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Medical hypotheses
Medical Hypotheses Medical Hypotheses (1995) 45, 341-342 © Pearson Professional Ltd 1995
Towards a Unifying Hypothesis of Neurodegenerative Diseases and a Concomitant Rational Strategy for Their Prophylaxis and Therapy R. J. OKEN PO Box 412, Hopatcong, New Jersey 07843, USA. (Tel: 201-770-0006; Fax: 201-770-0527)
A b s t r a c t - Many neurodegenerative diseases have been found to present activated microglia, implying that immunologic processes operate which might exacerbate their basic pathologies. We consider 14 such disorders which are known or believed to exhibit these phenomena. Alzheimer's disease, the principal member of this group, has had its progression arrested in clinical trials by an antiinflammatory agent, leading us to suggest the possibility of successful prophylactic and therapeutic intervention at the immunologic level against these diseases with antiinflammatory drugs. It is further suggested that in neurodegenerative disorders of unknown etiology or pathogenesis the possible presence of activated microglia should be investigated. Finally, the possible relevance of these concepts for schizophrenia is examined. We consider first the neurodegenerative disorders: Alzheimer's disease (AD) and its Lewy body variant (LBV), Down's syndrome (DS), Parkinson's disease (PD), amyotrophic lateral sclerosis (ALS), lytico-bodig disease (LBD, the AD-PD-ALS dementia complex of Guam), Pick's disease (PID), multiple sclerosis, the human prion diseases (kuru, Creutzfeldt-Jakob disease, Gerstmann-Str~ussler-Scheinker syndrome, fatal familial insomnia, atypical dementia with octapeptide inserts) and Shy-Drager syndrome. The primary etiologic/pathogenic mechanisms of most of these disorders, many of them dementing and/ or fatal, are unknown. However, those that have been studied immunohistochemically have been found to have present activated microglia (ref. I and references therein), the resident macrophages of the brain, suggesting that immunologic processes of varying strength may exacerbate their basic pathologies. The
activated microglia are associated with the generation of components of the classical complement pathway of the immune system, including the membrane attack complex, and this generation can lead to significant autodestruction of neurons (2). Further, some of these complement cascade components stimulate the respiratory burst system of the microglia, resulting in the production of copious quantities of toxic reactive oxygen species (ROS), including superoxide anion, hydrogen peroxide and hydroxyl radical (1). While the brain has endogenous protective mechanisms against autodestructive processes, including upregulation of the production of the proteins clusterin, vitronectin and protectin (3), in several diseases, such as AD, LBV, DS, LBD and PID, these defenses are insufficient to insure survival. The failure of the homeostasis seeking controls of the immune system in these disorders can, at least in part, perhaps be
Date received 17 February 1995 Date accepted 12 May 1995
341
342 ascribed to the monotonic diminution of the efficacy of the immune system with age. Despite the fact that the primary etiopathogenic mechanisms of most of these disorders are unelucidated, we can perhaps intervene therapeutically and prophylactically by addressing the inappropriate immune system hyper-responses that are present. This strategy has proved effective in arresting the progression of AD in clinical trials of the non-steroidal antiinflammatory drug (NSAID) indomethacin (4), a member of the cyclooxygenase inhibitor class of agents, which rapidly and efficiently penetrates the blood-brain barrier, and would thus also likely be effective against LBV, LBD, DS and PID, by virtue of their neuropathological similarities to AD. Further, several of the NSAIDs are free radical traps and inhibitors, including (but not limited to) aspirin (5), ibuprofen (6), and indomethacin (7) and can therefore be expected to combat the toxicity of the copious ROS production by the activated microglia noted above. A study of 50 elderly twin pairs by Breitner et al (8), one member of each pair having developed AD, found that ACTH or steroids might also be effective in preventing or delaying the onset