- Email: [email protected]
The rotenone model of Parkinson's disease
Update
TRENDS in Neurosciences Vol.26 No.7 July 2003
unlikely that the stimulus we used could have triggered tetrodotoxin-insensitive [Ca2þ]i elevations in astrocytes, subsequent a Ca2þ-dependent release of glutamate and, finally, activation of metabotropic glutamate receptors in other astrocytes. However, we fully agree with Anderson and Nedergaard that there is an enormous amount of experimental and theoretical work yet to be done to characterize neurone-to-astrocyte signalling at the synaptic level. A better understanding of the rules governing neuronal activity-dependent activation of astrocytes is, indeed, crucial to dissection of the distinct role of these cells as modulators of neuronal transmission (through the release of glutamate, in addition to other neuroactive compounds) on the one hand, and as mediators of the neurovascular coupling (through the release of vasoactive agents) on the other.
345
References 1 Zonta, M. et al. (2003) Central role of neuron-to-astrocyte signaling in the dynamic control of brain microcirculation. Nat. Neurosci. 6, 43 – 50 2 Guthrie, P.B. et al. (1999) ATP released from astrocytes mediates glial calcium waves. J. Neurosci. 19, 520 – 528 3 Leybaert, L. et al. (1998) Inositol-trisphosphate-dependent intercellular calcium signaling in and between astrocytes and endothelial cells. Glia 24, 398 – 407 4 Braedt, K. et al. (2001) Astrocyte – endothelial cell calcium signals conveyed by two signalling pathways. Eur. J. Neurosci. 13, 79 – 91 5 Porter, J.T. and McCarthy, K.D. (1996) Hippocampal astrocytes in situ respond to glutamate released from synaptic terminals. J. Neurosci. 16, 5073– 5081 6 Pasti, L. et al. (1997) Intracellular calcium oscillations in astrocytes: a highly plastic, bidirectional form of communication between neurons and astrocytes in situ. J. Neurosci. 17, 7817– 7830 0166-2236/03/$ - see front matter q 2003 Elsevier Science Ltd. All rights reserved. doi:10.1016/S0166-2236(03)00142-5
| Letters
The rotenone model of Parkinson’s disease Ce´line Perier1, Jordi Bove´2, Miquel Vila1 and Serge Przedborski1,3,4 1
Department of Neurology, Columbia University, 650 West 168th Street, New York, NY 10032, USA Laboratori de Neurologia Experimental, Fundacio Clinic, Institut d’Investigacions Biomediques August Pi i Sunyer (IDIBAPS), Hospital Clinic, 08036 Barcelona, Spain 3 Department of pathology, Columbia University, 650 West 168th Street, New York, NY 10032, USA 4 Center of Neurobiology and Behavior, Columbia University, 650 West 168th Street, New York, NY 10032, USA 2
Parkinson’s disease (PD) is a common neurodegenerative disorder of unknown etiology, the cardinal features of which include tremor, rigidity, slowness of movement and postural instability [1]. Its pathological hallmarks are the loss of the nigrostriatal dopaminergic neurons and the presence of neuronal proteinacious cytoplasmic inclusions, known as Lewy bodies [1]. Rotenone, a mitochondrial poison whose relevance to the etiology of PD is unknown, represents the most recent approach to modeling PD in rats [2]. However, to date not enough time has passed for full evaluation of the rotenone model of PD and the published data raise several important questions pertaining to its significance and reliability. Rotenone freely crosses cellular membranes and accumulates in subcellular organelles such as mitochondria, where it impairs oxidative phosphorylation by inhibiting complex I of the electron transport chain [3]. Rotenone is often used as a prototypic mitochondrial poison in cell cultures but is used less frequently in living animals. In the latter, it has been administered orally [4], intravenously [5], stereotaxically [6] and by subcutaneous infusion [7] without, at least initially, any specific effects on dopaminergic neurons. Subsequently, Greenamyre and collaborators have found that intra-jugular and subcutaneous infusion of 2 – 3 mg kg21 d21 of rotenone for 28 – 56 days (or until behavioral abnormalities developed) to male Lewis rats produced specific nigrostriatal dopaminergic neurodegeneration [2,8]. Independently, Hirsch and Corresponding author: Serge Przedborski ([email protected]). http://tins.trends.com
