Preclinical findings on the potential of intranasal neuropeptide Y for treating hyperarousal features of PTSD

Nwokafor, Chiso; Serova, Lidia; Sabban, Esther L.

doi:10.1111/nyas.14172

Cited by 14 publications

(12 citation statements)

References 70 publications

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“…The majority of animal models for PTSD, including the Single Prolonged Stress (SPS) paradigm, have been studied predominantly with males. The SPS model elicits many stress-associated maladaptive behaviors relevant to PTSD, such as anxiety, depression, hyperarousal, impaired social interaction, and impaired fear memory extinction, as well as molecular changes including dysregulation of the HPA axis and activation of the noradrenergic system (Liberzon et al, 1997 ; Khan and Liberzon, 2004 ; Kohda et al, 2007 ; Knox et al, 2012 ; Eagle et al, 2013 ; Keller et al, 2015b ; Liu et al, 2016 ; Souza et al, 2017 ; Lisieski et al, 2018 ; Nwokafor et al, 2019b ; Serova et al, 2019 ; Mancini et al, 2020 ). Particularly in the locus coeruleus, the major source for norepinephrine in the brain, SPS induced gene expression of key stress-related enzymes and receptors (Serova et al, 2013b , 2019 ; Sabban et al, 2015 ).…”

Section: Introductionmentioning

confidence: 99%

Intranasal Neuropeptide Y as a Potential Therapeutic for Depressive Behavior in the Rodent Single Prolonged Stress Model in Females

Nahvi

Tanelian

Nwokafor

et al. 2021

Front. Behav. Neurosci.

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The susceptibility to stress-elicited disorders is markedly influenced by sex. Women are twice as likely as men to develop posttraumatic stress disorder (PTSD), depression, anxiety disorders, and social impairments following exposure to traumatic stress. However, most of the studies in animal models examining putative therapeutics for stress-triggered impairments, including single prolonged stress (SPS), were performed predominantly with males. Previous studies in males demonstrated that intranasal neuropeptide Y (NPY) can provide therapeutic relief of many SPS-triggered behaviors, but is ineffective in females at the same dose. Thus, females may need a higher dose of exogenous NPY to attain a therapeutically significant concentration since the overwhelming majority of studies found that NPY levels in females in many brain regions are lower than in male rodents. Here, we examined SPS as an appropriate model to elicit many PTSD-associated symptoms in females and whether intranasal NPY at higher doses than with males is able to alter the development of SPS-triggered behavioral impairments. Sprague-Dawley female rats were exposed to SPS only, or in a separate cohort after SPS stressors were immediately infused intranasally with one of several doses of NPY, starting with 600 μg/rat—four times the dose effective in males. In the third cohort of animals, females were infused intranasally with either 600 μg NPY, omarigliptin [a dipeptidyl peptidase IV (DPP4) inhibitor], or both right after the SPS stressors. After 19 days they were tested on several behavioral tests. SPS elicited significant depressive/despair like behavior on the forced swim test (FST), anxiety behavior on the elevated plus maze (EPM), as well as impaired social interaction. On the FST, there was a dose-response effect of intranasal NPY, with 1,200 μg, but not 600 μg, preventing the development of the SPS-elicited depressive-like behavior. The omarigliptin and 600 μg NPY combined treatment, but neither alone, was also sufficient at preventing depressive-like behavior on the FST. The results demonstrate that: (1) SPS elicits several behavioral manifestations of PTSD in females; (2) early intervention with a high dose of intranasal NPY has therapeutic potential also for females; and (3) NPY cleavage by DPP4 may play a role in the higher dose requirement for females.

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Section: Introductionmentioning

confidence: 99%

Intranasal Neuropeptide Y as a Potential Therapeutic for Depressive Behavior in the Rodent Single Prolonged Stress Model in Females

Nahvi

Tanelian

Nwokafor

et al. 2021

Front. Behav. Neurosci.

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“…Since hyperarousal is associated with activation of the NE/LC system (Naegeli et al, 2018 ) and is elevated in PTSD (O’Donnell et al, 2004 ) as well as by SPS (Serova et al, 2013 ; Nwokafor et al, 2019 ), we examined the relationship between SPS triggered changes in acoustic startle response (ASR) and NET gene expression in the LC (Experiment 3). For this experiment, basal ASR (ASR1) was determined, and one group was exposed to SPS and the other remained unstressed.…”

Section: Resultsmentioning

confidence: 99%

“…Hyperarousal was assessed by deviation from the basal Acoustic Startle Response (ASR1). ASR was measured as previously described (Nwokafor et al, 2019 ) in a sound-proof chamber (SR-LAB; San Diego Instruments, San Diego, CA, USA). The piezoelectric accelerometer was calibrated using a stabilimeter for reliable and consistent sensitivity among the chambers.…”

Section: Methodsmentioning

confidence: 99%

Variable Response of Norepinephrine Transporter to Traumatic Stress and Relationship to Hyperarousal

Nwokafor

Serova

Tanelian

et al. 2021

Front. Behav. Neurosci.

