Activation of NPY-Y2 receptors ameliorates disease pathology in the R6/2 mouse and PC12 cell models of Huntington's disease

Fatoba, Oluwaseun; Kloster, Eugen; Reick, Christiane; Saft, Carsten; Gold, Ralf; Epplen, Jörg T.; Arning, Larissa; Ellrichmann, Gisa

doi:10.1016/j.expneurol.2018.01.001

Cited by 22 publications

(21 citation statements)

References 98 publications

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“…In their study, rats received intracerebroventricular (icv) injection of STZ exhibited decreased discrimination index in the novel object recognition test, reduced BDNF, and increased Aβ plaques in the brain, which were reversed by treatment with NAD-299 or TCB-2 [ 17 ]. Influence of neuropeptide Y (NPY), which is implicated as potential therapeutic target of HD, in expression of BDNF has been reported [ 18 ]. Activation of Y2 receptor (Y2R) by NPY or NPY13-16 (a selective agonist for Y2R) resulted in significant recovery from motor dysfunction in R6/2 mouse, a mouse model of HD.…”

Section: Activation Of Bdnf/trkb System By Compoundsmentioning

confidence: 99%

“…Activation of Y2 receptor (Y2R) by NPY or NPY13-16 (a selective agonist for Y2R) resulted in significant recovery from motor dysfunction in R6/2 mouse, a mouse model of HD. The activation of Y2R also decreased aggregated mutant huntingtin and increased levels of cAMP-regulated phosphoproteins, BDNF, and activated ERK1/2 in the HD model mice while selectively antagonizing Y2R by SF31 blocked the beneficial effects [ 18 ]. Recently, using R6/2 mice, Pardo et al have shown that A-971432, a new selective agonist for sphingosine-1-phosphate (S1P) receptor 5, is a therapeutic candidate for the treatment of HD [ 19 ].…”

Section: Activation Of Bdnf/trkb System By Compoundsmentioning

confidence: 99%

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Actions of Brain-Derived Neurotrophin Factor in the Neurogenesis and Neuronal Function, and Its Involvement in the Pathophysiology of Brain Diseases

Numakawa

Odaka

Adachi

2018

IJMS

246

138

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It is well known that brain-derived neurotrophic factor, BDNF, has an important role in a variety of neuronal aspects, such as differentiation, maturation, and synaptic function in the central nervous system (CNS). BDNF stimulates mitogen-activated protein kinase/extracellular signal-regulated kinase (MAPK/ERK), phosphoinositide-3kinase (PI3K), and phospholipase C (PLC)-gamma pathways via activation of tropomyosin receptor kinase B (TrkB), a high affinity receptor for BDNF. Evidence has shown significant contributions of these signaling pathways in neurogenesis and synaptic plasticity in in vivo and in vitro experiments. Importantly, it has been demonstrated that dysfunction of the BDNF/TrkB system is involved in the onset of brain diseases, including neurodegenerative and psychiatric disorders. In this review, we discuss actions of BDNF and related signaling molecules on CNS neurons, and their contributions to the pathophysiology of brain diseases.

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Section: Activation Of Bdnf/trkb System By Compoundsmentioning

confidence: 99%

Section: Activation Of Bdnf/trkb System By Compoundsmentioning

confidence: 99%

Actions of Brain-Derived Neurotrophin Factor in the Neurogenesis and Neuronal Function, and Its Involvement in the Pathophysiology of Brain Diseases

Numakawa

Odaka

Adachi

2018

IJMS

246

138

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“…Values represent means ± SEM, (a-e) n = 6-9, (f) n = 6-7, *p ≤ 0.05, **p ≤ 0.01, ****p ≤ 0.0001 vs. VEH groups (main effect, two-way ANOVA). NPY = neuropeptide Y, NR3C1 = nuclear receptor subfamily 3 group C member 1, CORT = corticosterone activation and cerebral TNF-α expression in a transgenic murine model of Huntington's disease [15].…”

Section: Discussionmentioning

confidence: 99%

“…Since IN infusion of NPY at several dosages has been shown to reach distinct rodent brain areas including the hypothalamus within 30 min after its infusion [12,14,15], we administered NPY IN at a frequently used dose (100 μg) 30 min before i.p. injection of LPS.…”

