Several reports have highlighted the potential roles for the VIP-related neuropeptides in regeneration/neuroprotection after brain or nerve injuries. We previously reported that peripheral inflammation worsened ibotenate-induced cystic white matter lesions. Because VIP is also known as an immunomodulator, we wonder if VIP could also limit the deleterious effects of local inflammation. Therefore, we first tested the effects of peripheral IL-1beta on VIP and PACAP central production. Second, we observed that cox-2 activation by IL-1beta was essential to generate changes in ligand/receptor gene expression. We further tested whether the intraperitoneal injection of IL-1beta, known to aggravate the ibotenate-induced lesions, could modify the expression pattern of VIP-related genes. Finally, we concluded using histological analysis that VIP[ala(11,22,28)], a synthetic VPAC(1) agonist completely reversed the aggravating effects of IL-1beta on ibotenate-induced lesions of the periventricular white matter. Conversely, VIP-neurotensin hybrid, a nonselective VIP receptor antagonist, worsened the lesions. All together, our results suggest that an activation of VIP/VPAC(1) signaling cascade in the vicinity of the injury site could circumvent the synergizing degenerative effects of ibotenate and pro-inflammatory cytokines. Therefore, development of therapeutic tools inducing/sustaining the activation of VIP/VPAC(1) signaling cascade may lead to future preventive treatments for inflammatory conditions during pregnancy.