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The noradrenergic systems play a key role in stress triggered disorders such as post-traumatic stress disorder (PTSD). We hypothesized that traumatic stress will alter expression of norepinephrine transporter (NET) in locus coeruleus (LC) and its target brain regions which could be related to hyperarousal. Male Sprague-Dawley rats were subjected to single prolonged stress (SPS) and several weeks later the LC was isolated. NET mRNA levels in LC, determined by RT-PCR, displayed variable response with high and low responsive subgroups. In different cohort, acoustic startle response (ASR) was measured 2 weeks after SPS and levels of NET mRNA and protein in LC determined. The high NET responsive subgroup had greater hyperarousal. Nevertheless, NET protein levels, as determined by western blots, were lower than unstressed controls in LC, ventral hippocampus and medial prefrontal cortex and displayed considerable variability. Hypermethylation of specific CpG region in promoter of SLC6A2 gene, encoding NET, was present in the low, but not high, NET mRNA responsive subgroup. Taken together, the results demonstrate variability in stress elicited changes in NET gene expression and involvement of epigenetic changes. This may underlie mechanisms of susceptibility and resilience to traumatic stress triggered neuropsychiatric symptoms, especially hyperarousal.

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“…With a further delay of 2 weeks post-SPS before initiating treatment with IN-NPY, the proportion of mice displaying severe anxiety (as assessed by elevated plus maze) also increased from 17.5% to 57.1% (indicative of delayed onset/worsening progression of the PTSD-like induced phenotype) and only a higher dose of 300 µg was able to effectively reverse elevated anxiety, depressive-like, and hyperarousal behaviors [ 128 ]. However, further testing another 7 days post-NPY revealed that the therapeutic benefit of IN-NPY lasted only 7 days, but that a second IN-NPY dose sustained NPY’s neuroprotective role [ 129 ]. Intranasal administration of NPY receptor subtype 1 (Y1R) and 2 (Y2R) agonists to stressed rats revealed that these resiliency effects are dependent on NPY receptor subtype 1 [ 130 ].…”

Section: Npymentioning

confidence: 99%

Intranasal Peptide Therapeutics: A Promising Avenue for Overcoming the Challenges of Traditional CNS Drug Development

Bose

Quipildor

Ehrlich

et al. 2022

Cells

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The central nervous system (CNS) has, among all organ systems in the human body, the highest failure rate of traditional small-molecule drug development, ranging from 80–100% depending on the area of disease research. This has led to widespread abandonment by the pharmaceutical industry of research and development for CNS disorders, despite increased diagnoses of neurodegenerative disorders and the continued lack of adequate treatment options for brain injuries, stroke, neurodevelopmental disorders, and neuropsychiatric illness. However, new approaches, concurrent with the development of sophisticated bioinformatic and genomic tools, are being used to explore peptide-based therapeutics to manipulate endogenous pathways and targets, including “undruggable” intracellular protein-protein interactions (PPIs). The development of peptide-based therapeutics was previously rejected due to systemic off-target effects and poor bioavailability arising from traditional oral and systemic delivery methods. However, targeted nose-to-brain, or intranasal (IN), approaches have begun to emerge that allow CNS-specific delivery of therapeutics via the trigeminal and olfactory nerve pathways, laying the foundation for improved alternatives to systemic drug delivery. Here we review a dozen promising IN peptide therapeutics in preclinical and clinical development for neurodegenerative (Alzheimer’s, Parkinson’s), neuropsychiatric (depression, PTSD, schizophrenia), and neurodevelopmental disorders (autism), with insulin, NAP (davunetide), IGF-1, PACAP, NPY, oxytocin, and GLP-1 agonists prominent among them.

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Preclinical findings on the potential of intranasal neuropeptide Y for treating hyperarousal features of PTSD

Cited by 14 publications

References 70 publications

Intranasal Neuropeptide Y as a Potential Therapeutic for Depressive Behavior in the Rodent Single Prolonged Stress Model in Females

Intranasal Neuropeptide Y as a Potential Therapeutic for Depressive Behavior in the Rodent Single Prolonged Stress Model in Females

Variable Response of Norepinephrine Transporter to Traumatic Stress and Relationship to Hyperarousal

Intranasal Peptide Therapeutics: A Promising Avenue for Overcoming the Challenges of Traditional CNS Drug Development

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