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      6-Shogaol, an active compound of ginger, protects dopaminergic neurons in Parkinson's disease models via anti-neuroinflammation

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          Abstract

          Aim:

          6-Shogaol [1-(4-hydroxy-methoxyphenyl)-4-decen-one], a pungent compound isolated from ginger, has shown various neurobiological and anti-inflammatory effects. The aim of this study was to examine the effects of 6-shogaol on neuroinflammatory-induced damage of dopaminergic (DA) neurons in Parkinson's disease (PD) models.

          Methods:

          Cultured rat mesencephalic cells were treated with 6-shogaol (0.001 and 0.01 μmol/L) for 1 h, then with MPP +(10 μmol/L) for another 23 h. The levels of TNF-α and NO in medium were analyzed spectrophotometrically. C57/BL mice were administered 6-shogaol (10 mg·kg −1·d −1, po) for 3 d, and then MPTP (30 mg/kg, ip) for 5 d. Seven days after the last MPTP injection, behavioral testings were performed. The levels of tyrosine hydroxylase (TH) and macrophage antigen (MAC)-1 were determined with immunohistochemistry. The expression of iNOS and COX-2 was measured using RT PCR.

          Results:

          In MPP +-treated rat mesencephalic cultures, 6-shogaol significantly increased the number of TH-IR neurons and suppressed TNF-α and NO levels. In C57/BL mice, treatment with 6-shogaol reversed MPTP-induced changes in motor coordination and bradykinesia. Furthermore, 6-shogaol reversed MPTP-induced reductions in TH-positive cell number in the substantia nigra pars compacta (SNpc) and TH-IR fiber intensity in stratum (ST). Moreover, 6-shogaol significantly inhibited the MPTP-induced microglial activation and increases in the levels of TNF-α, NO, iNOS, and COX-2 in both SNpc and ST.

          Conclusion:

          6-Shogaol exerts neuroprotective effects on DA neurons in in vitro and in vivo PD models.

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          Most cited references20

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          Inflammation as a causative factor in the aetiology of Parkinson's disease.

          Parkinson's disease (PD) is a progressive neurodegenerative disorder affecting mainly the elderly, although a small proportion of PD patients develop the illness at a much younger age. In the former group, idiopathic PD patients, the causes of the illness have been the subject of longstanding debate with environmental toxins, mitochondrial dysfunction, abnormal protein handling and oxidative stress being suggested. One problem has been that the epidemiology of PD has offered few clues to provide evidence for a single major causative factor. Comparatively recently it has been found that in both patients and experimental models of PD in animals neuroinflammation appears to be a ubiquitous finding. These cases present with all of the classical features of inflammation including phagocyte activation, increased synthesis and release of proinflammatory cytokines and complement activation. Although this process is vital for normal function and protection in both the CNS, as in the periphery, it is postulated that in the aetiology of PD this process may spiral out of control with over activation of microglia, over production of cytokines and other proinflammatory mediators as well as the release of destructive molecules such as reactive oxygen species. Given that dopaminergic neurons in the substantia nigra are relatively vulnerable to 'stress' and the region has a large population of microglia in comparison to other CNS structures, these events may easily trigger neurodegeneration. These factors are examined in this review along with a consideration of the possible use of anti-inflammatory drugs in PD.
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            Pharmacokinetics of 6-gingerol, 8-gingerol, 10-gingerol, and 6-shogaol and conjugate metabolites in healthy human subjects.

