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.
Highlights
Pituitary adenylate cyclase-activating peptide (PACAP) is a member of the vasoactive intestinal peptide (VIP)/secretin/glucagon peptide family and has two biologically active isoforms—PACAP-27 and PACAP-38, with the latter being predominant in mammals [1]
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 [2–6]
Vehicle treated diabetic and PACAP-treated diabetic groups had a significant rise in blood sugar levels after the 7th day of the experiment
Summary
Pituitary adenylate cyclase-activating peptide (PACAP) is a member of the vasoactive intestinal peptide (VIP)/secretin/glucagon peptide family and has two biologically active isoforms—PACAP-27 and PACAP-38, with the latter being predominant in mammals [1]. PACAP acts through G-protein-coupled receptors: its specific receptor is PAC1, while VPAC1 and VPAC2 receptors bind PACAP and VIP with the same affinity. 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 [2–6]. One of the established effects of the neuropeptide is its neurotrophic/neuroprotective action [17–22]. This has been proven in numerous neuronal insults and models of neurodegenerative diseases, such as spinal atrophy [23], amyotrophic lateral sclerosis [24], Alzheimer’s disease [25–27], stroke [28–30], Parkinson’s disease [20,31–33], Huntington chorea [34], and several types of retinal injuries [21,35–37]
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