Neuroprotective Clinical Strategies for Pxkmson’s Disease Ira Shoulson. M D
Increasing knowledge of the role of brain iron in health and disease has prompted consideration of therapeutic strategies aimed at attenuating the effects of iron and its untoward oxidative consequences. The success of this approach is critically dependent on a better understanding of the pathogenesis of Parkinson’s disease. The controlled trial “Deprenyl and Tocopherol Antioxidative Therapy of Parkinsonism” (DATATOP) represents a clinical strategy to detect neuroprotective effects of antioxidative interventions. Validation of reliable biological markers of nigral degeneration is central to development of therapies that exert genuine neuroprotective effects in slowing the progression and preventing the onset of Parkinson’s disease. Shoulson I. Neuroprotective clinical strategies for Parkinson’s disease. Ann Neurol 1992;32:S1434145
In broad terms, the hypothesis that oxidative stress causes Parkinson’s disease (PD) is based on the proposition that altered or excessive oxidation of endogenous or exogenous substances promotes generation of oxygen radicals, which leads to lipid peroxidation and mitochondrial dysfunction 11, 2). In turn, these malfunctions are believed to cause further oxidation and cellular injury, resulting in irreversible nigral dysfunction and death. Once a threshold of nigral depletion has been reached (approximately 80%), features of P D emerge. Although these notions may be crude by molecular standards and are largely supported by circumstantial evidence, the oxidative stress hypothesis provides a unifying concept for the pathogenesis of nigral degeneration underlying PD. Studies of postmortem P D brains have demonstrated alterations in mitochondrial function 131 and reductions in naturally occurring antioxidants such as glutathione {41 and catalase 151. A variety of heavy metals, including zinc and iron, have also been found to accumulate in the substantia nigra of postmortem PD brains [2, 61. Because iron may promote the formation of hydroxyl radicals from superoxide radicals and hydrogen peroxide 171, the abnormal presence of this catalyst may further contribute to oxidative stress and PD. Although these postmortem abnormalities may well be a consequence of a more fundamental defect, the oxidative stress hypothesis has generated neuroprotective experimental strategies aimed at slowing the pace of nigral degeneration and the progressively disabling course of PD 18). In this context, neuroprotective therapy may be defined as an intervention that preserves
the function and integrity of vulnerable neurons and thereby slows or halts onset of illness or clinical decline. Experimental neuroprotective therapies are still in an early phase of development. De-coppering therapies for Wilson’s disease remain the gold standard of neuroprotective therapy. In this autosomal recessive disorder, agents that deplete brain copper, such as penicillamine, are remarkably effective in slowing basal ganglia damage, restoring neurological function, and even preventing the onset of illness in presymptomatic homozygotes [9). Assuming that increased brain iron is involved in the pathogenesis of PD, it is reasonable to consider strategies that reduce brain iron or that attenuate the untoward oxidative effects of this transition metal.
From the University of Rochester Medical Center, Rochester, NY.
Address correspondence to Dr Shoulson, Box 673, Department of Neurology, University of Rochester Medical Center, 601 Elmwood Ave, Rochester, N Y 14642.