Section: Discussionmentioning

confidence: 99%

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Intranasal Neuropeptide Y Blunts Lipopolysaccharide-Evoked Sickness Behavior but Not the Immune Response in Mice

et al. 2019

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Neuropeptide Y (NPY) has been demonstrated to exert stress buffering effects and promote resilience. Non-invasive intranasal (IN) application of NPY to rodents is able to mitigate traumatic stress-induced behavioral changes as well as dysfunction of the hypothalamic-pituitary-adrenal (HPA) axis. However, it is unknown whether IN NPY could prevent the behavioral, proinflammatory and neurochemical responses to peripheral immune activation by the Toll-like receptor 4 (TLR4) stimulant lipopolysaccharide (LPS). Therefore, we analyzed the effects of IN NPY (100 μg) on the behavioral sickness response (reduced locomotion and exploration) and the underlying molecular mechanisms, 3 h and 21 h after intraperitoneal injections of LPS (0.03 mg/kg) in male C57BL/6N mice. The acute behavioral sickness response was significantly dampened by pretreatment with IN NPY 3 h after LPS injection. This effect was accompanied by diminished weight loss and lowered plasma corticosterone (CORT) levels 21 h after LPS injection. In contrast, acute circulating cytokine levels and hypothalamic cytokine mRNA expression remained unaltered by IN NPY, which indicates that the peripheral and cerebral immune response to LPS was left undisturbed. Our findings are in agreement with the reported activity of NPY to dampen the response of the HPA axis to stress. We propose that IN NPYablates sickness behavior at a site beyond the peripheral and cerebral cytokine response, an action that is associated with reduced activity of the HPA axis as determined by decreased plasma CORT. These results indicate that IN NPY administration may be relevant to the management of neuropsychiatric disorders arising from immune-induced neuroendocrine dysfunction.

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Intranasal neuropeptide Y1 receptor antagonism improves motor deficits in symptomatic SOD1 ALS mice

Clark,

Lewis

et al. 2023

Ann Clin Transl Neurol

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ObjectiveNeuropeptide Y (NPY) is a 36 amino acid peptide widely considered to provide neuroprotection in a range of neurodegenerative diseases. In the fatal motor neuron disease amyotrophic lateral sclerosis (ALS), recent evidence supports a link between NPY and ALS disease processes. The goal of this study was to determine the therapeutic potential and role of NPY in ALS, harnessing the brain‐targeted intranasal delivery of the peptide, previously utilised to correct motor and cognitive phenotypes in other neurological conditions.MethodsTo confirm the association with clinical disease characteristics, NPY expression was quantified in post‐mortem motor cortex tissue of ALS patients and age‐matched controls. The effect of NPY on ALS cortical pathophysiology was investigated using slice electrophysiology and multi‐electrode array recordings of SOD1G93A cortical cultures in vitro. The impact of NPY on ALS disease trajectory was investigated by treating SOD1G93A mice intranasally with NPY and selective NPY receptor agonists and antagonists from pre‐symptomatic and symptomatic phases of disease.ResultsIn the human post‐mortem ALS motor cortex, we observe a significant increase in NPY expression, which is not present in the somatosensory cortex. In vitro, we demonstrate that NPY can ameliorate ALS hyperexcitability, while brain‐targeted nasal delivery of NPY and a selective NPY Y1 receptor antagonist modified survival and motor deficits specifically within the symptomatic phase of the disease in the ALS SOD1G93A mouse.InterpretationTaken together, these findings highlight the capacity for non‐invasive brain‐targeted interventions in ALS and support antagonism of NPY Y1Rs as a novel strategy to improve ALS motor function.

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Activation of NPY-Y2 receptors ameliorates disease pathology in the R6/2 mouse and PC12 cell models of Huntington's disease

Cited by 22 publications

References 98 publications

Actions of Brain-Derived Neurotrophin Factor in the Neurogenesis and Neuronal Function, and Its Involvement in the Pathophysiology of Brain Diseases

Actions of Brain-Derived Neurotrophin Factor in the Neurogenesis and Neuronal Function, and Its Involvement in the Pathophysiology of Brain Diseases

Intranasal Neuropeptide Y Blunts Lipopolysaccharide-Evoked Sickness Behavior but Not the Immune Response in Mice

Intranasal neuropeptide Y1 receptor antagonism improves motor deficits in symptomatic SOD1 ALS mice

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