George Cotzias, Neuromelanin, and Levodopa for Parkinson's Disease

Over four decades ago, Cotzias and coworkers noted (8,9) the likely role of mid-brain melanin and charge-transfer processes ( including oxidative stress ) in (e.g.) chronic manganism and other extrapyramidal syndromes, particularly Parkinsonism. Patton (10) quotes Cotzias: �I don't believe God put the melanin granule in the central nervous system for nothing. It must be doing something. Something big, something that will win me the Noble prize." Eventually this led to their development of Levodopa therapy for Parkinson's disease( 9 ) -- again, still a primary treatment.

Redox-Mediated Neurotransmission

Similarly, in the late 1960's, we encountered a patient with Lesch-Nyhan Syndrome. Lesch-Nyhan's is characterized by massive overproduction of purines and their metabolite uric acid, along with bizarre behavior (including self-mutilation ) and choreoathetoid dyskinesia. Significantly, this patient had originally been diagnosed as �schizophrenic�. Lesch-Nyhans Syndrome is now thought a primary model for bipolar mania. This disorder is often acutely-indistinguishable from schizophrenia, except by clinical history.

Thus oxidative and nitrosative stress likely plays a role in bipolar and maigraine comorbidity. See, e.g.,The Comorbidity of Bipolar Disorder and Migraine: The Role of Inflammation and Oxidative and Nitrosative Stress.. The same authors report that the xanthine oxidase-inhibitor allopurinol works in bipolar mania.

Synthesis of uric acid by xanthine oxidase produces reactive oxygen species. On the other hand, oxypurines are powerful-reducing agents. Thus, the classic clinical assay for urate depends upon its singular ability to directly reduce phosphotungstic acid, a property it shares with another antioxidant reducing substance, ascorbate (2). Also like ascorbate, uric acid is conditionally pro-oxidant (2), as are other purines (12).

Thus, drawing upon Cotzias et al (8) we proposed that electron-transfer processes produce the neuropsychiatric symptoms of Lesch-Nyhan's (2-6, 13-16), as they do those of chronic manganism. Most-importantly, oxidative-stress-mediated tissue damage alone seemed an unlikely cause of such bizarre and specific messenger-mediated neuropsychiatric symptoms as self-mutilation and choreoathetoid dyskinesia. The same seemed to hold for analogous symptoms in alcaptonuria, etc. (2-5,12-16).

Even four decades ago, the clear implication was that electron-transfer processes likely specifically mediate CNS cellular function-- say, by �doping� some organic semiconductor such as neuromelanin (2) and/or by (e.g.) modulating dopaminergic processes (13). This phenomenon is but one manifestation of what is now dubbed �redox signaling�.

Subsequent workers ( e.g.,17-20) refined the role of both dopaminergic processes and oxidative stress in Lesch-Nyhan's syndrome. Similarly, urate and/or xanthine oxidase-induced oxidative-stress have been implicated in (e.g.) atherosclerosis (6, 21), stroke (18,22,23), and diabetes (7, 23, 24 ). Moreover, SOD ameliorates hyperuricemic syndrome in Dalmatian dogs ( 25,26 ). As further proof of concept, such animals also tend to be both deaf and �bronzed� (25), a visible sign of underlying electronically-activated processes.

Likewise, higher primates have uniquely lost both the ability to make ascorbate and to break-down uric acid. So, we suggested that urate may substitute for ascorbate in human evolution (27), say, as an antioxidant or enzyme cofactor. Most importantly, �this does not exclude other physiological roles for uric acid� (27) . Other proposed functions (2-5) of uric acid and similar charge-transfer agents such as homocysteine included (e.g.) acting as a pro- or anti-oxidant, a �dopant� for some semiconducting biopolymer such as neuromelanin, or some more direct action as a cellular messenger. Accordingly, urate elevation is now in clinical trials for both stroke and Parkinson's disease.

