期刊
ACS CHEMICAL NEUROSCIENCE
卷 8, 期 12, 页码 2766-2777出版社
AMER CHEMICAL SOC
DOI: 10.1021/acschemneuro.7b00310
关键词
Melanin; neuromelanin; redox-cycling; acetaminophen; clozapine; drug; reverse engineering
资金
- United State's National Science Foundation [CBET-1435957]
- Department of Defense (Defense Threat Reduction Agency) [HDTRA1-13-1-0037]
Melanins are ubiquitous but their complexity and insolubility has hindered characterization of their structures and functions. We are developing electrochemical reverse engineering methodologies that focus on properties and especially on redox properties. Previous studies have shown that melanins (i) are redox-active and can rapidly and repeatedly exchange electrons with diffusible oxidants and reductants, and (ii) have redox potentials in midregion of the physiological range. These properties suggest the functional activities of melanins will depend on their redox context. The brain has a complex redox context with steep local gradients in O-2 that can promote redox-cycling between melanin and diffusible redox-active chemical species. Here, we performed in vitro reverse engineering studies and report that melanins can redox-cyde with two common redox-active drugs. Experimentally, we used two melanin models: a convenient natural melanin derived from cuttlefish (Sepia melanin) and a synthetic cysteinyldopamine-dopamine core-shell model of neuromelanin. One drug, acetaminophen (APAP), has been used clinically for over a century, and recent studies suggest that low doses of APAP can protect the brain from oxidative-stress-induced toxicity and neurodegeneration, while higher doses can have toxic effects in the brain. The second drug, clozapine (CLZ), is a second generation antipsychotic with polypharmacological activities that remain incompletely understood. These in vitro observations suggest that the redox activities of drugs may be relevant to their modes of-action, and that melanins may interact with drugs in ways that affect their activities, metabolism, and toxicities.
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