Pituitary adenylate cyclase-activating polypeptide prevents cell death in the spinal cord with traumatic injury

doi:10.1016/j.neulet.2005.04.070

Neuroscience Letters

Volume 384, Issues 1–2, 12–19 August 2005, Pages 117-121

https://doi.org/10.1016/j.neulet.2005.04.070 Get rights and content

Abstract

Pituitary adenylyl cyclase-activating polypeptide (PACAP) is a potent factor in the regulation of neurotransmission, neuroprotection, neurogenesis and anti-inflammation. We here examined the neuroprotective effect of PACAP on injury to the spinal cord tissue of adult rats, induced by dropping a 10 g NYU impactor from the height of 25 mm (moderate injury) or 50 mm (severe injury). PACAP was found to effectively attenuate cell apoptosis in the spinal cord with moderate injury. However, treatment with PACAP had a lesser effect on decreasing DNA fragmentation in the lesion center of the spinal cord with severe contusion injury. Yet, greater extended neural fibers and motor neurons were observed in the rostral and caudal regions of the PACAP-treated spinal cord when compared to that seen in the PBS-treated control. Our findings indicate the beneficial effect of PACAP for the treatment of spinal cord injury (SCI).

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Acknowledgements

The authors thank Ms. Jey-Pei Wu for her skillful technical assistance. The study was supported in part by National Health Research Institutes (NHRI grant NHRI-EX91-8907BC), Taiwan, ROC, and Taichung Veterans General Hospital (TCVGH-917309D), Taiwan, ROC.

