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Ethnopharmacological Relevance: Isolated from Uncaria rhynchophylla (U. rhynchophylla), rhynchophylline (Rhy) has been applied for treating diseases related to central nervous system such as Parkinson's disease. Nevertheless, the molecular mechanism of the neuroprotective effect has not been well interpreted., Aim of the Study: To investigate the effects of Rhy on MPTP/MPP + -induced neurotoxicity in C57BL/6 mice or PC12 cells and study the mechanisms involved., Materials and Methods: The neuroprotective effect of Rhy on MPTP-induced neurotoxicity was evaluated by spontaneous motor activity test, as well as a test of rota-rod on a rat model of Parkinson's disease. The numbers of TH-positive neurons in the substantia nigra pars compacta (SNpc) was assessed by immunohistological. CCK-8, lactate dehydrogenase (LDH), reactive oxygen species (ROS), the concentration of intracellular calcium ([Ca 2+ ]i) and flow cytometry analysis were performed to evaluate the pharmacological property of Rhy on 1-methyl-4-phenylpyridinium (MPP + ) induced neurotoxicity in PC12 cells. Besides, LY294002, a PI3K inhibitor was employed to determine the underlying molecular signaling pathway revealing the effect of Rhy by western-blot analysis., Results: The results showed that Rhy exhibited a protective effect against the MPTP-induced decrease in tyrosine hydroxylase (TH)-positive fibers in the substantia nigra at 30 mg/kg, demonstrated by the immunohistological and behavioral outcomes. Furthermore, it has been indicated that cell viability was improved and the MPP + -induced apoptosis was inhibited after the treatment of Rhy at 20 μM, which were severally analyzed by the CCK-8 and the Annexin V/propidium iodide staining method. In addition, Rhy treatment attenuated MPP + -induced up-regulation of LDH, ([Ca 2+ ]i), and the levels of ROS. Besides, it can be revealed from the Western blot assay that LY294002, as a selective Phosphatidylinositol 3-Kinase (PI3K) inhibitor, effectively inhibited the Akt phosphorylation caused by Rhy, which suggested that Rhy showed its protective property through the activated the PI3K/Akt signaling pathway. Moreover, the Rhy-induced decreases of Bax and caspase-3 as the proapoptotic markers and the increase of Bcl-2 as the antiapoptotic marker, were blocked by LY294002 in the MPP + -treated PC12 cells., Conclusions: Rhy exerts a neuroprotective effect is partly mediated by activating the PI3K/Akt signaling pathway., (Copyright © 2020 Elsevier B.V. All rights reserved.)

Ethnopharmacological Relevance: Alkaloids isolated from Uncaria rhynchophylla (Miq.) Miq. ex Havil. (Rubiaceae), alkaloids (URA) have been used to treat diseases related to the central nervous system, such as Parkinson's disease. Nevertheless, the potential mechanisms underlying their neuroprotective effects are not well-understood., Aim of the Study: We investigated the neuroprotective effects of URAs in a mouse model of 1-methyl-4-phenyl-1, 2, 3, 6-tetrahydropyridine (MPTP)-induced Parkinson's disease (PD) and the possible involvement of a molecular signaling pathway., Materials and Methods: Two typical experiments for animal behavior despair, the spontaneous motor activity and the rotarod experiments, were employed to evaluate the efficacy of URAs in mice with PD symptoms. Dopamine (DA) neurons and their metabolism were evaluated using high-performance liquid chromatography-tandem mass spectrometry. The mechanism of action of the alkaloids was investigated by analyzing their effects on the phosphoinositide 3-kinase/Akt/mammalian target of rapamycin (PI3K/Akt/mTOR) signaling pathway using western blotting., Results: URA treatment effectively improved the behaviors of the mice during the "spontaneous motor activity and latency to fall off the rotarod test". Moreover, URAs demonstrated a protective role in dopaminergic neurons by increasing the expression of the dopamine transporter and tyrosine hydroxylase, which were supposed to be reduced by MPTP, inhibiting dopamine turnover, and changing dopamine and relevant metabolites. In addition to its association with the increase in the Bcl-2/Bad ratio, URA treatment also attenuated the cleaved caspase-3 level and enhanced the phosphorylation of Akt and mTOR., Conclusion: These findings provide evidence that URA can effectively protect neurons from the neurotoxicity caused by MPTP in mouse models of PD by up-regulating the PI3K/Akt/mTOR signaling pathway., (Copyright © 2020 Elsevier B.V. All rights reserved.)