of AD. However, steroids are notorious for causing major side effects, some life threatening (9), and are thus deemed inappropriate for the purposes discussed herein. The NSAIDs too have side effects, the major one being gastrointestinal ulceration; however, protection against this is possible with misoprostol (10) or other gastroprotective agents. We hypothesize that the immunologic concepts and therapeutic and prophylactic strategy discussed in this paper might well be applicable to many other neurodegenerative diseases. In such disorders of unknown etiology and pathogenesis, a search for the possible presence of activated microglia should be undertaken. Finally, although schizophrenia is widely regarded as a neurodevelopmental disorder, nevertheless, its victims frequently present with phenomena which can be interpreted, at least in part, as neurodegenerative. These include abnormally low brain mass, cortical atrophy, hippocampal insufficiency, increased cortical sulcal volume and ventricular enlargement (11), perhaps at the expense of periventricular structures. Complement studies of schizophrenic brain are thus warranted. Some or all of these phenomena may well have a genetic basis; however, this would not, a priori, preclude their relationship to neurodegenerative processes. By way of precedent and analogy, consider the DS phenotype, which etiologically stems from a
MEDICAL HYPOTHESES
trisomic 21 genotype. Genes for the amyloid precursor protein (APP) and Cu/Zn superoxide dismutase (SOD) reside on chromosome 21 and it is thought that the hyperproduction of APP and/or SOD stemming from the gene dosage effect, is implicated in the cerebral neurodegeneration that afflicts all DS patients over the age of 35-40, ultimately leading to AD for most of them (12,13). Further, it is of interest to note that a free radical theory of schizophrenia has been proposed (14) and, to the extent that it is valid, intervention with ROS quenchers (possibly including several NSAIDs) would be appropriate.
References 1. Klegeris A, McGeer P L. Rat brain microglia and peritoneal macrophages show responses to respiratory burst stimulants. J Neuroimmunol 1994; 53 83-90 (and references therein). 2. McGeer P L, Rogers J. Anti-inflammatory agents as a therapeutic approach to Alzheimer's disease. Neurology 1992; 42: 447-449. 3. Yasuhara O, Aimi Y, McGeer E G, McGeer P L. Expression of the complement membrane attack complex and its inhihitors in Pick disease brain. Brain Res 1994; 652: 346-349. 4. Rogers J, Kirby L C, Hempelman S R et al. Clinical trial of indomethacin in Alzheimer's disease. Neurology 1993; 43: 1609-1611. 5. Udassin R, Ariel I, Haskel Y, Kitrassky N, Cherion M. Salicylate as an in vivo free radical trap: studies in ischemic insult to the rat intestine. Free Radic Biol Med 1991; 10: 1-6. 6. Schmeling D J, Drongowski R A, Coran A G. The beneficial effects of ibuprofen on a lethal live E. coli septic shock model and the relationship of these effects to superoxide radical production. Prog Clin Biol Res 1989; 299: 53-61. 7. Schreiber J, Foureman G L, Hughes M F, Mason R P, Eling T E. Detection of glutathione thiyl free radical catalyzed by prostaglandin H synthase present in keratinocytes. Study of co-oxidation in a cellular system. J Biol Chem 1989; 264: 7936-7943. 8. Breitner J C S, Gan B A, Welsh K A et al. Inverse association of anti-inflammatory treatments and Alzheimer's disease: initial results of a co-twin study. Neurology 1994; 44: 227-232. 9. Asien P S, Davis K L. Inflammatory mechanisms in Alzheimer's disease: implications for therapy. Am J Psychiatry 1994; 151: 1105-1113. 10. Graham D Y, Agrawal N M, Roth S H. Prevention of NSAIDinduced gastric ulcer with misoprostol: multicentre, doubleblind, placebo-controlled trial. Lancet 1988; 11: 1277-1278. 11. Waddington J L. Neurodynamics of abnormalities in cerebral metabolism and structure in schizophrenia. Schizophr Bull 1993; 19: 55-69. 12. Dickinson M J, Singh I. Down's syndrome dementia and superoxide dismutase. Br J Psychiatry 1993; 162:811-817. 13. Lei F, Williams R S. A prospective study of Alzheimer's disease in Down's syndrome. Arch Neurol 1989; 46: 849-853. 14. Cadet J L, Lohr J B. Free radicals and the developmental pathobiology or schizophrenia burnout. Integr Psychiatry 1987; 5: 40M3.
