PACAP deficiency sensitizes nigrostriatal dopaminergic neurons to paraquat-induced damage and modulates central and peripheral inflammatory activation in mice

Abstract

Exposure to the pesticide paraquat (PQ) increases the risk of Parkinson’s disease (PD), and its effect may be modulated by genetic or other environmental factors. The neuropeptide PACAP (pituitary adenylyl cyclase activating polypeptide, Adcyap1) has been shown to enhance tyrosine hydroxylase (TH) and VMAT2 expression, protect dopaminergic (DA) neurons against the neurotoxin 6-hydroxydopamine, regulate neuronal mitochondria, and inhibit inflammation. Decreased expression of PACAP may thus interact with environmental factors such as PQ to increase the risk of PD. To mimic a low level environmental exposure to PQ, wild type (WT) and PACAP knockout (KO) mice were given a single [10 mg/kg] dose of PQ, a regimen that did not induce loss of TH expression or DA neurons in WT mice. This treatment reduced the number of TH-positive cell bodies in the substantia nigra pars compacta (SNpc) of PACAP KO. Because inflammation is also a risk factor for PD, we performed a quantitative analysis of SNpc Iba+ microglia. As expected, PQ increased the number of larger microglial profiles, indicative of activation, in WT mice. Strikingly, microglial activation was already evident in PACAP KO mice in the basal state. PQ caused no further activation in these mice, although TNF-α gene expression was enhanced. In the periphery, PQ had no effects on the abundance of proinflammatory Th1 or Th17 cells in WT mice, but increased the numbers of anti-inflammatory regulator T cells (Tregs). PACAP KO mice, in contrast, had elevated numbers of Th17 cells after PQ, and the induction of Tregs was impaired. The results indicate that endogenous PACAP acts to maintain the integrity of dopaminergic neurons during exposure to PQ, an action that may be linked to its ability to regulate microglia and/or other immune cells.

Current disease modifying approaches to treat Parkinson’s disease

“…Accumulating evidences support the view that PACAP is neuroprotective on dopaminergic neurons as shown in cell culture experiments [124,125] and in vivo PD models using the neurotoxins, 6-OHDA and MPTP [126]. Dopaminergic neurons in PACAP-deficient mice are also more susceptible to the toxin paraquat and show changes in microglia and immune responses [127].…”

Assessment of the Effects of MPTP and Paraquat on Dopaminergic Neurons and Microglia in the Substantia Nigra Pars Compacta of C57BL/6 Mice

“…A review of quantitative inflammatory effects was not provided in 7 of 8 previously mentioned unblinded studies that reported more activated microglia activation in PQ treated mice (S3 Appendix). One blinded study [54] that used a statistical bootstrapping procedure found significantly more 7–8 μm diameter (activated) microglia and fewer 3 μm diameter microglia in PQ-treated mice compared to controls. Interestingly, in this study, PQ had no effect on the mean number of TH + neurons in the SNpc.…”

PACAP27 prevents Parkinson-like neuronal loss and motor deficits but not microglia activation induced by prostaglandin J2

“…PACAP was shown to mitigate 6-OHDA and MPTP-induced loss of dopaminergic neurons in animal models of PD [17,71,72,89]. Furthermore, PACAP deficiency sensitizes dopaminergic neurons to paraquat-induced neuroinflammation in vivo [92]. Some studies support the view that PACAP27 is a more potent neuropeptide than PACAP38 and VIP (vasoactive intestinal peptide) in, for example, voltage clamped preparations of rat jejunum [15].…”