collaborators found that intra-femoral venous infusion of 2.5 mg kg21 d21 of rotenone for 28 days to male Lewis rats also produced nigrostriatal dopaminergic neurodegeneration [9]. In these infusion studies, the severity of the striatal dopaminergic damage was highly variable within rat strains (ranging from none to near complete) and between rat strains [2,8,9]. Although this should not prevent the performance of meaningful studies aimed at elucidating the mechanisms of neuronal death in this model, it is a major impediment to using the model for testing experimental neuroprotective strategies. Perhaps this striking interindividual susceptibility to rotenone is worth investigating from the angle of genetic differences among rats, as it might provide insights into the environmental and/or genetic interaction hypothesis of PD pathogenesis. In successfully rotenone-lesioned rats, qualitative analyses failed to detect any striatal lesion [2,8] but, upon quantification, the numbers of DARP-32 (dopamine-and-cAMP-regulated phosphoprotein)-positive projecting neurons, cholinergic interneurons and NADPH-diaphorase-positive neurons in the striatum were all markedly reduced [9]. Similar to the loss of dopaminergic fibers, the loss of striatal neurons was maximal at the center of the striatum, which is reminiscent not of the lesion seen in PD but of the one produced by another mitochondrial poison, 3-nitropropionic acid [10]. These results underscore the importance of utilizing quantitative methods to address accurately the extent and specificity of the damage to the CNS caused by a toxin such as rotenone. They also suggest that rotenone exerts a much more widespread neurotoxicity than originally thought and,
346
Update
TRENDS in Neurosciences Vol.26 No.7 July 2003
contrary to the initial contention, that it does not cause a specific lesion of nigrostriatal dopaminergic neurons. So far, the two most popular toxic models of PD, produced by 6-hydroxydopamine and MPTP (1-methyl-4phenyl-1,2,3,6-tetrahydropyridine), have failed to produce typical Lewy-body-like inclusions in mammals; intraneuronal inclusions reminiscent of early Lewy bodies have been described occasionally in the MPTP model [11,12]. By contrast, in rotenone-infused rats, some of the residual nigrostriatal dopaminergic neurons contain proteinacious inclusions [2,8,9]. Although Lewy bodies are not specific to PD [13] and their role with respect to cell death remains controversial, their identification in the rotenone model is an unquestionable competitive advantage over the other common neurotoxic models of PD. However, whether this reflects differences in the neurotoxic mechanisms or merely differences in the mode of administration remains to be determined. Behaviorally, rotenone-infused rats exhibit reduced mobility, flexed posture and, in some cases, rigidity [8] and even catalepsy [14]. However, behaviors claimed to result from striatal dopaminergic deficiency should be demonstrated to improve with L -dopa or dopamine-agonist administration, as in PD. Thus far, it is unknown whether any of the rotenone-related motor alterations improve with administration of L -dopa or dopamine agonists. In addition, some rotenone-infused rats without nigrostriatal dopaminergic damage have been reported to exhibit a similar set of motor abnormalities [8]. Therefore, although the rotenonerelated motor abnormalities are dramatic, it is questionable whether they result from a loss of nigrostriatal dopaminergic neurons; hence, the use of these behavioral alterations as an experimental correlate of PD symptoms must be avoided until it has been properly validated. The rotenone model is clearly capable of killing nigrostriatal dopaminergic neurons in association with the formation of Lewy bodies, which so far has not been achieved by either 6-hydroxydopamine or MPTP. It might, therefore, be an invaluable tool for investigating the molecular basis of Lewy body formation and the link between this and nigrostriatal dopaminergic neuronal death. However, its eligibility as a model of PD beyond these two features is less certain, as quantitative data from at least one group have now documented striatal lesion of
non-dopaminergic neurons using the same regimen of rotenone infusion [9]. Acknowledgements We wish to acknowledge the support from the NIH/NINDS (NS37345, NS38586, NS42269 NS38370), the US Department of Defense Grant (DAMD 17-99-1-9471, DAMD 17-03-1), the Lowenstein Foundation, the Lillian Goldman Charitable Trust and the Parkinson’s Disease Foundation. J.B. is a recipient of a fellowship from the IDIBAPS (Barcelona, Spain).