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Targeted deletion of PAC1 receptors in retinal neurons enhances neuron loss and axonopathy in a model of multiple sclerosis and optic neuritis
2021, Neurobiology of Disease
Citation Excerpt :
PACAP is an endogenous, evolutionarily highly conserved neuropeptide that is upregulated in response to injury, ischemia, and inflammation. It has been shown to protect neurons and reduce inflammation in animal models of neurodegenerative diseases such as Alzheimer's disease, Parkinson's disease, diabetic retinopathy (Maugeri et al., 2019; Giunta et al., 2012; Szabadfi et al., 2012a), stroke, and MS (Brifault et al., 2014; Chen and Tzeng, 2005; Lee and Seo, 2014; Reglodi et al., 2011; Tan et al., 2009; Dejda et al., 2008; Tan et al., 2013). The dual properties of neuroprotection and modulation of inflammation implicate PACAP as a target of interest in developing treatments for neurodegenerative diseases.
Chronic inflammation drives synaptic loss in multiple sclerosis (MS) and is also commonly observed in other neurodegenerative diseases. Clinically approved treatments for MS provide symptomatic relief but fail to halt neurodegeneration and neurological decline. Studies in animal disease models have demonstrated that the neuropeptide pituitary adenylate cyclase-activating polypeptide (PACAP, ADCYAP1) exhibits anti-inflammatory, neuroprotective and regenerative properties. Anti-inflammatory actions appear to be mediated primarily by two receptors, VPAC1 and VPAC2, which also bind vasoactive intestinal peptide (VIP). Pharmacological experiments indicate that another receptor, PAC1 (ADCYAP1R1), which is highly selective for PACAP, provides protection to neurons, although genetic evidence and other mechanistic information is lacking. To determine if PAC1 receptors protect neurons in a cell-autonomous manner, we used adeno-associated virus (AAV2) to deliver Cre recombinase to the retina of mice harboring floxed PAC1 alleles. Mice were then subjected to chronic experimental autoimmune encephalomyelitis (EAE), a disease model that recapitulates major clinical and pathological features of MS and associated optic neuritis. Unexpectedly, deletion of PAC1 in naïve mice resulted in a deficit of retinal ganglionic neurons (RGNs) and their dendrites, suggesting a homeostatic role of PAC1. Moreover, deletion of PAC1 resulted in increased EAE-induced loss of a subpopulation of RGNs purported to be vulnerable in animal models of glaucoma. Increased axonal pathology and increased secondary presence of microglia/macrophages was also prominently seen in the optic nerve. These findings demonstrate that neuronal PAC1 receptors play a homeostatic role in protecting RGNs and directly protects neurons and their axons against neuroinflammatory challenge.
Chronic inflammation is a major component of neurodegenerative diseases and plays a central role in multiple sclerosis (MS). Current treatments for MS do not prevent neurodegeneration and/or neurological decline. The neuropeptide pituitary adenylate cyclase-activating polypeptide (PACAP) has been shown to have anti-inflammatory, neuroprotective and regenerative properties but the cell type- and receptor-specific mechanisms are not clear. To test whether the protective effects of PACAP are direct on the PAC1 receptor subtype on neurons, we delete PAC1 receptors from neurons and investigate neuropathologigical changes in an animal model of MS. The findings demonstrate that PAC1 receptors on neurons play a homeostatic role in maintaining neuron health and can directly protect neurons and their axons during neuroinflammatory disease.
Changes of PACAP level in cerebrospinal fluid and plasma of patients with severe traumatic brain injury
2014, Peptides
Citation Excerpt :
In spite of the similarities in the pathogenesis of ischemic and traumatic brain injuries [7], until the most recent years, only a few of studies have investigated the potential neuroprotective role of PACAP in traumatic brain or spinal cord injuries. In the extradural static weight compression model of spinal cord injury in rat, post-injury PACAP treatment significantly reduced the number of apoptotic cells in the injured spinal cord [8,21]. PACAP has also been shown to attenuate the increase of tumor necrosis factor after spinal cord transection [22].
PACAP has well-known neuroprotective potential including traumatic brain injury (TBI). Its level is up-regulated following various insults of the CNS in animal models. A few studies have documented alterations of PACAP levels in human serum. The time course of post-ictal PACAP levels, for example, show correlation with migraine severity. Very little is known about the course of PACAP levels following CNS injury in humans and the presence of PACAP has not yet been detected in cerebrospinal fluid (CSF) of subjects with severe TBI (sTBI). The aim of the present study was to determine whether PACAP occurs in the CSF and plasma (Pl) of patients that suffered sTBI and to establish a time course of PACAP levels in the CSF and Pl. Thirty eight subjects with sTBI were enrolled with a Glasgow Coma Scale ≤8 on admission. Samples were taken daily, until the time of death or for maximum 10 days. Our results demonstrated that PACAP was detectable in the CSF, with higher concentrations in patients with TBI. PACAP concentrations markedly increased in both Pl and CSF in the majority of patients 24–48 h after the injury stayed high thereafter. In cases of surviving patients, Pl and CSF levels displayed parallel patterns, which may imply the damage of the blood–brain barrier. However, in patients, who died within the first week, Pl levels were markedly higher than CSF levels, possibly indicating the prognostic value of high Pl PACAP levels.
