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

Jansen, MI; Mahmood, Y; Lee, J; Broome, ST; Waschek, JA; Castorina, A

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

Jansen, MI Mahmood, Y Lee, J Broome, ST Waschek, JA Castorina, A

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Publisher:: WILEY
Publication Type:: Journal Article
Citation:: J Neurochem, 2024, 168, (9), pp. 3250-3267
Issue Date:: 2024-09

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Field	Value	Language
dc.contributor.author	Jansen, MI
dc.contributor.author	Mahmood, Y
dc.contributor.author	Lee, J
dc.contributor.author	Broome, ST
dc.contributor.author	Waschek, JA
dc.contributor.author	Castorina, A https://orcid.org/0000-0001-7037-759X
dc.date.accessioned	2024-12-10T23:55:17Z
dc.date.available	2024-07-25
dc.date.available	2024-12-10T23:55:17Z
dc.date.issued	2024-09
dc.identifier.citation	J Neurochem, 2024, 168, (9), pp. 3250-3267
dc.identifier.issn	0022-3042
dc.identifier.issn	1471-4159
dc.identifier.uri	http://hdl.handle.net/10453/182466
dc.description.abstract	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.
dc.format	Print-Electronic
dc.language	eng
dc.publisher	WILEY
dc.relation.ispartof	J Neurochem
dc.relation.isbasedon	10.1111/jnc.16199
dc.rights	info:eu-repo/semantics/openAccess
dc.subject	0601 Biochemistry and Cell Biology, 1109 Neurosciences
dc.subject.classification	Neurology & Neurosurgery
dc.subject.classification	3101 Biochemistry and cell biology
dc.subject.classification	3209 Neurosciences
dc.subject.mesh	Animals
dc.subject.mesh	Male
dc.subject.mesh	Mice
dc.subject.mesh	Astrocytes
dc.subject.mesh	Cuprizone
dc.subject.mesh	Demyelinating Diseases
dc.subject.mesh	Disease Models, Animal
dc.subject.mesh	Insect Proteins
dc.subject.mesh	Locomotion
dc.subject.mesh	Mice, Inbred C57BL
dc.subject.mesh	Myelin Sheath
dc.subject.mesh	Pituitary Adenylate Cyclase-Activating Polypeptide
dc.subject.mesh	Receptors, Pituitary Adenylate Cyclase-Activating Polypeptide, Type I
dc.subject.mesh	Vasoactive Intestinal Peptide
dc.subject.mesh	Astrocytes
dc.subject.mesh	Myelin Sheath
dc.subject.mesh	Animals
dc.subject.mesh	Mice, Inbred C57BL
dc.subject.mesh	Mice
dc.subject.mesh	Demyelinating Diseases
dc.subject.mesh	Disease Models, Animal
dc.subject.mesh	Cuprizone
dc.subject.mesh	Vasoactive Intestinal Peptide
dc.subject.mesh	Insect Proteins
dc.subject.mesh	Locomotion
dc.subject.mesh	Male
dc.subject.mesh	Pituitary Adenylate Cyclase-Activating Polypeptide
dc.subject.mesh	Receptors, Pituitary Adenylate Cyclase-Activating Polypeptide, Type I
dc.subject.mesh	Animals
dc.subject.mesh	Male
dc.subject.mesh	Mice
dc.subject.mesh	Astrocytes
dc.subject.mesh	Cuprizone
dc.subject.mesh	Demyelinating Diseases
dc.subject.mesh	Disease Models, Animal
dc.subject.mesh	Insect Proteins
dc.subject.mesh	Locomotion
dc.subject.mesh	Mice, Inbred C57BL
dc.subject.mesh	Myelin Sheath
dc.subject.mesh	Pituitary Adenylate Cyclase-Activating Polypeptide
dc.subject.mesh	Receptors, Pituitary Adenylate Cyclase-Activating Polypeptide, Type I
dc.subject.mesh	Vasoactive Intestinal Peptide
dc.title	Targeting the PAC1 receptor mitigates degradation of myelin and synaptic markers and diminishes locomotor deficits in the cuprizone demyelination model.
dc.type	Journal Article
utslib.citation.volume	168
utslib.location.activity	England
utslib.for	0601 Biochemistry and Cell Biology
utslib.for	1109 Neurosciences
pubs.organisational-group	University of Technology Sydney
pubs.organisational-group	University of Technology Sydney/Faculty of Science
pubs.organisational-group	University of Technology Sydney/Faculty of Science/School of Life Sciences
utslib.copyright.status	open_access	*
dc.rights.license	This work is licensed under a Creative Commons Attribution 4.0 International License (CC BY 4.0). To view a copy of this license, visit https://creativecommons.org/licenses/by/4.0/
dc.date.updated	2024-12-10T23:55:14Z
pubs.issue	9
pubs.publication-status	Published
pubs.volume	168
utslib.citation.issue	9

Abstract:

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.

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http://hdl.handle.net/10453/182466