Vasoactive intestinal peptide (VIP) prevents neurotoxicity in neuronal cultures: relevance to neuroprotection in Parkinson's disease

Vasoactive intestinal peptide (VIP) provides neuroprotection against beta-a myloid toxicity in models of Alzheimer's disease. A superactive analogue, s tearyl-Nle17-VIP (SNV) is a 100-fold more potent than VIP. In primary neuro nal cultures, VIP protective activity may be mediated by femtomolar-acting glial proteins such as activity-dependent neurotrophic factor (ADNF), activ ity-dependent neuroprotective protein (ADNP), peptide derivatives ADNF-9 (9 aa) and NAP (8aa), respectively. It has been hypothesized that beta-amyloid induces oxidative stress leading to neuronal cell death. Similarly, dopami ne and its oxidation products were suggested to trigger dopaminergic nigral cell death in Parkinson's disease. We now examined the possible protective effects of VIP against toxicity of dopamine, 6-hydroxydopamine (6-OHDA) an d 1-methyl-4-phenylpyridinium ion (MPP+) in neuronal cultures [rat pheochro mocytoma (PC12), human neuroblastoma (SH-SY5Y) and rat cerebellar granular cells]. Remarkably low concentrations of VIP (10(-16)-10(-8) M), ADNF-9 and NAP (10(-18)-10(-10) M) protected against dopamine and 6-OHDA toxicity in PC12 and neuroblastoma cells. VIP (10(-11)-10(-9) M) and SNV(10(-13)-10(-11 ) M), protected cerebellar granule neurons against 6-OHDA. In contrast, VIP did not rescue neurons from death associated with MPP+. Since dopamine tox icity is linked to the red/ ox state of the cellular glutathione, we invest igated neuroprotection in cells depleted of reduced glutathione (GSH). Buth ionine sulfoximine (BSO), a selective inhibitor of glutathione synthesis, c aused a marked reduction in GSH in neuroblastoma cells and their viability decreased by 70-90%. VIP, SNV or NAP (over a wide concentration range) prov ided significant neuroprotection against BSO toxicity. These results show t hat the mechanism of neuroprotection by VIP/SNV/NAP may be mediated through raising cellular resistance against oxidative stress. Our data suggest the se compounds as potential lead compounds for protective therapies against P arkinson's disease. (C) 2000 Elsevier Science B.V. All rights reserved.