Towards a Unifying Hypothesis of Neurodegenerative Diseases and a Concomitant Rational Strategy for Their Prophylaxis and Therapy R. J. OKEN PO Box 412, Hopatcong, New Jersey 07843, USA. (Tel: 201-770-0006; Fax: 201-770-0527)
A b s t r a c t - Many neurodegenerative diseases have been found to present activated microglia, implying that immunologic processes operate which might exacerbate their basic pathologies. We consider 14 such disorders which are known or believed to exhibit these phenomena. Alzheimer's disease, the principal member of this group, has had its progression arrested in clinical trials by an antiinflammatory agent, leading us to suggest the possibility of successful prophylactic and therapeutic intervention at the immunologic level against these diseases with antiinflammatory drugs. It is further suggested that in neurodegenerative disorders of unknown etiology or pathogenesis the possible presence of activated microglia should be investigated. Finally, the possible relevance of these concepts for schizophrenia is examined. We consider first the neurodegenerative disorders: Alzheimer's disease (AD) and its Lewy body variant (LBV), Down's syndrome (DS), Parkinson's disease (PD), amyotrophic lateral sclerosis (ALS), lytico-bodig disease (LBD, the AD-PD-ALS dementia complex of Guam), Pick's disease (PID), multiple sclerosis, the human prion diseases (kuru, Creutzfeldt-Jakob disease, Gerstmann-Str~ussler-Scheinker syndrome, fatal familial insomnia, atypical dementia with octapeptide inserts) and Shy-Drager syndrome. The primary etiologic/pathogenic mechanisms of most of these disorders, many of them dementing and/ or fatal, are unknown. However, those that have been studied immunohistochemically have been found to have present activated microglia (ref. I and references therein), the resident macrophages of the brain, suggesting that immunologic processes of varying strength may exacerbate their basic pathologies. The
activated microglia are associated with the generation of components of the classical complement pathway of the immune system, including the membrane attack complex, and this generation can lead to significant autodestruction of neurons (2). Further, some of these complement cascade components stimulate the respiratory burst system of the microglia, resulting in the production of copious quantities of toxic reactive oxygen species (ROS), including superoxide anion, hydrogen peroxide and hydroxyl radical (1). While the brain has endogenous protective mechanisms against autodestructive processes, including upregulation of the production of the proteins clusterin, vitronectin and protectin (3), in several diseases, such as AD, LBV, DS, LBD and PID, these defenses are insufficient to insure survival. The failure of the homeostasis seeking controls of the immune system in these disorders can, at least in part, perhaps be
Date received 17 February 1995 Date accepted 12 May 1995
341
342 ascribed to the monotonic diminution of the efficacy of the immune system with age. Despite the fact that the primary etiopathogenic mechanisms of most of these disorders are unelucidated, we can perhaps intervene therapeutically and prophylactically by addressing the inappropriate immune system hyper-responses that are present. This strategy has proved effective in arresting the progression of AD in clinical trials of the non-steroidal antiinflammatory drug (NSAID) indomethacin (4), a member of the cyclooxygenase inhibitor class of agents, which rapidly and efficiently penetrates the blood-brain barrier, and would thus also likely be effective against LBV, LBD, DS and PID, by virtue of their neuropathological similarities to AD. Further, several of the NSAIDs are free radical traps and inhibitors, including (but not limited to) aspirin (5), ibuprofen (6), and indomethacin (7) and can therefore be expected to combat the toxicity of the copious ROS production by the activated microglia noted above. A study of 50 elderly twin pairs by Breitner et al (8), one member of each pair having developed AD, found that ACTH or steroids might also be effective in preventing or delaying the onset of AD. However, steroids are notorious for causing major side effects, some