Antioxidative Clinical Strategies: DATATOP Neuroprotective clinical strategies for P D have focused largely on interventions that inhibit monoamine oxidase type B (MAO-B) activity or attenuate the adverse effects of free radical formation. The multicenter clinical trial “Deprenyl and Tocopherol Antioxidative Therapy of Parkinsonism” (DATATOP) is a placebo-controlled, double-blind study using a 2 x 2 factorial design to assess the effects of the MAO-B inhibitor deprenyl (selegiline) and the antioxidant alpha-tocopherol (vitamin E) in otherwise untreated patients with early PD 181. The 34 participating investigators in the DATATOP trial enrolled 800 patients with early, otherwise untreated P D between September 1987 and November 1988. Patients were randomized to one of four
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treatment groups: deprenyl (10 mg/day) and alphatocopherol placebo; deprenyl placebo and alphatocopherol (2,000 IU/day); deprenyl (10 mgiday) and alpha-tocopherol (2,000 IUlday); or deprenyl placebo and alpha-tocopherol placebo. Enrolled patients were followed at approximately 3-month intervals to determine if and when they developed sufficient disability so as to require the initiation of levodopa therapy {S]. Prompted by independent monitoring, an unplanned interim analysis of the DATATOP trial indicated that deprenyl reduced the risk of disability requiring levodopa therapy by approximately 50% and similarly reduced the loss of full-time employment {lo]. Although encouraging, these interim results are by no means conclusive in supporting that deprenyl exerts neuroprotective effects in PD. Because the observed functional benefits were also accompanied by slight but statistically significant improvements in the clinical measures of PD, the findings may reflect the symptomatic antiparkinsonian effects of deprenyl {l0-12). The DATATOP study has been modified to extend the period of blinded observation, to examine the effects of withdrawal of experimental treatments over 2 months, and to assess the longer-term independent and interactive effects of deprenyl and alpha-tocopherol [12). Samples of cerebrospinal fluid obtained at baseline and at follow-up evaluations after withdrawal of treatments may help to address further the neurobiological relevance of the observed clinical effects. Experimental Interventions Affecting Brain Iron To the extent that iron exerts direct toxic effects on nigral neurons, experimental therapeutic strategies may involve reducing entry of iron into the brain, increasing nontoxic storage of iron, removing (chelating) accumulated iron, or a combination of these interventions. There is as yet insufficient knowledge regarding the metabolism of iron in the human brain to reliably and safely attempt to reduce entry of iron or to redistribute its storage in patients with PD. A variety of iron chelating agents have been used clinically to remove excess iron from the periphery in overload disorders such as thalassemia {13}. Deferoxamine (Desferal, desferrioxamine) is the most widely used chelating agent that combines with iron in the form of ferritin and hemosiderin. This chelating agent, however, does not enter the brain after systemic administration, and it is not well understood how peripheral iron depletion affects iron concentration or distribution in the adult human brain. In experimental animals, intraventricular administration of deferoxamine retards 6-hydroxydopamine-induced degeneration of nigral dopamine neurons {14]. Although this approach is clinically impractical, iron chelating agents
deserve further examination as potential neuroprotective agents in PD. Until the metabolism of brain iron and its putative role in PD are better clarified, experimental neuroprotective strategies may be reasonably focused on the indirect consequences of increased brain iron. A variety of agents are purported to inhibit iron-dependent lipid peroxidation, including deferoxamine [151, ascorbic acid { 161, alpha-tocopherol [8}, superoxide dismutase {ll}, and 21-amino steroids C171. Because depleted brain levels of glutathione may be a neurochemical marker of presymptomatic PD {2], efforts to buttress glutathione activity also warrant investigation. Shortcomings of Neuroprotective Strategies The DATATOP trial was designed to detect relatively small but meaningful clinical effects in a large sample size 181. Trials using fewer patients could detect very robust and substantive neuroprotective effects. For example, the magnitude of the de-coppering effect in Wilson’s disease is so large and uniform that only small sample sizes, perhaps 10 or 20 patients, would be necessary to detect the effect of such interventions. Given the inexorably progressive course of untreated Wilson’s disease and the robust effects of de-coppering treatments in both symptomatic and presymptomatic individuals, placebo-controlled trials may not always be required to confirm neuroprotective efficacy. Perhaps such substantive intervention for PD will be forthcoming. Although the clinical outcomes used in the DATATOP trial and similarly controlled trials are highly relevant to patients who have PD, these response variables are not necessarily valid markers of underlying nigral degeneration. More objective biological markers of neuronal degeneration, which reflect both the presence (trait) and extent (state) of PD, would greatly enhance the power of clinical trials aimed at developing neuroprotective therapy. Preparation of this manuscript was supported by a USPHS grant (NS24778) from the National Institute of Neurological Disorders and Stroke and by the Parkinson Study Group (Rochester, NY).
