N-Propargyl Caffeamide (PACA) Ameliorates Dopaminergic Neuronal Loss and Motor Dysfunctions in MPTP Mouse Model of Parkinson’s Disease and in MPP+-Induced Neurons via Promoting the Conversion of proNGF to NGF

Abstract

Insufficient production of nerve growth factor (NGF) is implicated in Parkinson's disease (PD). We recently discovered that caffeic acid derivative N-propargyl caffeamide (PACA) not only potentiated NGF-induced neurite outgrowth but also attenuated 6-hydroxydopamine neurotoxicity in neuronal culture. The aim of the present study was to investigate whether PACA could increase NGF levels against 1-methyl-4-phenyl-1, 2, 3, 6-tetrahydropyridine (MPTP) neurotoxicity in a mouse PD model. We induced parkinsonism in mice by intraperitoneal injection of MPTP for seven consecutive days. Animal motor functions were assessed by rotarod test and pole test. Our results showed that PACA ameliorated motor impairments in MPTP-challenged mice. Based on Western blot analysis and/or immunofluorescence staining of NGF and tyrosine hydroxylase (TH), PACA preserved TH levels in the midbrain substantia nigra pars compacta. PACA also increased NGF expression while it decreased proNGF accumulation. Interestingly, NGF was widely induced in the midbrains including astrocytes. To elucidate the mechanisms by which PACA induces NGF, we focused on the effects of PACA on two neurotrophic signaling pathways, the PI3K and MEK pathways. We found that PACA induced the phosphorylation of Akt, ERK, and CREB against MPTP-mediated alterations. Importantly, PACA increased NGF levels and subsequently induced TrkA activation in MPTP-treated mice. Consistently, PACA also increased NGF levels in dopaminergic PC12 cells and primary rat midbrain neurons against N-methyl-4-phenylpyridinium iodide (MPP) toxicity. ERK and PI3K inhibitors attenuated the effects of PACA on NGF levels. Collectively, our results suggest that PACA may rescue NGF insufficiency via sequential activation of PI3K/Akt, ERK1/2, and CREB signaling pathways. Graphical Abstract ᅟ.

Signaling transduction regulated by 5-hydroxytryptamine 1A receptor and orexin receptor 2 heterodimers

“…Additionally, the results from a genome-wide association study demonstrated that CREB interacting with some of risk genes of mental disorders, suggesting that CREB probably be identified as one of the risk factors for psychiatric disorders including schizophrenia and major depression disorder [62]. Besides, enhancement of p-ERK/p-CREB signaling ameliorated the death of dopaminergic cell line SH-SY5Y cells after neurotoxin MPP + challenge and dopaminergic neurons in substantia nigra (SN) by neurotoxin MPTP treatment [40,63]. Together, these findings revealed that cAMP-calcium-ERK-CREB signaling was a very important regulator of neurological disease.…”

“…As one member of mitogen-activated protein kinases (MAPK) family, extracellular signal-related kinase (ERK) plays vital roles in cell migration, cell proliferation, cell differentiation and apoptosis [39]. Early studies showed that enhancement of p-ERK protected dopaminergic neurons in substantia nigra from death caused by neurotoxin MPTP [40], indicating the important role of ERK in brain disorders. Moreover, previous research demonstrated that both 5-HT1AR and OX2R regulated the levels of [15,20].…”

Botanical Drug Puerarin Promotes Neuronal Survival and Neurite Outgrowth against MPTP/MPP+-Induced Toxicity via Progesterone Receptor Signaling

“…Mice were evaluated for motor impairments with a rotarod apparatus (Harvard apparatus, Holliston, MA, USA) as described [ 26 , 27 ]. In brief, at 3 days after last dosage of MPTP treatment, mice were subjected to behavioral assessments.…”

“…The expression of TH in the midbrain was detected by immunohistochemical staining as previously described [ 27 ]. In brief, mice were transcardially perfused sequentially with saline and 4% paraformaldehyde under anesthetic condition.…”

“…Primary rat midbrain neurons were isolated from 17-day-old Sprague-Dawley (SD) rat embryos as previously described [ 27 ]. Briefly, 1 day before the isolation of the midbrain neurons, 6-well plates were precoated with poly-D-lysine.…”