Neuroprotective effects of vasoactive intestinal peptide against excitotoxic brain damage

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Vasoactive intestinal peptide (VIP) is a central nervous system neurotransmitter and neuromodulator with neurotrophic properties, including stimulation of astrocytic mitoses [18], increase of neuronal survival [19-21], promotion of early embryonic growth [22, 23], and neuronal differentiation of murine embryonic stem cells [24]. VIP was also shown to attenuate excitotoxic pulmonary edema [25], suggesting some interactions between transduction pathways of VIP and glutamate. Based on these data, the potential protective effects of VIP against excitotoxic damage have been evaluated in the developing rodent brain.

In the P0 hamster, co-treatment with VIP and a high dose of ibotenate produced a pattern of neuronal heterotopias similar to the one observed in animals treated with low doses of ibotenate alone. Pups co-injected with a low dose of ibotenate and a neurotensin-VIP hybrid VIP antagonist displayed cortical dysgeneses similar to those observed in animals treated with high doses of ibotenate alone. These data show that VIP can modulate migration disorders induced by ibotenate administration [26].

In the P0 mouse, co-treatment with ibotenate and VIP induced a dose-dependent reduction of the cortical lesion size (77% decrease of the lesion sizes with 1µg VIP) [27]. With the highest dose of VIP, 47% of co-treated animals displayed completely normal cortex.

In the P5 mouse, co-treatment with ibotenate and VIP had only a moderate effect on the ibotenate-induced neuronal death [27]. In contrast, VIP provided a very significant and dose-dependent protection against the excitotoxic white matter cyst (85% decrease of the white matter cyst size with 1µg VIP). With the highest dose of VIP, 38% of co-treated animals displayed completely normal white matter. Co-treatment with a neurotensin-VIP hybrid VIP antagonist [27] and ibotenate aggravated the excitotoxic lesion (64% increase of white matter cyst size), suggesting that endogenous VIP partially protect the developing white matter against excitotoxic insults.