References 1 Fahn, S. and Przedborski, S. (2000) In Merritt’s neurology (Rowland, L.P., ed.), pp. 679 – 693, Lippincott Williams & Wilkins 2 Betarbet, R. et al. (2000) Chronic systemic pesticide exposure reproduces features of Parkinson’s disease. Nat. Neurosci. 3, 1301– 1306 3 Schuler, F. and Casida, J.E. (2001) Functional coupling of PSST and ND1 subunits in NADH:ubiquinone oxidoreductase established by photoaffinity labeling. Biochim. Biophys. Acta 1506, 79 – 87 4 Marking, L. (1988) Oral toxicity of rotenone to mammals. U. S. Fish and Wildlife Serv. Investigations in Fish Control 94, 1 – 5 5 Ferrante, R.J. et al. (1997) Systemic administration of rotenone produces selective damage in the striatum and globus pallidus, but not in the substantia nigra. Brain Res. 753, 157 – 162 6 Heikkila, R.E. et al. (1985) Dopaminergic toxicity of rotenone and the 1-methyl-4-phenylpyridinium ion after their stereotaxic administration to rats: implication for the mechanism of 1-methyl-4-phenyl-1, 2,3,6-tetrahydropyridine toxicity. Neurosci. Lett. 62, 389– 394 7 Thiffault, C. et al. (2000) Increased striatal dopamine turnover following acute administration of rotenone to mice. Brain Res. 885, 283–288 8 Sherer, T.B. et al. (2003) Subcutaneous rotenone exposure causes highly selective dopaminergic degeneration and a-synuclein aggregation. Exp. Neurol. 179, 9 – 16 9 Ho¨glinger, G.U. et al. (2003) Chronic systemic complex I inhibition induces a hypokinetic multisystem degeneration in rats. J. Neurochem. 84, 1 – 12 10 Brouillet, E. et al. (1999) Replicating Huntington’s disease phenotype in experimental animals. Prog. Neurobiol. 59, 427– 468 11 Forno, L.S. et al. (1986) Locus ceruleus lesions and eosinophilic inclusions in MPTP-treated monkeys. Ann. Neurol. 20, 449 – 455 12 Kowall, N.W. et al. (2000) MPTP induces a-synuclein aggregation in the substantia nigra of baboons. NeuroReport 11, 211 – 213 13 Gibb, W.R. and Lees, A.J. (1988) The relevance of the Lewy body to the pathogenesis of idiopathic Parkinson’s disease. J. Neurol. Neurosurg. Psychiatry 51, 745 – 752 14 Alam, M. and Schmidt, W.J. (2002) Rotenone destroys dopaminergic neurons and induces parkinsonian symptoms in rats. Behav. Brain Res. 136, 317 – 324
0166-2236/03/$ - see front matter q 2003 Elsevier Science Ltd. All rights reserved. doi:10.1016/S0166-2236(03)00144-9
TINS online – making the most of your personal subscription High-quality printouts (from PDF files) Links to other articles, other journals and cited software and databases All you have to do is: Obtain your subscription key from the address label of your print subscription. Then go to http://www.trends.com, click on the Claim online access button and select Trends in Neurosciences. You will see a BioMedNet login screen. Enter your BioMedNet username and password. If you are not already a BioMedNet member, please click on the Register button. Once registered, you will be asked to enter your subscription key. Following confirmation, you will have full access to Trends in Neurosciences. If you obtain an error message please contact Customer Services ([email protected]) stating your subscription key and BioMedNet username and password. Please note that you only need to enter your subscription key once; BioMedNet ’remembers’ your subscription. Institutional online access is available at a premium. If your institute is interested in subscribing to print and online, please ask them to contact [email protected] http://tins.trends.com
TRENDS in Neurosciences Vol.26 No.7 July 2003
unlikely that the stimulus we used could have triggered tetrodotoxin-insensitive [Ca2þ]i elevations in astrocytes, subsequent a Ca2þ-dependent release of glutamate and, finally, activation of metabotropic glutamate receptors in other astrocytes. However, we fully agree with Anderson and Nedergaard that there is an enormous amount of experimental and theoretical work yet to be done to characterize neurone-to-astrocyte signalling at the synaptic level. A better understanding of the rules governing neuronal activity-dependent activation of astrocytes is, indeed, crucial to dissection of the distinct role of these cells as modulators of neuronal transmission (through the release of glutamate, in addition to other neuroactive compounds) on the one hand, and as mediators of the neurovascular coupling (through the release of vasoactive agents) on the other.