Such multifunctionality ( including cell signaling ) has proven the case. However, researchers can still only speculate whether uric acid is causative, ameliorative, or (most likely) both in, e.g., atherosclerosis and stroke (22-24). We likewise extended this to more human diseases and more characteristic symptoms ( 2-5 ). This includes additional putative oxidative-stress-related symptoms such as psychosis, pigmentary abnormalities, and deafness, as well as atherosclerosis and diabetes ( e.g., in hemochromatosis ). E.g., ref (2) seems to be the first suggestion that homocysteine pathogenesis involves oxidative stress.

Szent-Gyorgyi* Vindicated

Investigating another aspect of redox signaling and as proof of concept for McGinness' mobility gap conduction model (28), we also constructed (29) an �active� organic polymer electronic device. An "active" device is one in which a current or voltage controls resistivity, as in a transistor. This was a voltage-controlled bistable switch using melanin. The �ON� state of this switch exhibits almost metallic conductivity. Significantly, doping with charge-transfer agents associated with (e.g.) neuropsychiatric symptomology modulated the electrical properties of the device, a la Szent-Gyorgyi. Cytochrome-C also switched, but at a much higher voltage gradient, though one achievable in vivo.

Concerning this device, Hush's history (36) of organic electronics states: �Also in 1974 came the first experimental demonstration of an operating molecular electronic device that functions along the lines of the biopolymer conduction ideas of Szent-Gyorgi.�. Hush also notes that the electronically-active material exhibits negative differential resistance, a hall-mark of present-day electronically-active organic polymers. Similar materials are now used in actual (literally) printed circuits. Organic electronics is also part of �nanotechnology�. So this is arguably the first �nanotech� device, well before the term was coined. Paradoxically, although virtually unknown in redox cell signalling, this organic semiconductor electronic device is now on the short Smithsonian chips list (37) of historic milestones in a rather different area, semiconductor physics and technology. It is also in the Smithsonian National Museum of American History's collection of historic electrical devices.** This device may also be an early example of protonic conduction in biological materials.

For more modern examples of the possible role of organic semiconductor processes in redox signaling, see references 39 and 40.

Redox Signaling Initially Rejected

By the late 1970's, convincing evidence had accumulated indicating redox signaling is a general phenomenon, mediating much more than neuropsychiatric symptoms and dermal melanization. We also had experimental evidence (28,29) supporting Szent-Gyorgyi's conjectures about conductive biological polymers and their modulation by charge-transfer processes. So, at a 1979 �International Congress of Free Radical Researchers� we proposed (21) that "One explanation for this data is that various active oxygen species ( or such products as hydroperoxides ) may act as specific transmitter substances" and �...We suggest that active oxygen metabolites act as specific intermediary transmitter substances for a variety of biological processes including inflammation, fibrosis, and possibly, neurotransmission ..".

Simply-stated, electron-transfer processes mediate, e.g.. dyskinetic symptoms in various diseases, self-mutilation in Lesch-Nyhan's, and melanocyte function. So why not also equally complex processes such as (say) inflammation and fibrosis ?

This initial effort to generalize the concept of redox signaling failed to gain traction. In fact, due to strong reviewer objection, this manuscript was omitted from the published proceedings of the conference, although another paper from our group was included (30). Among other things, the latter paper reports (as did others at the meeting) that superoxide dismutase suppresses tumor growth in experimental animals. This was one more indirect confirmation of the cellular messenger properties of reactive species. ROS are now known to be important mediators of cell growth and replication in cancer.

Now a given, for a time opposition to a messenger role for electronically-active species was so strong that it took years to publish. Tellingly, this was only by taking advantage of the freedom allowed reviews and invited book chapters (4,5).

Eventually, other researchers such as Bochner et al ( 31 ) began to relate oxidative stress to modulation of specific biochemical pathways, making the concept more generally-palatable. By the mid-1990's, the concept was respectable enough that major review articles started to appear (39). Meanwhile, the early work had been forgotten.

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