Intrabladder PAC1 Receptor Antagonist, PACAP(6-38), Reduces Urinary Bladder Frequency and Pelvic Sensitivity in Mice Exposed to Repeated Variate Stress (RVS)

Girard, Beatrice M.; Campbell, Susan; Beča, Katharine I.; Perkins, Megan; Hsiang, Harrison; May, Víctor; Vizzard, Margaret A.

doi:10.1007/s12031-020-01649-x

Cited by 19 publications

(21 citation statements)

References 96 publications

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“…Adcyap1r1 encoding the PACAP-specific, PAC1 receptor, did not correlate with Adnp in the bladder, despite the significant increase seen in the Adnp +/− females compared to Adnp +/+ females and the amelioration with NAP treatment. These findings are of significant interest, as intra-bladder administration of the PAC1 receptor antagonist, PACAP(6–38), reduces urinary bladder frequency and pelvic sensitivity in mice exposed to repeated variate stress [ 48 ], with PACAP ameliorating Adnp -deficiency exacerbated stress response [ 3 ]. While ADNP was directly linked to cognitive impairment/language acquisition in humans [ 14 , 17 , 49 ] and in mice (vocalization) [ 13 ], indirect evidence also ties PACAP to the vocalization response [ 50 ].…”

Section: Discussionmentioning

confidence: 99%

Age and Sex-Dependent ADNP Regulation of Muscle Gene Expression Is Correlated with Motor Behavior: Possible Feedback Mechanism with PACAP

Kapitansky

Sragovich

Jaljuli

et al. 2020

IJMS

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The activity-dependent neuroprotective protein (ADNP), a double-edged sword, sex-dependently regulates multiple genes and was previously associated with the control of early muscle development and aging. Here we aimed to decipher the involvement of ADNP in versatile muscle gene expression patterns in correlation with motor function throughout life. Using quantitative RT-PCR we showed that Adnp+/− heterozygous deficiency in mice resulted in aberrant gastrocnemius (GC) muscle, tongue and bladder gene expression, which was corrected by the Adnp snippet, drug candidate, NAP (CP201). A significant sexual dichotomy was discovered, coupled to muscle and age-specific gene regulation. As such, Adnp was shown to regulate myosin light chain (Myl) in the gastrocnemius (GC) muscle, the language acquisition gene forkhead box protein P2 (Foxp2) in the tongue and the pituitary-adenylate cyclase activating polypeptide (PACAP) receptor PAC1 mRNA (Adcyap1r1) in the bladder, with PACAP linked to bladder function. A tight age regulation was observed, coupled to an extensive correlation to muscle function (gait analysis), placing ADNP as a muscle-regulating gene/protein.

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Section: Discussionmentioning

confidence: 99%

Age and Sex-Dependent ADNP Regulation of Muscle Gene Expression Is Correlated with Motor Behavior: Possible Feedback Mechanism with PACAP

Kapitansky

Sragovich

Jaljuli

et al. 2020

IJMS

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“…A significant sexual dichotomy was revealed, coupled to muscle and age-specific gene regulation. Thus, Adnp regulated myosin light chain ( Myl ) transcript in the gastrocnemius muscle, the language acquisition gene forkhead box protein P2 ( Foxp2 ) transcript in the tongue muscle, and the pituitary adenylate cyclase-activating polypeptide (PACAP) receptor PAC1 mRNA (Adcyap1r1) in the bladder, with PACAP, linked to bladder function [ 11 ] and partly controlling Adnp expression [ 12 ]. A sex-dependent Adnp -regulated gene transcript correlation to gait patterns (CatWalk) was discovered, placing ADNP as a muscle-regulating gene/protein [ 10 ].…”

Section: Introductionmentioning

confidence: 99%

Single Cell ADNP Predictive of Human Muscle Disorders: Mouse Knockdown Results in Muscle Wasting

