Vasoactive intestinal peptide (VIP) prevents neurotoxicity in neuronal cultures: relevance to neuroprotection in Parkinson's disease1This manuscript is based on a poster presented at the Brain Research Interactive Symposium on “Neuropeptides at the Millennium”, Miami, October 1999.1

Abstract

Ž . Vasoactive intestinal peptide VIP provides neuroprotection against b-amyloid toxicity in models of Alzheimer’s disease. A Ž . superactive analogue, stearyl-Nle17-VIP SNV is a 100-fold more potent than VIP. In primary neuronal cultures, VIP protective activity Ž . may be mediated by femtomolar-acting glial proteins such as activity-dependent neurotrophic factor ADNF , activity-dependent Ž . Ž . Ž . neuroprotective protein ADNP , peptide derivatives ADNF-9 9aa and NAP 8aa , respectively. It has been hypothesized that b-amyloid induces oxidative stress leading to neuronal cell death. Similarly, dopamine 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 Ž . Ž q. w dopamine, 6-hydroxydopamine 6-OHDA and 1-methyl-4-phenylpyridinium ion MPP in neuronal cultures rat pheochromocytoma Ž . Ž . x Ž y16 y8 . PC12 , human neuroblastoma SH-SY5Y and rat cerebellar granular cells . Remarkably low concentrations of VIP 10 –10 M , Ž y18 y10 . ADNF-9 and NAP 10 –10 M protected against dopamine and 6-OHDA toxicity in PC12 and neuroblastoma cells. VIP Ž y11 y9 . Ž y13 y11 . 10 –10 M and SNV 10 –10 M , protected cerebellar granule neurons against 6-OHDA. In contrast, VIP did not rescue neurons from death associated with MPPq. Since dopamine toxicity is linked to the redr ox state of the cellular glutathione, we Ž . Ž . investigated neuroprotection in cells depleted of reduced glutathione GSH . Buthionine sulfoximine BSO , a selective inhibitor of glutathione synthesis, caused a marked reduction in GSH in neuroblastoma cells and their viability decreased by 70–90%. VIP, SNV or Ž . NAP over a wide concentration range provided significant neuroprotection against BSO toxicity. These results show that the mechanism of neuroprotection by VIPrSNVrNAP may be mediated through raising cellular resistance against oxidative stress. Our data suggest these compounds as potential lead compounds for protective therapies against Parkinson’s disease. q 2000 Elsevier Science B.V. All rights reserved. Ž . Ž .

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