Pituitary Adenylate Cyclase-Activating Polypeptide (PACAP) Protects Striatal Cells and Improves Motor Function in Huntington’s Disease Models: Role of PAC1 Receptor

Abstract

Huntington’s disease (HD) is a hereditary neurodegenerative disorder caused by the expression of mutant huntingtin (mHtt). One of the main features of HD is the degeneration of the striatum that leads to motor discoordination. Pituitary adenylate cyclase-activating polypeptide (PACAP) is a neuropeptide that acts through three receptors named PAC1R, VPAC1R, and VPAC2R. In the present study, we first investigated the effect of PACAP on STHdhQ7/Q7 and STHdhQ111/Q111 cells that express wild-type Htt with 7 and mHtt with 111 glutamines, respectively. Then we explored the capacity of PACAP to rescue motor symptoms in the R6/1, a murine model of HD. We found that PACAP treatment (10–7 M) for 24 h protects STHdhQ111/Q111 cells from mHtt-induced apoptosis. This effect is associated with an increase in PAC1R transcription, phosphorylation of ERK and Akt, and an increase of intracellular c-fos, egr1, CBP, and BDNF protein content. Moreover, the use of pharmacological inhibitors revealed that activation of ERK and Akt mediates these antiapoptotic and neurotrophic effects of PACAP. To find out PAC1R implication, we treated STHdh cells with vasoactive intestinal peptide (VIP), which exhibits equal affinity for VPAC1R and VPAC2R, but lower affinity for PAC1R, in contrast to PACAP which has same affinity for the three receptors. VIP reduced cleaved caspase-3 protein level, without promoting the expression of c-fos, egr1, CBP, and the neurotrophin BDNF. We next measured the protein level of PACAP receptors in the striatum and cortex of R6/1 mice. We observed a specific reduction of PAC1R at the onset of motor symptoms. Importantly, the intranasal administration of PACAP to R6/1 animals restored the motor function and increased the striatal levels of PAC1R, CBP, and BDNF. In conclusion, PACAP exerts antiapoptotic and neurotrophic effects in striatal neurons mainly through PAC1R. This effect in HD striatum allows the recovery of motor function and point out PAC1R as a therapeutic target for treatment of HD.

Agonist of growth hormone-releasing hormone improves the disease features of spinal muscular atrophy mice

“…Interestingly, activation of GHRH-R promotes cAMP elevation, which has been implicated in the protective effect of GHRH and its agonistic analogs in different in vitro and in vivo models of disease, including ischemic stroke and neurodegeneration ( 17 , 19 , 23 , 26 , 28 ). Moreover, GHRH belongs to the family of the so-called brain-gut peptides, which also includes pituitary adenylate cyclase-activating polypeptide, a neuropeptide with beneficial effects in models of spinal cord injury, spinal and bulbar muscular atrophy and Huntington disease, acting via cAMP-mediated mechanisms ( 15 , 53 ). Although we did not address it in this study, we assume that the cAMP pathway may be involved in the protective effects of MR-409, along with others activated by GHRH-R, such as PI3K/Akt, GSK-3b, mTOR, and MAPK/ERK ( 19 , 21 , 28 ), which are also protective in SMA ( 54 ).…”

Potential Crosstalk between the PACAP/VIP Neuropeptide System and Endoplasmic Reticulum Stress—Relevance to Multiple Sclerosis Pathophysiology

“…Importantly, in this review, these protective effects are suggested to be indirectly linked via the inhibition of downstream pro-apoptotic effectors of different UPR branches and the elevation of anti-apoptotic molecules, or possibly directly linked to the inhibitory activities of ER stress key players. Overall, it can be implied that there remains much to explore and consider regarding the role of PACAP/VIP system in the modulation of ER stress responses produced in the demyelinating CNS [90,139]. The bidirectionality of this regulatory activity is suggested to be a plausible theory, in which chronic ER stress could downregulate the endogenous expression of PACAP/VIP receptors, thereby reducing the endogenous ability of PACAP/VIP to afford neuroprotection; this must be clarified via further experimentation.…”

Brain-Derived Neurotrophic Factor Dysregulation as an Essential Pathological Feature in Huntington’s Disease: Mechanisms and Potential Therapeutics

“…Somewhat encouragingly, the positive effects of P42 are potentiated by habitat enrichment in this model, an environmental modification that is well-connected with a beneficial BDNF response [ 246 ]. Another group reported that the intranasal administration of a recombinant vasoactive intestinal peptide (VIP) upregulated striatal BDNF in the R6/1 model, likely through coupling with the cAMP–PKA–CREB pathway ( Figure 2 ) [ 247 ]. In summary, advancements in neurotrophin drug discovery and delivery will unlock previously inaccessible therapeutic options for the treatment of HD and various neurodegenerative diseases.…”