The concept of electronically-activated species as messengers in both normal metabolism and in pathogenesis goes back to the 19th century. E.g., the biological pigment melanin is a stable free radical. Charles Darwin noted that white blue-eyed cats are usually deaf and that this may be secondary to some defect in neuronal development secondary to the absence of melanin pigment. Similarly, it has been known for centuries that radical-generating transition-series metals such as interocular copper or iron may produce massive vitreous fibrosis (scarring) as they oxidize. We now know that reactive oxygen species likely play a key role in fibrocyte activation.
Similarly, the "Adrenochrome Hypothesis" of Abram Hoffer and Humphry Osmond for the causation of schizophrenia involves the radical oxidation of the neurotransmitter epinephrine to the psychoactive compound adrenochrome.
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