345
References 1 Zonta, M. et al. (2003) Central role of neuron-to-astrocyte signaling in the dynamic control of brain microcirculation. Nat. Neurosci. 6, 43 – 50 2 Guthrie, P.B. et al. (1999) ATP released from astrocytes mediates glial calcium waves. J. Neurosci. 19, 520 – 528 3 Leybaert, L. et al. (1998) Inositol-trisphosphate-dependent intercellular calcium signaling in and between astrocytes and endothelial cells. Glia 24, 398 – 407 4 Braedt, K. et al. (2001) Astrocyte – endothelial cell calcium signals conveyed by two signalling pathways. Eur. J. Neurosci. 13, 79 – 91 5 Porter, J.T. and McCarthy, K.D. (1996) Hippocampal astrocytes in situ respond to glutamate released from synaptic terminals. J. Neurosci. 16, 5073– 5081 6 Pasti, L. et al. (1997) Intracellular calcium oscillations in astrocytes: a highly plastic, bidirectional form of communication between neurons and astrocytes in situ. J. Neurosci. 17, 7817– 7830 0166-2236/03/$ - see front matter q 2003 Elsevier Science Ltd. All rights reserved. doi:10.1016/S0166-2236(03)00142-5
| Letters
The rotenone model of Parkinson’s disease Ce´line Perier1, Jordi Bove´2, Miquel Vila1 and Serge Przedborski1,3,4 1
Department of Neurology, Columbia University, 650 West 168th Street, New York, NY 10032, USA Laboratori de Neurologia Experimental, Fundacio Clinic, Institut d’Investigacions Biomediques August Pi i Sunyer (IDIBAPS), Hospital Clinic, 08036 Barcelona, Spain 3 Department of pathology, Columbia University, 650 West 168th Street, New York, NY 10032, USA 4 Center of Neurobiology and Behavior, Columbia University, 650 West 168th Street, New York, NY 10032, USA 2
Parkinson’s disease (PD) is a common neurodegenerative disorder of unknown etiology, the cardinal features of which include tremor, rigidity, slowness of movement and postural instability [1]. Its pathological hallmarks are the loss of the nigrostriatal dopaminergic neurons and the presence of neuronal proteinacious cytoplasmic inclusions, known as Lewy bodies [1]. Rotenone, a mitochondrial poison whose relevance to the etiology of PD is unknown, represents the most recent approach to modeling PD in rats [2]. However, to date not enough time has passed for full evaluation of the rotenone model of PD and the published data raise several important questions pertaining to its significance and reliability. Rotenone freely crosses cellular membranes and accumulates in subcellular organelles such as mitochondria, where it impairs oxidative phosphorylation by inhibiting complex I of the electron transport chain [3]. Rotenone is often used as a prototypic mitochondrial poison in cell cultures but is used less frequently in living animals. In the latter, it has been administered orally [4], intravenously [5], stereotaxically [6] and by subcutaneous infusion [7] without, at least initially, any specific effects on dopaminergic neurons. Subsequently, Greenamyre and collaborators have found that intra-jugular and subcutaneous infusion of 2 – 3 mg kg21 d21 of rotenone for 28 – 56 days (or until behavioral abnormalities developed) to male Lewis rats produced specific nigrostriatal dopaminergic neurodegeneration [2,8]. Independently, Hirsch and Corresponding author: Serge Przedborski ([email protected]). http://tins.trends.com
collaborators found that intra-femoral venous infusion of 2.5 mg kg21 d21 of rotenone for 28 days to male Lewis rats also produced nigrostriatal dopaminergic neurodegeneration [9]. In these infusion studies, the severity of the striatal dopaminergic damage was highly variable within rat strains (ranging from none to near complete) and between rat strains [2,8,9]. Although this should not prevent the performance of meaningful studies aimed at elucidating the mechanisms of neuronal death in this model, it is a major impediment to using the model for testing experimental neuroprotective strategies. Perhaps this striking interindividual susceptibility to rotenone is worth