life threatening (9), and are thus deemed inappropriate for the purposes discussed herein. The NSAIDs too have side effects, the major one being gastrointestinal ulceration; however, protection against this is possible with misoprostol (10) or other gastroprotective agents. We hypothesize that the immunologic concepts and therapeutic and prophylactic strategy discussed in this paper might well be applicable to many other neurodegenerative diseases. In such disorders of unknown etiology and pathogenesis, a search for the possible presence of activated microglia should be undertaken. Finally, although schizophrenia is widely regarded as a neurodevelopmental disorder, nevertheless, its victims frequently present with phenomena which can be interpreted, at least in part, as neurodegenerative. These include abnormally low brain mass, cortical atrophy, hippocampal insufficiency, increased cortical sulcal volume and ventricular enlargement (11), perhaps at the expense of periventricular structures. Complement studies of schizophrenic brain are thus warranted. Some or all of these phenomena may well have a genetic basis; however, this would not, a priori, preclude their relationship to neurodegenerative processes. By way of precedent and analogy, consider the DS phenotype, which etiologically stems from a
MEDICAL HYPOTHESES
trisomic 21 genotype. Genes for the amyloid precursor protein (APP) and Cu/Zn superoxide dismutase (SOD) reside on chromosome 21 and it is thought that the hyperproduction of APP and/or SOD stemming from the gene dosage effect, is implicated in the cerebral neurodegeneration that afflicts all DS patients over the age of 35-40, ultimately leading to AD for most of them (12,13). Further, it is of interest to note that a free radical theory of schizophrenia has been proposed (14) and, to the extent that it is valid, intervention with ROS quenchers (possibly including several NSAIDs) would be appropriate.
References 1. Klegeris A, McGeer P L. Rat brain microglia and peritoneal macrophages show responses to respiratory burst stimulants. J Neuroimmunol 1994; 53 83-90 (and references therein). 2. McGeer P L, Rogers J. Anti-inflammatory agents as a therapeutic approach to Alzheimer's disease. Neurology 1992; 42: 447-449. 3. Yasuhara O, Aimi Y, McGeer E G, McGeer P L. Expression of the complement membrane attack complex and its inhihitors in Pick disease brain. Brain Res 1994; 652: 346-349. 4. Rogers J, Kirby L C, Hempelman S R et al. Clinical trial of indomethacin in Alzheimer's disease. Neurology 1993; 43: 1609-1611. 5. Udassin R, Ariel I, Haskel Y, Kitrassky N, Cherion M. Salicylate as an in vivo free radical trap: studies in ischemic insult to the rat intestine. Free Radic Biol Med 1991; 10: 1-6. 6. Schmeling D J, Drongowski R A, Coran A G. The beneficial effects of ibuprofen on a lethal live E. coli septic shock model and the relationship of these effects to superoxide radical production. Prog Clin Biol Res 1989; 299: 53-61. 7. Schreiber J, Foureman G L, Hughes M F, Mason R P, Eling T E. Detection of glutathione thiyl free radical catalyzed by prostaglandin H synthase present in keratinocytes. Study of co-oxidation in a cellular system. J Biol Chem 1989; 264: 7936-7943. 8. Breitner J C S, Gan B A, Welsh K A et al. Inverse association of anti-inflammatory treatments and Alzheimer's disease: initial results of a co-twin study. Neurology 1994; 44: 227-232. 9. Asien P S, Davis K L. Inflammatory mechanisms in Alzheimer's disease: implications for therapy. Am J Psychiatry 1994; 151: 1105-1113. 10. Graham D Y, Agrawal N M, Roth S H. Prevention of NSAIDinduced gastric ulcer with misoprostol: multicentre, doubleblind, placebo-controlled trial. Lancet 1988; 11: 1277-1278. 11. Waddington J L. Neurodynamics of abnormalities in cerebral metabolism and structure in schizophrenia. Schizophr Bull 1993; 19: 55-69. 12. Dickinson M J, Singh I. Down's syndrome dementia and superoxide dismutase. Br J Psychiatry 1993; 162:811-817. 13. Lei F, Williams R S. A prospective study of Alzheimer's disease in Down's syndrome. Arch Neurol 1989; 46: 849-853. 14. Cadet J L, Lohr J B. Free radicals and the developmental pathobiology or schizophrenia burnout. Integr Psychiatry 1987; 5: 40M3.