References 1. Cohen G. Oxidative stress in the nervous system. In: Sies H, ed. Oxidative stress. Orlando, FL: Academic Press, 1985:383-402 2. Jenner P. Oxidative stress as a cause of Parkinson’s disease. Acta Neurol Scand 1991;84(suppl 136):6-15 3. Schapira AHV, Cooper JM, Dexter D, et al. Mitochondria] complex I deficiency in Parkinson’s disease. J Neurochem 1990; 54:820-827 4. Lederer P, Sofic E, Rausch W-D, et al. Transition metals, ferritin, glutathione, and ascorbic acid in parkinsonian brains. J Neurochem 1989;52:515-520 5. Ambani LM, Van Woert WH, Murphy S. Brain peroxidase and catalase in Parkinson’s disease. Arch Neurol 1975;32:114-118
S144 Annals of Neurology Supplement to Volume 32, 1992
6. Youdim MBH, Ben-Shachar D, Riederer P. Is Parkinson’s disease a progressive siderosis of substantia nigra resulting in iron and melanin induced neurodegeneration? Acta Neurol Scand 1989;126:47-54 7. Halliwell B, Gutteridge JMC. Iron as a biological pro-oxidant. IS1 Atlas Sci Biochem 1988;1:48-52 8. Parkinson Study Group. DATATOP: a multicenter controlled clinical trial in early Parkinson’s disease. Arch Neurol 1989; 46: 1052-1060 9. Scheinberg IH, Sternlieb 1. Wilson’s disease. Philadelphia: WB Saunders, 1984 10. Parkinson Study Group. Effect of deprenyl on the progression of disability in early Parkinson’s disease. N Eng J Med 1989; 321:1364-1371 11. Olanow CW, Calne D. Does selegiline monotherapy in Parkinson’s disease act by symptomatic or protective mechanisms? Neurology 1991;42(suppl4):13-26
12. Shoulson I. Protective therapy for Parlunson’s disease. In: Marsden CD, Fahn S, eds. Movement disorders 3. London: Butterworths, in press. 13. Cerami A, Grady RW, Peterson CM, Bhargava KK. The status of new iron chelators. Ann NY Acad Sci 1980;344:425-435 14. Ben-Shachar D, Eshel G, Finberg JPM, et al. The iron chelator desferrioxarnine (Desferal) retards 6-hydroxydopamine-induced degeneration of nigrostriatal dopamine neurons. J Neurochem 1991;56:1441-1444 15. Halliwell B. Protection against tissue damage in vivo by desferrioxamine: what is its mechanism of action? Free Radic Biol Med 1989;7:645-65 1 16. Halliwell B. Oxidants and the central nervous system: some fundamental questions. Acta Neurol Scand 1989;126:23-33 17. Braughler JM, Pregenzer JF, Chase XU, et al. Novel 21-amino steroids as potent inhibitors of iron-dependent lipid peroxidation. J Biol Chem 1987;262:10438-10440
Shoulson: Neuroprotection for PD S145
Increasing knowledge of the role of brain iron in health and disease has prompted consideration of therapeutic strategies aimed at attenuating the effects of iron and its untoward oxidative consequences. The success of this approach is critically dependent on a better understanding of the pathogenesis of Parkinson’s disease. The controlled trial “Deprenyl and Tocopherol Antioxidative Therapy of Parkinsonism” (DATATOP) represents a clinical strategy to detect neuroprotective effects of antioxidative interventions. Validation of reliable biological markers of nigral degeneration is central to development of therapies that exert genuine neuroprotective effects in slowing the progression and preventing the onset of Parkinson’s disease. Shoulson I. Neuroprotective clinical strategies for Parkinson’s disease. Ann Neurol 1992;32:S1434145
In broad terms, the hypothesis that oxidative stress causes Parkinson’s disease (PD) is based on the proposition that altered or excessive oxidation of endogenous or exogenous substances promotes generation of oxygen radicals, which leads to lipid peroxidation and mitochondrial dysfunction 11, 2). In turn, these malfunctions are believed to cause further oxidation and cellular injury, resulting in irreversible nigral dysfunction and death. Once a threshold of nigral depletion has been reached (approximately 80%), features of P D emerge. Although these notions may be crude by molecular standards and are largely supported by circumstantial evidence, the oxidative stress hypothesis provides a unifying concept for the pathogenesis of nigral degeneration underlying PD. Studies of postmortem P D brains have demonstrated alterations in mitochondrial function 131 and reductions in naturally occurring antioxidants such as glutathione {41 and catalase 151. A variety of heavy metals, including zinc and iron, have also been found to accumulate in the substantia nigra of postmortem PD brains [2, 61. Because iron may promote the formation of hydroxyl radicals from superoxide radicals and hydrogen peroxide 171, the abnormal presence of this catalyst may further contribute to oxidative stress and PD. Although these postmortem abnormalities may well be a consequence of a more fundamental defect, the oxidative stress hypothesis has generated neuroprotective experimental strategies aimed at slowing the pace of nigral degeneration and the progressively disabling course of PD 18). In this context, neuroprotective therapy may be defined as an intervention that preserves
the function and integrity of vulnerable neurons and thereby slows or halts onset of illness or clinical decline. Experimental neuroprotective therapies are still in an early phase of development. De-coppering therapies for Wilson’s disease remain the gold standard of neuroprotective therapy. In this autosomal recessive disorder, agents that deplete brain copper, such as penicillamine, are remarkably effective in slowing basal ganglia damage, restoring neurological function, and even preventing the onset of illness in presymptomatic homozygotes [9). Assuming that increased brain iron is involved in the pathogenesis of PD, it is reasonable to consider strategies that reduce brain iron or that attenuate the untoward oxidative effects of this transition metal.