investigating from the angle of genetic differences among rats, as it might provide insights into the environmental and/or genetic interaction hypothesis of PD pathogenesis. In successfully rotenone-lesioned rats, qualitative analyses failed to detect any striatal lesion [2,8] but, upon quantification, the numbers of DARP-32 (dopamine-and-cAMP-regulated phosphoprotein)-positive projecting neurons, cholinergic interneurons and NADPH-diaphorase-positive neurons in the striatum were all markedly reduced [9]. Similar to the loss of dopaminergic fibers, the loss of striatal neurons was maximal at the center of the striatum, which is reminiscent not of the lesion seen in PD but of the one produced by another mitochondrial poison, 3-nitropropionic acid [10]. These results underscore the importance of utilizing quantitative methods to address accurately the extent and specificity of the damage to the CNS caused by a toxin such as rotenone. They also suggest that rotenone exerts a much more widespread neurotoxicity than originally thought and,
346
Update
TRENDS in Neurosciences Vol.26 No.7 July 2003
contrary to the initial contention, that it does not cause a specific lesion of nigrostriatal dopaminergic neurons. So far, the two most popular toxic models of PD, produced by 6-hydroxydopamine and MPTP (1-methyl-4phenyl-1,2,3,6-tetrahydropyridine), have failed to produce typical Lewy-body-like inclusions in mammals; intraneuronal inclusions reminiscent of early Lewy bodies have been described occasionally in the MPTP model [11,12]. By contrast, in rotenone-infused rats, some of the residual nigrostriatal dopaminergic neurons contain proteinacious inclusions [2,8,9]. Although Lewy bodies are not specific to PD [13] and their role with respect to cell death remains controversial, their identification in the rotenone model is an unquestionable competitive advantage over the other common neurotoxic models of PD. However, whether this reflects differences in the neurotoxic mechanisms or merely differences in the mode of administration remains to be determined. Behaviorally, rotenone-infused rats exhibit reduced mobility, flexed posture and, in some cases, rigidity [8] and even catalepsy [14]. However, behaviors claimed to result from striatal dopaminergic deficiency should be demonstrated to improve with L -dopa or dopamine-agonist administration, as in PD. Thus far, it is unknown whether any of the rotenone-related motor alterations improve with administration of L -dopa or dopamine agonists. In addition, some rotenone-infused rats without nigrostriatal dopaminergic damage have been reported to exhibit a similar set of motor abnormalities [8]. Therefore, although the rotenonerelated motor abnormalities are dramatic, it is questionable whether they result from a loss of nigrostriatal dopaminergic neurons; hence, the use of these behavioral alterations as an experimental correlate of PD symptoms must be avoided until it has been properly validated. The rotenone model is clearly capable of killing nigrostriatal dopaminergic neurons in association with the formation of Lewy bodies, which so far has not been achieved by either 6-hydroxydopamine or MPTP. It might, therefore, be an invaluable tool for investigating the molecular basis of Lewy body formation and the link between this and nigrostriatal dopaminergic neuronal death. However, its eligibility as a model of PD beyond these two features is less certain, as quantitative data from at least one group have now documented striatal lesion of
non-dopaminergic neurons using the same regimen of rotenone infusion [9]. Acknowledgements We wish to acknowledge the support from the NIH/NINDS (NS37345, NS38586, NS42269 NS38370), the US Department of Defense Grant (DAMD 17-99-1-9471, DAMD 17-03-1), the Lowenstein Foundation, the Lillian Goldman Charitable Trust and the Parkinson’s Disease Foundation. J.B. is a recipient of a fellowship from the IDIBAPS (Barcelona, Spain).