PACAP signaling exerts opposing effects on neuroprotection and neuroinflammation during disease progression in the SOD1(G93A) mouse model of amyotrophic lateral sclerosis
2013, Neurobiology of Disease
Citation Excerpt :
Endogenous PACAP, as well as exogenously applied PACAP, have been shown to be neuroprotective in several pathophysiological contexts. PACAP reduced infarct volume following ischemia (Chen et al., 2006; Ohtaki et al., 2006; Reglodi et al., 2002) and neuronal loss after traumatic damage of spinal cord (Chen and Tzeng, 2005). In models of facial and spinal axotomy, PACAP was found up-regulated in sensory, motor and sympathetic neurons (Armstrong et al., 2003; Moller et al., 1997; Pettersson et al., 2004; Zhang et al., 1996; Zhou et al., 1999), and the depletion of PACAP resulted in an enhanced microglia reaction and delayed axon re-growth (Armstrong et al., 2008).
Pituitary adenylate cyclase-activating polypeptide (PACAP) is a pleiotropic peptide with autocrine neuroprotective and paracrine anti-inflammatory properties in various models of acute neuronal damage and neurodegenerative diseases. Therefore, we examined a possible beneficial role of endogenous PACAP in the superoxide dismutase 1, SOD1(G93A), mouse model of amyotrophic lateral sclerosis (ALS), a lethal neurodegenerative disease particularly affecting somatomotor neurons. In wild-type mice, somatomotor and visceromotor neurons in brain stem and spinal cord were found to express the PACAP specific receptor PAC1, but only visceromotor neurons expressed PACAP as a potential autocrine source of regulation of these receptors. In SOD1(G93A) mice, only a small subset of the surviving somatomotor neurons showed induction of PACAP mRNA, and somatomotor neuron degeneration was unchanged in PACAP-deficient SOD1(G93A) mice. Pre-ganglionic sympathetic visceromotor neurons were found to be resistant in SOD1(G93A) mice, while pre-ganglionic parasympathetic neurons degenerated during ALS disease progression in this mouse model. PACAP-deficient SOD1(G93A) mice showed even greater pre-ganglionic parasympathetic neuron loss compared to SOD1(G93A) mice, and additional degeneration of pre-ganglionic sympathetic neurons. Thus, constitutive expression of PACAP and PAC1 may confer neuroprotection to central visceromotor neurons in SOD1(G93A) mice via autocrine pathways. Regarding the progression of neuroinflammation, the switch from amoeboid to hypertrophic microglial phenotype observed in SOD1(G93A) mice was absent in PACAP-deficient SOD1(G93A) mice. Thus, endogenous PACAP may promote microglial cytodestructive functions thought to drive ALS disease progression. This hypothesis was consistent with prolongation of life expectancy and preserved tongue motor function in PACAP-deficient SOD1(G93A) mice, compared to SOD1(G93A) mice. Given the protective role of PACAP expression in visceromotor neurons and the opposing effect on microglial function in SOD1(G93A) mice, both PACAP agonism and antagonism may be promising therapeutic tools for ALS treatment, if stage of disease progression and targeting the specific auto- and paracrine signaling pathways are carefully considered.
The functional recombinant first extracellular (EC1) domain of PACAP receptor PAC1 normal form (PAC1-EC1(N)) recognizes selective ligands and stimulates the proliferation of PAC1-CHO cells
2010, Neuroscience Letters
PAC1 is a pituitary adenylate cyclase-activating polypeptide (PACAP) preferring receptor, which is abundant in the central and peripheral nervous systems. PAC1 belongs to the class B family of G protein-coupled receptors (GPCRs). The N-terminal first extracellular (EC1) domain of PAC1 is responsible for ligand recognition and binding. In this study, the recombinant EC1 domain of the PAC1 normal (N) form (amino acids 21–155) with 6His tag at the C-terminus (named PAC1-EC1(N)) was first expressed in an Escherichia coli strain and purified by an Ni-NTA affinity column. About 6–8 mg of recombinant PAC1-EC1(N) protein with purity above 95% was produced from 1 L of bacterial culture. Mass spectrum and western blot were used to identify the recombinant PAC1-EC1(N). Intrinsic tryptophan fluorescence (ITF) assays showed that the purified PAC1-EC1(N) protein was able to recognize and bind to the PAC1 selective agonist maxadilan, the antagonist M65 and vasoactive intestinal polypeptide (VIP). Maxadilan and M65 had higher affinities for PAC1-EC1(N) than VIP. The results of MTT assays showed that PAC1-EC1(N) stimulated the viability of PAC-CHO cells but blocked the effects of maxadilan on the proliferation of CHO cells expressing PAC1 (PAC1-CHO), indicating that the functional soluble PAC1-EC1(N) may act as a regulator for the activation of PAC1.
Emerging Roles of the Neurotrophic Peptides IGF-1 and PACAP in Amyo-trophic Lateral Sclerosis PrSci
2022, Current Protein and Peptide Science
Oxidative DNA Damage in the Pathophysiology of Spinal Cord Injury: Seems Obvious, but Where Is the Evidence?
2022, Antioxidants

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Pituitary adenylate cyclase-activating polypeptide prevents cell death in the spinal cord with traumatic injury

Abstract

Section snippets

Acknowledgements

Neurochem. Int.

Dev. Biol.

Trends Pharmacol. Sci.

Prog. Brain Res.

Neuroscience

Neuron

Brain Res.