†These authors contributed equally.
Vasoactive intestinal peptide (VIP) and pituitary adenylate cyclase-activating polypeptide (PACAP) are two widely expressed neuropeptides with important immunomodulatory and neuroprotective properties in the central nervous system (CNS). Both VIP and PACAP have been implicated in several neurological diseases and have shown favourable effects in different animal models of multiple sclerosis (MS). MS is a chronic inflammatory and neurodegenerative disease of the CNS affecting over 2.5 million people worldwide. The disease is characterised by extensive neuroinflammation, demyelination and axonal loss. Currently, there is no cure for MS, with treatment options only displaying partial efficacy. Importantly, epidemiological studies in the MS population have demonstrated that there is a high incidence of neurological and psychological comorbidities such as depression, anxiety, epilepsy and stroke among afflicted people. Hence, given the widespread protective effects of the VIP/PACAP system in the CNS, this review will aim at exploring the beneficial roles of VIP and PACAP in ameliorating some of the most common neurological comorbidities associated with MS. The final scope of the review is to put more emphasis on how targeting the VIP/PACAP system may be an effective therapeutic strategy to modify MS disease course and its associated comorbidities.