References 1 Fahn, S. and Przedborski, S. (2000) In Merritt’s neurology (Rowland, L.P., ed.), pp. 679 – 693, Lippincott Williams & Wilkins 2 Betarbet, R. et al. (2000) Chronic systemic pesticide exposure reproduces features of Parkinson’s disease. Nat. Neurosci. 3, 1301– 1306 3 Schuler, F. and Casida, J.E. (2001) Functional coupling of PSST and ND1 subunits in NADH:ubiquinone oxidoreductase established by photoaffinity labeling. Biochim. Biophys. Acta 1506, 79 – 87 4 Marking, L. (1988) Oral toxicity of rotenone to mammals. U. S. Fish and Wildlife Serv. Investigations in Fish Control 94, 1 – 5 5 Ferrante, R.J. et al. (1997) Systemic administration of rotenone produces selective damage in the striatum and globus pallidus, but not in the substantia nigra. Brain Res. 753, 157 – 162 6 Heikkila, R.E. et al. (1985) Dopaminergic toxicity of rotenone and the 1-methyl-4-phenylpyridinium ion after their stereotaxic administration to rats: implication for the mechanism of 1-methyl-4-phenyl-1, 2,3,6-tetrahydropyridine toxicity. Neurosci. Lett. 62, 389– 394 7 Thiffault, C. et al. (2000) Increased striatal dopamine turnover following acute administration of rotenone to mice. Brain Res. 885, 283–288 8 Sherer, T.B. et al. (2003) Subcutaneous rotenone exposure causes highly selective dopaminergic degeneration and a-synuclein aggregation. Exp. Neurol. 179, 9 – 16 9 Ho¨glinger, G.U. et al. (2003) Chronic systemic complex I inhibition induces a hypokinetic multisystem degeneration in rats. J. Neurochem. 84, 1 – 12 10 Brouillet, E. et al. (1999) Replicating Huntington’s disease phenotype in experimental animals. Prog. Neurobiol. 59, 427– 468 11 Forno, L.S. et al. (1986) Locus ceruleus lesions and eosinophilic inclusions in MPTP-treated monkeys. Ann. Neurol. 20, 449 – 455 12 Kowall, N.W. et al. (2000) MPTP induces a-synuclein aggregation in the substantia nigra of baboons. NeuroReport 11, 211 – 213 13 Gibb, W.R. and Lees, A.J. (1988) The relevance of the Lewy body to the pathogenesis of idiopathic Parkinson’s disease. J. Neurol. Neurosurg. Psychiatry 51, 745 – 752 14 Alam, M. and Schmidt, W.J. (2002) Rotenone destroys dopaminergic neurons and induces parkinsonian symptoms in rats. Behav. Brain Res. 136, 317 – 324
0166-2236/03/$ - see front matter q 2003 Elsevier Science Ltd. All rights reserved. doi:10.1016/S0166-2236(03)00144-9
TINS online – making the most of your personal subscription High-quality printouts (from PDF files) Links to other articles, other journals and cited software and databases All you have to do is: Obtain your subscription key from the address label of your print subscription. Then go to http://www.trends.com, click on the Claim online access button and select Trends in Neurosciences. You will see a BioMedNet login screen. Enter your BioMedNet username and password. If you are not already a BioMedNet member, please click on the Register button. Once registered, you will be asked to enter your subscription key. Following confirmation, you will have full access to Trends in Neurosciences. If you obtain an error message please contact Customer Services ([email protected]) stating your subscription key and BioMedNet username and password. Please note that you only need to enter your subscription key once; BioMedNet ’remembers’ your subscription. Institutional online access is available at a premium. If your institute is interested in subscribing to print and online, please ask them to contact [email protected] http://tins.trends.com