Protective Effects of PACAP in a Rat Model of Diabetic Neuropathy

Abstract

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.

Distribution of PACAP and PAC1 Receptor in the Human Eye

“…This has been demonstrated in numerous in vitro and in vivo studies (Reglodi et al 2011 , 2017 ). Recently, it has been shown that in addition to the long-known protective effects in models of stroke and Parkinson’s disease (Ohtaki et al 2008 ; Zheng et al 2021 ), PACAP is protective in models of spinal and bulbar muscular atrophy (Martinez-Rojas et al 2021 ), fetal alcohol syndrome (Shili et al 2021 ), diabetic neuropathy (Kiss et al 2021 ), optic neuritis in multiple sclerosis (Van et al 2021 ), and noise-induced hearing loss (Ruel et al 2021 ). The large body of evidence, showing that PACAP is protective in animal models of several diseases, places PACAP on the list of emerging protective therapeutic agents in neurodegenerative disorders (Cheng et al 2020 ; Soles-Tarres et al 2020 ) and stroke (Cherait et al 2021 ; Fang et al 2020 ; Sadanandan et al 2021 ; Zheng et al 2021 ).…”

Unveiling adcyap1 as a protective factor linking pain and nerve regeneration through single-cell RNA sequencing of rat dorsal root ganglion neurons

“…Notably, intrathecal injection of PACAP38 during the acute phase of SNC attenuated mechanical allodynia and promoted axonal regeneration, indicating that Adcyap1 has significant implications for intraoperative intervention in PNI patients. Interestingly, PACAP38 has been identified as a promising therapeutic agent for diabetic neuropathy [ 56 ]. Overall, our findings suggest that Adcyap1 could potentially serve as an intrinsic protective factor promoting nerve regeneration and preventing pain during the acute phase after PNI.…”

An Examination of the Effects of Propolis and Quercetin in a Rat Model of Streptozotocin-Induced Diabetic Peripheral Neuropathy

“…All evaluations were recorded onto a computer using a Zeiss Axioscope II (Carl Zeiss Microscopy GmbH, Göttingen, Germany) microscope and photographed with a Zeiss Axiocam MRc camera attachment (Carl Zeiss MicroImaging GmbH, Göttingen, Germany). For transmission electron microscopic examinations, 50 nm ultra-fine sections were placed onto 200–300 mesh copper grids using a double contrast method by 2.5% uranyl–acetic acid and lead citrate [ 19 ]. The sections were then examined under a transmission electron microscope (JEOL-JEM-1010, Tokyo, Japan).…”