Kapitansky

Karmon

Sragovich

et al. 2020

Cells

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Activity-dependent neuroprotective protein (ADNP) mutations are linked with cognitive dysfunctions characterizing the autistic-like ADNP syndrome patients, who also suffer from delayed motor maturation. We thus hypothesized that ADNP is deregulated in versatile myopathies and that local ADNP muscle deficiency results in myopathy, treatable by the ADNP fragment NAP. Here, single-cell transcriptomics identified ADNP as a major constituent of the developing human muscle. ADNP transcript concentrations further predicted multiple human muscle diseases, with concentrations negatively correlated with the ADNP target interacting protein, microtubule end protein 1 (EB1). Reverting back to modeling at the single-cell level of the male mouse transcriptome, Adnp mRNA concentrations age-dependently correlated with motor disease as well as with sexual maturation gene transcripts, while Adnp expressing limb muscle cells significantly decreased with aging. Mouse Adnp heterozygous deficiency exhibited muscle microtubule reduction and myosin light chain (Myl2) deregulation coupled with motor dysfunction. CRISPR knockdown of adult gastrocnemius muscle Adnp in a Cas9 mouse resulted in treadmill (male) and gait (female) dysfunctions that were specifically ameliorated by treatment with the ADNP snippet, microtubule interacting, Myl2—regulating, NAP (CP201). Taken together, our studies provide new hope for personalized diagnosis/therapeutics in versatile myopathies.

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“…PACAP has a widespread distribution in the body, with the highest expression levels in the nervous system and endocrine glands, where it acts as a neurotransmitter, neuromodulator, and neurohormone [ 2 , 3 , 4 , 5 , 6 ]. In addition, PACAP and its receptors are widely expressed in peripheral organs [ 1 , 7 , 8 , 9 , 10 ], and the peptide plays different roles in numerous physiological processes in the cardiovascular, respiratory, urogenital, musculoskeletal, and digestive systems [ 11 , 12 , 13 , 14 , 15 , 16 ]. One of the established effects of the neuropeptide is its neurotrophic/neuroprotective action [ 17 , 18 , 19 , 20 , 21 , 22 ].…”

Section: Introductionmentioning

confidence: 99%

“…Sci. 2021, 22, 10691 2 of 18 organs [1,[7][8][9][10], and the peptide plays different roles in numerous physiological processes in the cardiovascular, respiratory, urogenital, musculoskeletal, and digestive systems [11][12][13][14][15][16]. One of the established effects of the neuropeptide is its neurotrophic/neuroprotective action [17][18][19][20][21][22].…”

Section: Introductionmentioning

confidence: 99%

Protective Effects of PACAP in a Rat Model of Diabetic Neuropathy

Kiss

Bánki

Gaszner

et al. 2021

IJMS

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Pituitary adenylate cyclase-activating peptide (PACAP) is a neuropeptide with a widespread occurrence and diverse effects. PACAP has well-documented neuro- and cytoprotective effects, proven in numerous studies. Among others, PACAP is protective in models of diabetes-associated diseases, such as diabetic nephropathy and retinopathy. As the neuropeptide has strong neurotrophic and neuroprotective actions, we aimed at investigating the effects of PACAP in a rat model of streptozotocin-induced diabetic neuropathy, another common complication of diabetes. Rats were treated with PACAP1-38 every second day for 8 weeks starting simultaneously with the streptozotocin injection. Nerve fiber morphology was examined with electron microscopy, chronic neuronal activation in pain processing centers was studied with FosB immunohistochemistry, and functionality was assessed by determining the mechanical nociceptive threshold. PACAP treatment did not alter body weight or blood glucose levels during the 8-week observation period. However, PACAP attenuated the mechanical hyperalgesia, compared to vehicle-treated diabetic animals, and it markedly reduced the morphological signs characteristic for neuropathy: axon–myelin separation, mitochondrial fission, unmyelinated fiber atrophy, and basement membrane thickening of endoneurial vessels. Furthermore, PACAP attenuated the increase in FosB immunoreactivity in the dorsal spinal horn and periaqueductal grey matter. Our results show that PACAP is a promising therapeutic agent in diabetes-associated complications, including diabetic neuropathy.

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Intrabladder PAC1 Receptor Antagonist, PACAP(6-38), Reduces Urinary Bladder Frequency and Pelvic Sensitivity in Mice Exposed to Repeated Variate Stress (RVS)

Cited by 19 publications

References 96 publications

Age and Sex-Dependent ADNP Regulation of Muscle Gene Expression Is Correlated with Motor Behavior: Possible Feedback Mechanism with PACAP

Age and Sex-Dependent ADNP Regulation of Muscle Gene Expression Is Correlated with Motor Behavior: Possible Feedback Mechanism with PACAP

Single Cell ADNP Predictive of Human Muscle Disorders: Mouse Knockdown Results in Muscle Wasting

Protective Effects of PACAP in a Rat Model of Diabetic Neuropathy

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