Alteration of the PAC1 Receptor Expression in the Basal Ganglia of MPTP-Induced Parkinsonian Macaque Monkeys

Abstract

Pituitary adenylate cyclase-activating polypeptide (PACAP) is a well-known neuropeptide with strong neurotrophic and neuroprotective effects. PACAP exerts its protective actions via three G protein-coupled receptors: the specific Pac1 receptor (Pac1R) and the Vpac1/Vpac2 receptors, the neuroprotective effects being mainly mediated by the Pac1R. The protective role of PACAP in models of Parkinson's disease and other neurodegenerative diseases is now well-established in both in vitro and in vivo studies. PACAP and its receptors occur in the mammalian brain, including regions associated with Parkinson's disease. PACAP receptor upregulation or downregulation has been reported in several injury models or human diseases, but no data are available on alterations of receptor expression in Parkinson's disease. The model closest to the human disease is the 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-induced macaque model. Therefore, our present aim was to evaluate changes in Pac1R expression in basal ganglia related to Parkinson's disease in a macaque model. Monkeys were rendered parkinsonian with MPTP, and striatum, pallidum, and cortex were evaluated for Pac1R immunostaining. We found that Pac1R immunosignal was markedly reduced in the caudate nucleus, putamen, and internal and external parts of the globus pallidus, while the immunoreactivity remained unchanged in the cortex of MPTP-treated parkinsonian monkey brains. This decrease was attenuated in some brain areas in monkeys treated with L-DOPA. The strong, specific decrease of the PACAP receptor immunosignal in the basal ganglia of parkinsonian macaque monkey brains suggests that the PACAP/Pac1R system may play an important role in the development/progression of the disease.

PACAP deficiency as a model of aging

“…In a recent study, the decrease in PAC1 receptor expression was found in structures undergoing degeneration in MPTP-induced macaque model of Parkinson's disease (Feher et al 2018). While there was no change in the receptor expression in an area not directly linked to Parkinson's disease (somatosensory cortex), marked reductions were observed in the striatum, external and internal pallidum, and putamen (Feher et al 2018). The strong, specific decrease of PACAP receptor immunosignal in the basal ganglia of parkinsonian macaque monkey brains suggests that the PACAP/PAC1R system may play an important role in the development/progression of this age-related disease (Feher et al 2018).…”

“…In a recent study, the decrease in PAC1 receptor expression was found in structures undergoing degeneration in MPTP-induced macaque model of Parkinson's disease (Feher et al 2018). While there was no change in the receptor expression in an area not directly linked to Parkinson's disease (somatosensory cortex), marked reductions were observed in the striatum, external and internal pallidum, and putamen (Feher et al 2018).…”

“…The action on the signaling pathways and thus, the physiological or pharmacological effects depend on the expressed receptors, tissue/cell types, and other factors present in the environment (Vaudry et al 2009). The expression of PACAP and the activation of PAC1/PACAP signaling also depend on a variety of factors, including developmental stage (Basille et al 2000), balance between signaling pathways (Fukuchi et al 2016), environmental factors (Horvath et al 2015), physiological conditions (Kiss et al 2007;Nemeth et al 2006;Rudecki and Gray 2016), daily rhythm (Jozsa et al 2001;Somogyvari-Vigh et al 2002), and the presence of harmful stimuli (Giunta et al 2012;Lam et al 2012;Pettersson et al 2014;Somogyvari-Vigh et al 2002;Szakaly et al 2010) and pathological conditions (Ergang et al 2015;Feher et al 2018;Han et al 2014aHan et al , 2014bHelyes et al 2015;Sarszegi et al 2018). PACAP's actions are very diverse, among others, it plays important roles during the development of the nervous system and several peripheral organs (Fulop et al 2018a;Watanabe et al 2016), influences anxiety, stress coping and addictionrelated behaviors (Iemolo et al 2016;King et al 2017;Kormos et al 2016;Mai et al 2018;Miles et al 2018), cognitive functions (Han et al 2014a(Han et al , 2014b, feeding (Sekar et al 2017), thermoregulation (Barrett et al 2017;Garami et al 2016), endocrine functions (Egri et al 2016;…”

Protective Effects of Pituitary Adenylate Cyclase-Activating Polypeptide and Vasoactive Intestinal Peptide Against Cognitive Decline in Neurodegenerative Diseases

“…Also, recent results obtained in different animal models of PD showed the dysregulation of PACAP and its receptors in brain areas related to cognition. A specific reduction of PAC1 receptor was reported in the basal ganglia of MPTP-induced parkinsonian macaques (Feher et al, 2018). Likewise, PACAP-knockout mice were shown to be more vulnerable to paraquat (a pesticide that increases the risk of PD) than wild-type (Watson et al, 2013).…”

Protective Role of Endogenous PACAP in Inflammation-induced Retinal Degeneration

“…The neuroprotective effects of PACAP have been shown in several different cell types in vitro against various toxic agents, such as oxidative stress, glutamate or 6-hydroxydopamine [14][15][16]. In vivo descriptions have also proven that PACAP is protective in global and focal cerebral ischemia [15,17,18], traumatic brain injury and neurodegenerative diseases [19,20].…”