            Ginger shows promising anticancer properties. No research has examined the pharmacokinetics of the ginger constituents 6-gingerol, 8-gingerol, 10-gingerol, and 6-shogaol in humans. We conducted a clinical trial with 6-gingerol, 8-gingerol, 10-gingerol, and 6-shogaol, examining the pharmacokinetics and tolerability of these analytes and their conjugate metabolites. Human volunteers were given ginger at doses from 100 mg to 2.0 g (N = 27), and blood samples were obtained at 15 minutes to 72 hours after a single p.o. dose. The participants were allocated in a dose-escalation manner starting with 100 mg. There was a total of three participants at each dose except for 1.0 g (N = 6) and 2.0 g (N = 9). No participant had detectable free 6-gingerol, 8-gingerol, 10-gingerol, or 6-shogaol, but 6-gingerol, 8-gingerol, 10-gingerol, and 6-shogaol glucuronides were detected. The 6-gingerol sulfate conjugate was detected above the 1.0-g dose, but there were no detectable 10-gingerol or 6-shogaol sulfates except for one participant with detectable 8-gingerol sulfate. The C(max) and area under the curve values (mean +/- SE) estimated for the 2.0-g dose are 0.85 +/- 0.43, 0.23 +/- 0.16, 0.53 +/- 0.40, and 0.15 +/- 0.12 microg/mL; and 65.6.33 +/- 44.4, 18.1 +/- 20.3, 50.1 +/- 49.3, and 10.9 +/- 13.0 microg x hr/mL for 6-gingerol, 8-gingerol, 10-gingerol, and 6-shogaol. The corresponding t(max) values are 65.6 +/- 44.4, 73.1 +/- 29.4, 75.0 +/- 27.8, and 65.6 +/- 22.6 minutes, and the analytes had elimination half-lives <2 hours. The 8-gingerol, 10-gingerol, and 6-shogaol conjugates were present as either glucuronide or sulfate conjugates, not as mixed conjugates, although 6-gingerol and 10-gingerol were an exception. Six-gingerol, 8-gingerol, 10-gingerol, and 6-shogaol are absorbed after p.o. dosing and can be detected as glucuronide and sulfate conjugates.
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              Effects of piperine, the pungent component of black pepper, at the human vanilloid receptor (TRPV1).

              1. We have characterised the effects of piperine, a pungent alkaloid found in black pepper, on the human vanilloid receptor TRPV1 using whole-cell patch-clamp electrophysiology. 2. Piperine produced a clear agonist activity at the human TRPV1 receptor yielding rapidly activating whole-cell currents that were antagonised by the competitive TRPV1 antagonist capsazepine and the non-competitive TRPV1 blocker ruthenium red. 3. The current-voltage relationship of piperine-activated currents showed pronounced outward rectification (25+/-4-fold between -70 and +70 mV) and a reversal potential of 0.0+/-0.4 mV, which was indistinguishable from that of the prototypical TRPV1 agonist capsaicin. 4. Although piperine was a less potent agonist (EC50=37.9+/-1.9 microM) than capsaicin (EC50=0.29+/-0.05 microM), it demonstrated a much greater efficacy (approximately two-fold) at TRPV1. 5. This difference in efficacy did not appear to be related to the proton-mediated regulation of the receptor since a similar degree of potentiation was observed for responses evoked by piperine (230+/-20%, n=11) or capsaicin (284+/-32%, n=8) upon acidification to pH 6.5. 6. The effects of piperine upon receptor desensitisation were also unable to explain this effect since piperine resulted in more pronounced macroscopic desensitisation (t(1/2)=9.9+/-0.7 s) than capsaicin (t(1/2)>20 s) and also caused greater tachyphylaxis in response to repetitive agonist applications. 7. Overall, our data suggest that the effects of piperine at human TRPV1 are similar to those of capsaicin except for its propensity to induce greater receptor desensitisation and, rather remarkably, exhibit a greater efficacy than capsaicin itself. These results may provide insight into the TRPV1-mediated effects of piperine on gastrointestinal function.
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                Author and article information

                Journal
                Acta Pharmacol Sin
                Acta Pharmacol. Sin
                Acta Pharmacologica Sinica
                Nature Publishing Group
                1671-4083
                1745-7254
                05 September 2013
                01 July 2013
                : 34
                : 9
                : 1131-1139
                Affiliations
                [1 ]Department of Life and Nanopharmaceutical Science, Kyung Hee University , Seoul 130–701, Republic of Korea
                [2 ]Department of Oriental Pharmaceutical Science, College of Pharmacy and Kyung Hee East-West Pharmaceutical Research Institute, Kyung Hee University , Seoul 130–701, Republic of Korea
                [3 ]Functional Materials Research Group, Korea Food Research Institute , Gyeonggi 463–746, Republic of Korea
                [4 ]College of Pharmacy, Gachon University , Incheon 406–799, Republic of Korea
                Author notes
                Article
                aps201357
                10.1038/aps.2013.57
                4003157
                23811724
                4d49cd9f-05b7-439c-9c6a-b51d0356e323
                Copyright © 2013 CPS and SIMM
                History
                : 15 February 2013
                : 12 April 2013
                Categories
                Original Article

                Pharmacology & Pharmaceutical medicine
                6-shogaol,ginger,dopaminergic neurons,substantia nigra,stratum,parkinson's disease,neuroinflammation,microglia,1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (mptp)

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