From the University of Rochester Medical Center, Rochester, NY.
Address correspondence to Dr Shoulson, Box 673, Department of Neurology, University of Rochester Medical Center, 601 Elmwood Ave, Rochester, N Y 14642.
Antioxidative Clinical Strategies: DATATOP Neuroprotective clinical strategies for P D have focused largely on interventions that inhibit monoamine oxidase type B (MAO-B) activity or attenuate the adverse effects of free radical formation. The multicenter clinical trial “Deprenyl and Tocopherol Antioxidative Therapy of Parkinsonism” (DATATOP) is a placebo-controlled, double-blind study using a 2 x 2 factorial design to assess the effects of the MAO-B inhibitor deprenyl (selegiline) and the antioxidant alpha-tocopherol (vitamin E) in otherwise untreated patients with early PD 181. The 34 participating investigators in the DATATOP trial enrolled 800 patients with early, otherwise untreated P D between September 1987 and November 1988. Patients were randomized to one of four
S 143
treatment groups: deprenyl (10 mg/day) and alphatocopherol placebo; deprenyl placebo and alphatocopherol (2,000 IU/day); deprenyl (10 mgiday) and alpha-tocopherol (2,000 IUlday); or deprenyl placebo and alpha-tocopherol placebo. Enrolled patients were followed at approximately 3-month intervals to determine if and when they developed sufficient disability so as to require the initiation of levodopa therapy {S]. Prompted by independent monitoring, an unplanned interim analysis of the DATATOP trial indicated that deprenyl reduced the risk of disability requiring levodopa therapy by approximately 50% and similarly reduced the loss of full-time employment {lo]. Although encouraging, these interim results are by no means conclusive in supporting that deprenyl exerts neuroprotective effects in PD. Because the observed functional benefits were also accompanied by slight but statistically significant improvements in the clinical measures of PD, the findings may reflect the symptomatic antiparkinsonian effects of deprenyl {l0-12). The DATATOP study has been modified to extend the period of blinded observation, to examine the effects of withdrawal of experimental treatments over 2 months, and to assess the longer-term independent and interactive effects of deprenyl and alpha-tocopherol [12). Samples of cerebrospinal fluid obtained at baseline and at follow-up evaluations after withdrawal of treatments may help to address further the neurobiological relevance of the observed clinical effects. Experimental Interventions Affecting Brain Iron To the extent that iron exerts direct toxic effects on nigral neurons, experimental therapeutic strategies may involve reducing entry of iron into the brain, increasing nontoxic storage of iron, removing (chelating) accumulated iron, or a combination of these interventions. There is as yet insufficient knowledge regarding the metabolism of iron in the human brain to reliably and safely attempt to reduce entry of iron or to redistribute its storage in patients with PD. A variety of iron chelating agents have been used clinically to remove excess iron from the periphery in overload disorders such as thalassemia {13}. Deferoxamine (Desferal, desferrioxamine) is the most widely used chelating agent that combines with iron in the form of ferritin and hemosiderin. This chelating agent, however, does not enter the brain after systemic administration, and it is not well understood how peripheral iron depletion affects iron concentration or distribution in the adult human brain. In experimental animals, intraventricular administration of deferoxamine retards 6-hydroxydopamine-induced degeneration of nigral dopamine neurons {14]. Although this approach is clinically impractical, iron chelating agents
