Pituitary adenylate cyclase-activating polypeptide (PACAP) has neuroprotective function in dopamine-based neurodegeneration developed in two parkinsonian models

Abstract

Pituitary adenylate cyclase-activating polypeptide (PACAP) rescues dopaminergic neurons from neurodegeneration and improves motor changes induced by 6-hydroxy-dopamine (6-OHDA) in rat parkinsonian models. Recently, we investigated the molecular background of the neuroprotective effect of PACAP in dopamine (DA)-based neurodegeneration using rotenone-induced snail and 6-OHDA-induced rat models of Parkinson's disease. Behavioural activity, monoamine (DA and serotonin), metabolic enzyme (S-COMT, MB-COMT and MAO-B) and PARK7 protein concentrations were measured before and after PACAP treatment in both models. Locomotion and feeding activity were decreased in rotenone-treated snails, which corresponded well to findings obtained in 6-OHDA-induced rat experiments. PACAP was able to prevent the behavioural malfunctions caused by the toxins. Monoamine levels decreased in both models and the decreased DA level induced by toxins was attenuated by ∼50% in the PACAP-treated animals. In contrast, PACAP had no effect on the decreased serotonin (5HT) levels. S-COMT metabolic enzyme was also reduced but a protective effect of PACAP was not observed in either of the models. Following toxin treatment, a significant increase in MB-COMT was observed in both models and was restored to normal levels by PACAP. A decrease in PARK7 was also observed in both toxin-induced models; however, PACAP had a beneficial effect only on 6-OHDA-treated animals. The neuroprotective effect of PACAP in different animal models of Parkinson's disease is thus well correlated with neurotransmitter, enzyme and protein levels. The models successfully mimic several, but not all etiological properties of the disease, allowing us to study the mechanisms of neurodegeneration as well as testing new drugs. The rotenone and 6-OHDA rat and snail in vivo parkinsonian models offer an alternative method for investigation of the molecular mechanisms of neuroprotective agents, including PACAP.

Neuroprotective effects of PACAP against paraquat-induced oxidative stress in the Drosophila central nervous system

“…(22,81). PACAP injection also prolonged the survival of pond snails (Lymnaea stagnalis) exposed to rotenone, and partly rescued the reduction in locomotor activity and CNS DA level triggered by the toxin in this invertebrate model (82).…”

PACAP Protects Against Ethanol and Nicotine Toxicity in SH-SY5Y Cells: Implications for Drinking-Smoking Co-morbidity

“…It is of relevance to note that moderate to high density of PACAP receptors have been identified in SN and other regions in the rat brain (Masuo et al 1992). Furthermore, PACAP injection directly into the SN prevents 6-OH-DA effects, supporting the suggestion of potential benefits of PACAP in PD (Reglodi et al 2004;Maasz et al 2017). PACAP receptors (specifically PAC1) have also been identified in SH-SY5Y cells (Lutz et al 2006), and a role for these receptors in induction of neurotropic factors and differentiation of SH-SY5Y cells has been suggested (Monaghan et al 2008).…”

Dopaminergic Dysfunction in Mammalian Dopamine Neurons Induced by Simazine Neurotoxicity

“…Under normal circumstances, each factor plays a role in maintaining a steady state in the dopamine system. When any of these factors are affected, this can disrupt the balance in the dopaminergic system and cause a series of physiological effects [ 29 , 30 ]. DYT5b is a key rate-limiting enzyme.…”