for intravenous administration. Striatal uptake of L-[18F]-fluorodopa is followed by applying positron emission tomography (PET) (Leenders 1986).
Single photon emission computed tomography (SPECT): monitoring of dopamine transporter (DAT). Iodine-123-β-CIT is used as a sensitive ligand for dopamine and serotonin transporters and was applied in monkeys and humans (Winogrodzka 2003).
Human neurological tests
A recent systematic review and evaluation of currently used rating scales for the assessment of motor impairment and disability in PD patients identified the 1) Columbia University rating scale, 2) the Northwestern University Disability Scale, and 3) the Unified Parkinsons Disease rating scale as the most evaluated and reliable scales available (Ramaker 2002). All scales evaluate several parameters, some of which are not motor related. Thus, only subscales are useful for readout of motor symptoms (e.g. 13 of the 42 UPDRS parameters). Of these, not all are equally dependent on nigrostriatal dopamine. Examination needs to be done by a trained neurologist.
Domain of Applicability
Parkinson’s disease (PD) is a progressive age-related human neurodegenerative disease with a multi-factorial pathogenesis implicating various genetic and environmental factors and is more prevalent in males (Fujita et al., 2014). There are no sex and species restriction for the application of this AO; however aged animals showed to be more suscieptible to parkinsonian motor deficits induced by chemical stressors (Rose et al., 1993, Irwin et al., 1993, Ovadia et al., 1995)
Regulatory Significance of the Adverse Outcome
Neurotoxic effects shall be carefully addressed and reported in routine required regulatory toxicological studies (acute toxicity studies,short-term toxicity studies, long term toxicity and carcinogenicity studies and reproductive toxicity studies). Regarding neurotoxicity in rodents, inclusion of neurotoxicity investigations in routine toxicology studies shall also be considered. For pesticide active substances the circumstances in which neurotoxicity studies should be performed are listed in Regulation (EU) No 283/2013:
Specific neurotoxicity studies in rodents shall be performed in case of one those following conditions:
- there is indication of neurotoxicity in routine toxicity studies carried out with the active substance;
- the active substance is a structurally related to known neurotoxic compound;
- the active substance has a neurotoxic mode of pesticidal action.
As a result, specific neurotoxicity studies are not routinely required for all pesticide active substances. Specific neurotoxicity testing becomes obligatory only if neurotoxicity has been observed during histopathological evaluation or in case of structural analogy with a known neurotoxic compound. Motor activity should be measured once in short-term repeated dose toxicity studies (OECD 407, 408 and 422) and several times in specific neurotoxicity studies (OECD 424, OECD 426 and cohort 2 of OECD 443). However, this is not a requirement in chronic toxicity studies unless neurotoxic effects have been reported in the shorter studies. The same test (measures horizontal and/or vertical movements in a test chamber) is implemented in both routine studies and neurotoxicity studies. Coordination and balance are evaluated by rotation or rotarod or pole tests, and gait abnormalities by forepaw stride length test. Those tests are not required by any repeated dose toxicity OECD guidelines and they can be optionally incorporated in the design of neurotoxicity studies OECD 424 and OECD 426.
Although motor deficits is the AO in this AOP, degeneration of DA neurons, is also considered an adverse effect in the regulatory framework, even in the absence of clear clinical symptoms or motor deficits. Morphological assessment of brain structures is a standard requirement in the regulatory toxicological studies supporting the risk assessment of chemical substances and it is a regulatory expectation that the anatomical structures belonging to the nigrostriatal pathway would be included and evaluated as part of the standard evaluation of the brain. Treatment related neuronal degeneration, when occurring as a consequence of the treatment, is generally dose-dependent in incidence and severity. However, if not accompanied by clinical signs or behavioral changes indicative of central nervous system pathology, minimal loss of DA neurons would likely remain undetected in the standard histological evaluation, due to the presence of non DA neurons or as a consequence of the subjectivity of non-quantifiable analysis, unless specific markers are used. As multiple forms of perturbation can affect the neurons, some changes are potentially still reversible (e.g. loss of TH or DA) and irreversibility should be confirmed as part of the assessment. It is then important to apply a sensitive and appropriate method (Switzer 2000) and evaluation of the phenotypic markers in the striatum and in the SNpc should be always performed as a minimum standard (Minnema et al., 2014) when investigating perturbation of the nigrostriatal pathway. It should additionally consider that rat is likely to be a poor model to capture this kind of hazard, as demonstrated by the poor sensitivity of rat to MPTP or related compounds and this should be taken into account for the design and interpretation of the studies.
Dissimilarities of chemical induced animal models to human disease are also important and should be carefully weighted when considering the duration and schedule of the study/treatment. Differently from the human disease, with the MPTP animal model, the damage occurs rapidly, is hardly progressive, is little age-dependent and formation of Lewy bodies is sometime not occurring (Efremova et al., 2015). Therefore, for different animals models, the standard 90 days toxicity study could not match with the chronic and progressive characteristics of the human disease and compensatory changes influencing DA metabolism and turnover and protein catabolism can occur during the treatment period with an impact on the time of onset of the lesion (Ossowska et al., 2005).
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