Pituitary adenylate cyclase-activating polypeptide (PACAP) has a neuroprotective function in dopamine-based neurodegeneration in rat and snail parkinsonian models.

G Maasz,T Kiss,D Petrovics,A Jungling,A Tamas,Z Zrinyi,Z Pirger,A Rivnyak,D Reglodi

doi:10.1242/dmm.027185

Abstract

ABSTRACTPituitary 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.

Highlights

Parkinson’s disease (PD) is characterized by dopaminergic (DAergic) neuron loss in the substantia nigra pars compacta (SNc) leading to progressive motor disability (Damier et al, 1999)
We investigated the neuroprotective effect of pituitary adenylate cyclase-activating polypeptide (PACAP) to prevent DAergic neurons from degeneration in the 6-OHDA-induced rat and rotenone-induced snail parkinsonian models
We investigated the effect of exogenous Pituitary adenylate cyclase-activating polypeptide (PACAP) on the behavioural activity, level of monoamines [dopamine (DA) and serotonin (5HT)], DA-metabolizing enzymes (S-COMT, membrane bound (MB)-COMT and MAO-B) and PARK7 protein in rat and snail parkinsonian models in vivo

Summary

Introduction

Parkinson’s disease (PD) is characterized by dopaminergic (DAergic) neuron loss in the substantia nigra pars compacta (SNc) leading to progressive motor disability (Damier et al, 1999). The most widely used parkinsonian models are generated by 6-hydroxy-dopamine (6OHDA), rotenone, 1-methyl-4phenyl-1,2,3,6-tetrahydropyridine (MPTP), paraquat and amphetamine (Jagmag et al, 2016) These chemicals have all been shown to be neurotoxins that induce a loss of DAergic neurons in the SNc and ventral tegmental area (VTA) in model animals. Neurotoxins reproduce one or more key pathological features of clinical PD within a shorter period of time in animals Both 6-OHDA and rotenone induce progressive DAergic neuronal degeneration by generating oxidative stress. The hydrophilic compound 6-OHDA (which cannot cross the BBB) is a generally used selective toxin to induce DAergic neuronal cell death by direct injection in the SNc or VTA in rats (Jagmag et al, 2016)

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