Ethnopharmacological Relevance: The totally-amounted glucosides of paeony (TGP), which are made up of paeoniflorin, albiflorin, oxypaeoniflorin as well as benzoylpaeoniflorin, constitute the Baishao' actively-working component extracted from Radix Paeonia alba employed in conventional oriental medicine aiming to treat cerebrovascular disorders, such as Parkinson's disease. However, its pharmacologic mechanism is not clear., Aim of the Study: The initial investigation was made on TGP's neuroprotective effects on PD of the mouse model based on 1-methyl-4-phenyl-1, 2, 3, 6-tetrahydropyridine (MPTP) as well as the identification of potential involvement of a molecular signaling pathway., Materials and Methods: The evaluation of the behavioral damage as well as neurotoxicity in mice was made through MPTP. Spontaneous motor activity test, as well as a test of Rota-rod on mice was employed for the measurement of bradykinesia symptom. Additionally, liquid chromatography-electrospray ionization tandem mass spectrometry (LC-ESI-MS-MS) works as the determiner of the main monoamine neurotransmitters dopamine (DA) along with its metabolites 3, 4-dihydroxyphenylacetic acid (DOPAC) as well as homovanillic acid (HVA) based on mouse hippocampus connected with the anti-Parkinson's disease like effect of TGP. Besides, the measurement of the effects of TGP treatment on the expressions level of TH, DAT, a-synuclein, p-CREBS 133 as well as apoptosis influence was made with the help of western-blot assay with apoptosis-related markers such as Bax and Bcl-2., Results: The results showed that TGP treatment lessened the behavior-based loss shown "in the spontaneous motor activity as well as the potential of falling to rotarod test". In addition, we found that pretreatment with TGP markedly improved motor coordination, striatal dopamine and its metabolite levels. Furthermore, pretreatment of TGP conducted the protection for dopaminergic neurons with the prevented MPTP-induced reductions within the tyrosine hydroxylase (TH), substantia nigra dopaminergic transporter (DAT), as well as increasing α-synuclein protein levels with transformed dopamine catabolism as well as inhibited dopamine turnover. Besides, TGP treatment helped reversed apoptosis signaling molecules Bcl-2/Bax' reduction; meanwhile improving p-CREBS 133 the factor of growth signaling in the substantia nigra' decrease., Conclusion: These results suggested that TGP can enhance dopaminergic neuron's cell survival in the SNpc in virtue of the activated cAMP/PKA/CREB factor of growth on inhibiting the pathway of second messenger apoptosis as well. In conclusion, the current findings indicate TGP is expected to be a new cure for PD., (Copyright © 2019. Published by Elsevier B.V.)

Ethnopharmacological Relevance: Apocynum venetum L. (Apocynaceae), a traditional medicinal plant, has been used for the improvement of emotions in Asian countries., Aim of the Study: We explored the antidepressant-like effect and monoaminergic mechanism of a flavonoids extract from Apocynum venetum leaves (AV-extract)., Materials and Methods: Effect of AV-extract (25, 50 and 100 mg/kg, i.g.) on mice's immobility time was assessed in forced swim test (FST) and tail suspension test (TST). The locomotor activity was evaluated in the open-field test (OFT). Additionally, the main monoamine neurotransmitters serotonin (5-HT), noradrenaline (NA) and dopamine (DA) and their metabolites 5-hydroxyindole-3-acetic acid (5-HIAA), 3,4-dihydroxyphenylacetic acid (DOPAC) and homovanillic acid (HVA) in the mouse hippocampus involved in the antidepressant-like effect of AV-extract was also determined by liquid chromatography-electrospray ionization tandem mass spectrometry (LC-ESI-MS-MS)., Results: AV-extract (50 and 100 mg/kg, i.g.) administration significantly reduced the immobility time in both the FST and TST without accompanying changes in locomotor activity in the OFT. It was also found that the AV-extract significantly increased the concentrations of the main neurotransmitters NE and DA along with their respective metabolites DOPAC, HVA in the hippocampus. The antidepressant-like effect of the AV-extract (50 mg/kg, i.g.) was prevented by the pretreatment of mice with SCH23390 (0.05 mg/kg, i.g., a dopamine D1 receptor antagonist) or sulpiride (50 mg/kg, i.g., a dopamine D2 receptor antagonist)., Conclusion: The AV-extract produced significant antidepressant-like effects, which likely attribute to increased NE and DA along with their respective metabolites DOPAC, HVA in the mouse hippocampus, and dependent on interaction with dopaminergic (D1 and D2 receptor) systems., (Copyright © 2013 Elsevier Ireland Ltd. All rights reserved.)