deserve further examination as potential neuroprotective agents in PD. Until the metabolism of brain iron and its putative role in PD are better clarified, experimental neuroprotective strategies may be reasonably focused on the indirect consequences of increased brain iron. A variety of agents are purported to inhibit iron-dependent lipid peroxidation, including deferoxamine [151, ascorbic acid { 161, alpha-tocopherol [8}, superoxide dismutase {ll}, and 21-amino steroids C171. Because depleted brain levels of glutathione may be a neurochemical marker of presymptomatic PD {2], efforts to buttress glutathione activity also warrant investigation. Shortcomings of Neuroprotective Strategies The DATATOP trial was designed to detect relatively small but meaningful clinical effects in a large sample size 181. Trials using fewer patients could detect very robust and substantive neuroprotective effects. For example, the magnitude of the de-coppering effect in Wilson’s disease is so large and uniform that only small sample sizes, perhaps 10 or 20 patients, would be necessary to detect the effect of such interventions. Given the inexorably progressive course of untreated Wilson’s disease and the robust effects of de-coppering treatments in both symptomatic and presymptomatic individuals, placebo-controlled trials may not always be required to confirm neuroprotective efficacy. Perhaps such substantive intervention for PD will be forthcoming. Although the clinical outcomes used in the DATATOP trial and similarly controlled trials are highly relevant to patients who have PD, these response variables are not necessarily valid markers of underlying nigral degeneration. More objective biological markers of neuronal degeneration, which reflect both the presence (trait) and extent (state) of PD, would greatly enhance the power of clinical trials aimed at developing neuroprotective therapy. Preparation of this manuscript was supported by a USPHS grant (NS24778) from the National Institute of Neurological Disorders and Stroke and by the Parkinson Study Group (Rochester, NY).
References 1. Cohen G. Oxidative stress in the nervous system. In: Sies H, ed. Oxidative stress. Orlando, FL: Academic Press, 1985:383-402 2. Jenner P. Oxidative stress as a cause of Parkinson’s disease. Acta Neurol Scand 1991;84(suppl 136):6-15 3. Schapira AHV, Cooper JM, Dexter D, et al. Mitochondria] complex I deficiency in Parkinson’s disease. J Neurochem 1990; 54:820-827 4. Lederer P, Sofic E, Rausch W-D, et al. Transition metals, ferritin, glutathione, and ascorbic acid in parkinsonian brains. J Neurochem 1989;52:515-520 5. Ambani LM, Van Woert WH, Murphy S. Brain peroxidase and catalase in Parkinson’s disease. Arch Neurol 1975;32:114-118
S144 Annals of Neurology Supplement to Volume 32, 1992
6. Youdim MBH, Ben-Shachar D, Riederer P. Is Parkinson’s disease a progressive siderosis of substantia nigra resulting in iron and melanin induced neurodegeneration? Acta Neurol Scand 1989;126:47-54 7. Halliwell B, Gutteridge JMC. Iron as a biological pro-oxidant. IS1 Atlas Sci Biochem 1988;1:48-52 8. Parkinson Study Group. DATATOP: a multicenter controlled clinical trial in early Parkinson’s disease. Arch Neurol 1989; 46: 1052-1060 9. Scheinberg IH, Sternlieb 1. Wilson’s disease. Philadelphia: WB Saunders, 1984 10. Parkinson Study Group. Effect of deprenyl on the progression of disability in early Parkinson’s disease. N Eng J Med 1989; 321:1364-1371 11. Olanow CW, Calne D. Does selegiline monotherapy in Parkinson’s disease act by symptomatic or protective mechanisms? Neurology 1991;42(suppl4):13-26
12. Shoulson I. Protective therapy for Parlunson’s disease. In: Marsden CD, Fahn S, eds. Movement disorders 3. London: Butterworths, in press. 13. Cerami A, Grady RW, Peterson CM, Bhargava KK. The status of new iron chelators. Ann NY Acad Sci 1980;344:425-435 14. Ben-Shachar D, Eshel G, Finberg JPM, et al. The iron chelator desferrioxarnine (Desferal) retards 6-hydroxydopamine-induced degeneration of nigrostriatal dopamine neurons. J Neurochem 1991;56:1441-1444 15. Halliwell B. Protection against tissue damage in vivo by desferrioxamine: what is its mechanism of action? Free Radic Biol Med 1989;7:645-65 1 16. Halliwell B. Oxidants and the central nervous system: some fundamental questions. Acta Neurol Scand 1989;126:23-33 17. Braughler JM, Pregenzer JF, Chase XU, et al. Novel 21-amino steroids as potent inhibitors of iron-dependent lipid peroxidation. J Biol Chem 1987;262:10438-10440
Shoulson: Neuroprotection for PD S145
