Targeting the PAC1 receptor mitigates degradation of myelin and synaptic markers and diminishes locomotor deficits in the cuprizone demyelination model.

Multiple sclerosis (MS) is a demyelinating disease of the central nervous system with a strong neuroinflammatory component. Current treatments principally target the immune system but fail to preserve long-term myelin health and do not prevent neurological decline. Studies over the past two decades have shown that the structurally related neuropeptides VIP and PACAP (vasoactive intestinal peptide and pituitary adenylate cyclase-activating polypeptide, respectively) exhibit pronounced anti-inflammatory activities and reduce clinical symptoms in MS disease models, largely via actions on their bivalent VIP receptor type 1 and 2. Here, using the cuprizone demyelination model, we demonstrate that PACAP and VIP, and strikingly the PACAP-selective receptor PAC1 agonist maxadilan, prevented locomotor deficits in the horizontal ladder and open field tests. Moreover, only PACAP and maxadilan were able to prevent myelin deterioration, as assessed by a reduction in the expression of the myelin markers proteolipid protein 1, oligodendrocyte transcription factor 2, quaking-7 (APC) and Luxol Fast Blue staining. Furthermore, PACAP and maxadilan (but not VIP), prevented striatal synaptic loss and diminished astrocyte and microglial activation in the corpus callosum of cuprizone-fed mice. In vitro, PACAP or maxadilan prevented lipopolysaccharide (LPS)-induced polarisation of primary astrocytes at 12-24 h, an effect that was not seen with maxadilan in LPS-stimulated microglia. Taken together, our data demonstrates for the first time that PAC1 agonists provide distinctive protective effects against white matter deterioration, neuroinflammation and consequent locomotor dysfunctions in the cuprizone model. The results indicate that targeting the PAC1 receptor may provide a path to treat myelin-related diseases in humans.

Targeting the neurological comorbidities of multiple sclerosis: the beneficial effects of VIP and PACAP neuropeptides.

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.

Early Alterations of PACAP and VIP Expression in the Female Rat Brain Following Spinal Cord Injury.

Previous evidence shows that rapid changes occur in the brain following spinal cord injury (SCI). Here, we interrogated the expression of the neuropeptides pituitary adenylyl cyclase-activating peptide (PACAP), vasoactive intestinal peptides (VIP), and their binding receptors in the rat brain 24 h following SCI. Female Sprague-Dawley rats underwent thoracic laminectomy; half of the rats received a mild contusion injury at the level of the T10 vertebrate (SCI group); the other half underwent sham surgery (sham group). Twenty-four hours post-surgery, the hypothalamus, thalamus, amygdala, hippocampus (dorsal and ventral), prefrontal cortex, and periaqueductal gray were collected. PACAP, VIP, PAC1, VPAC1, and VPAC2 mRNA and protein levels were measured by real-time quantitative polymerase chain reaction and Western blot. In SCI rats, PACAP expression was increased in the hypothalamus (104-141% vs sham) and amygdala (138-350%), but downregulated in the thalamus (35-95%) and periaqueductal gray (58-68%). VIP expression was increased only in the thalamus (175-385%), with a reduction in the amygdala (51-68%), hippocampus (40-75%), and periaqueductal gray (74-76%). The expression of the PAC1 receptor was the least disturbed by SCI, with decrease expression in the ventral hippocampus (63-68%) only. The expression levels of VPAC1 and VPAC2 receptors were globally reduced, with more prominent reductions of VPAC1 vs VPAC2 in the amygdala (21-70%) and ventral hippocampus (72-75%). In addition, VPAC1 downregulation also extended to the dorsal hippocampus (69-70%). These findings demonstrate that as early as 24 h post-SCI, there are region-specific disruptions of PACAP, VIP, and related receptor transcript and protein levels in supraspinal regions controlling higher cognitive functions.

PACAP and VIP Mitigate Rotenone-Induced Inflammation in BV-2 Microglial Cells.

Rotenone is a commercial pesticide commonly used to model Parkinson's disease (PD) due to its ability to induce dopaminergic degeneration. Studies have confirmed that rotenone causes microglial activation, which seems to contribute to the toxic effects seen in rodent models. Pituitary adenylate cyclase-activating polypeptide (PACAP) and vasoactive intestinal peptide (VIP) are two structurally related neuropeptides that have robust neuroprotective and anti-inflammatory properties. However, their ability to regulate microglial activity in response to rotenone is not fully understood. Using rotenone as an inflammatory stimulus, we tested whether PACAP or VIP could mitigate microglial activation in BV2 microglial cells. Rotenone dose-dependently reduced cell viability and the percentage of apoptotic cells. It also increased the release of nitric oxide (NO) in culture media and the expression of microglial activation markers and pro-inflammatory markers, including CD11b, MMP-9 and IL-6, and heightened the endogenous levels of PACAP and its preferring receptor PAC1. Co-treatment with PACAP or VIP prevented rotenone-induced increase of NO, CD11b, MMP-9 and IL-6. These results indicate that both PACAP and VIP are able to prevent the pro-inflammatory effects of rotenone in BV2 cells, supporting the idea that these molecules can have therapeutic value in slowing down PD progression.