Potent Neuroprotective Properties against the Alzheimer β-Amyloid by an Endogenous Melatonin-related Indole Structure, Indole-3-propionic Acid

Abstract

Widespread cerebral deposition of a 40 -43-amino acid peptide called the amyloid ␤-protein (A␤) in the form of amyloid fibrils is one of the most prominent neuropathologic features of Alzheimer's disease. Numerous studies suggest that A␤ is toxic to neurons by free radical-mediated mechanisms. We have previously reported that melatonin prevents oxidative stress and death of neurons exposed to A␤. In the process of screening indole compounds for neuroprotection against A␤, potent neuroprotective properties were uncovered for an endogenous related species, indole-3-propionic acid (IPA). This compound has previously been identified in the plasma and cerebrospinal fluid of humans, but its functions are not known. IPA completely protected primary neurons and neuroblastoma cells against oxidative damage and death caused by exposure to A␤, by inhibition of superoxide dismutase, or by treatment with hydrogen peroxide. In kinetic competition experiments using free radical-trapping agents, the capacity of IPA to scavenge hydroxyl radicals exceeded that of melatonin, an indoleamine considered to be the most potent naturally occurring scavenger of free radicals. In contrast with other antioxidants, IPA was not converted to reactive intermediates with pro-oxidant activity. These findings may have therapeutic applications in a broad range of clinical situations.Brains of patients afflicted with Alzheimer's disease show abnormal expression of numerous oxidative stress indicators (1-5) as well as extensive evidence of oxidative damage to proteins (6) and nucleic acids (7,8). A prominent feature of the Alzheimer's disease brain is the widespread cerebral deposition of a 40 -43-amino acid peptide called the amyloid ␤-protein (A␤) 1 in the form of amyloid fibrils within senile plaques and in cerebral and meningeal blood vessels (9, 10). A large body of data suggests that A␤ causes neuronal degeneration and death by mechanisms that involve reactive oxygen species reviewed in Ref. 15).Since the severity of the dementia in Alzheimer's disease has been correlated best with the extent of synaptic loss and the degree of neuronal death (16, 17), enhancing neuronal survival has been a primary objective of many therapeutic strategies. We have recently reported that melatonin prevents oxidative stress and death of neurons exposed to the amyloid peptide (18,19). In the process of screening indole compounds as neuroprotective agents, new properties were uncovered for an endogenous species, indole-3-propionic acid (IPA). IPA has previously been identified in the plasma and cerebrospinal fluid of humans, but its functions are not known (20,21). IPA has, like melatonin, a heterocyclic aromatic ring structure with high resonance stability, which led us to suspect similar neuroprotective and antioxidant properties. Here, we report that IPA prevented oxidative stress and death of primary neurons and neuroblastoma cells exposed to A␤. In addition, IPA also showed a strong level of neuroprotection in two other paradigms of oxidative stress. We found...

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