Parkinson and Hypericum perforatum: a medical hypothesis

Parkinson's disease (PD) is a common neurological disorder that is defined by a progressive loss of dopaminergic neurons in the substantia nigra pars compacta, eventually leading to striatal dopamine depletion.Resting tremors, rigid muscles, bradykinesia, and in rare circumstances, postural instability are symptoms of low dopamine levels.One to two percent of people over 65 worldwide is affected with PD, making it the second most common neurological illness in the world [1, 2].Uncertainty about the cause and course of PD persists, as do the biological pathways that drive the disease [3].

Mutations in the leucine-rich repeat kinase 2 (LRRK2) gene are the most common cause of familial PD [4].LRRK2 missense mutations increase the risk of developing late-onset autosomal dominant PD,which is clinically comparable to sporadic PD [5, 6].LRRK2 PD neuropathology is comparable to sporadic PD neuropathology, with LRRK2 patients experiencing progressive neurodegeneration of the nigrostriatal pathway, frequently resulting in alpha-Synuclein-positive Lewy bodies and brain tau pathology [5, 7–9].While LRRK2 coding mutations are associated with sporadic PD, frequent non-coding variants at the LRRK2 locus are associated with an increased risk of developing PD [10–13].

LRRK2 and Glycogen synthase kinase-3 beta (GSK-3β) are two such kinases that have been directly linked to the production of tau and alpha-Synuclein proteins, which cause PD [14].Dysregulation of GSK-3 affects the central nervous system and leads to neurodegenerative and neuroinflammation diseases.GSK-3β is one of its isomers having an effective role in neuronal apoptosis [15].

2.1 子宮內(nèi)膜組織中ER、PR的表達(dá)水平 所有患者子宮內(nèi)膜均有不同程度ER、PR的表達(dá)，腺體中ER陽(yáng)性率為66.2%，PR陽(yáng)性率為58.1 %；內(nèi)膜間質(zhì)中ER陽(yáng)性率為42.6%，PR陽(yáng)性率為36.0%，有統(tǒng)計(jì)學(xué)意義(P<0.05)。見(jiàn)表2。

These results indicate that in addition to causing neuropathology in familial PD, LRRK2 contributes to pathways implicated in sporadic PD.As a result, inhibiting LRRK2-dependent molecular pathways is a potential strategy for discovering new treatment goals for familial and sporadic PD.

Seung-Hwan Kwon and colleagues showed that hyperoside shields cultured dopaminergic neurons from death through reactive oxygen species-dependent processes, that hyperoside also has neuroprotective impacts on 6-OHDA-induced neurotoxicity in neurons, as well as the potential underlying systems.Hyperoside substantially reduced neuronal cell viability loss, lactate dehydrogenase release,uncontrolled reactive oxygen species buildup, and mitochondrial membrane potential malfunction linked to 6-OHDA-induced neurotoxicity.Additionally, hyperoside therapy activated the nuclear erythroid 2-related factor 2 (Nrf2), a molecule upstream of heme oxygenase-1.Hyperoside also increased the levels of the antioxidant response gene heme oxygenase-1 (HO-1).The neuroprotective benefits of hyperoside were reduced by an Nrf2 small interfering RNA, which inhibited hyperoside's capacity to prevent neuronal death,demonstrating the importance of HO-1.Altogether, hyperoside inhibits neuronal death induced by 6-OHDA-induced oxidative stress via inducing Nrf2-dependent HO-1 activation.Furthermore,Nrf2-dependent HO-1 signaling activation is a potential preventative and curative purpose in PD treatment [28].

Treatments for PD patients are currently available; however, they do not prevent the disease from progressing [1, 2].Alternative and complementary therapies for PD have been shown to be effective in delaying the onset of the disease and alleviating its symptoms [16].Natural products continue to be a promising source of biochemical specificity, chemical variety, and various molecular properties,making them well-suited for modulating many signaling cascades/pathways in various clinical states, such as cancer and neurological illnesses [17].

Hesperidin is a flavanone glycoside that possesses many therapeutic qualities, most notably neuroprotective properties [14].Hesperidin significantly protected SH-SY5Y (ATCC CRL-2266) cells from 6-hydroxydopamine (6-OHDA)-induced neurotoxicity in vitro and in vivo by downregulating oxidative stress indicators and also by downregulating the kinases GSK-3 β and LRRK2 as well as polg, casp3,and casp9 [14].

According to studies,

extracts contain extremely high hesperidin, hyperoside, and quercetin [20].

extracts have been demonstrated to be effective in treating mild/moderate depression in numerous studies [21, 22].Anti-cancer, antiviral,neuroprotective, wound healing, and antioxidant are some of the other key pharmacological features of

[23–27] (Figure 1).

L.(Hypericaceae) commonly referred to as St.John's wort, is one of the most important and widespread species in the

genus.Because

extracts have no notable harmful effects on humans or animals, their use has expanded dramatically during the last decade [18].

is recognized as one of the greatest herbs available today due to its established market position, appeal, and efficacy.

formulations are sold in numerous countries as nutritional supplements,antidepressants, mood enhancers, and relaxants [19].

【12】湯顯祖《牡丹亭記題詞》，見(jiàn)《牡丹亭記題詞》，見(jiàn)徐朔方箋?！稖@祖全集》，北京古籍出版社1999年版，第1153頁(yè)。

例4 (2018年株洲中考卷)如圖9，O為坐標(biāo)原點(diǎn)，△OAB是等腰直角三角形，∠OAB=90°，點(diǎn)B的坐標(biāo)為將該三角形沿x軸向右平移得到Rt△O′A′B′，此時(shí)點(diǎn)B′的坐標(biāo)為則線段OA在平移過(guò)程中掃過(guò)部分的圖形面積為_(kāi)_______.

Quercetin is a potent flavonoid having anti-inflammatory,antioxidant, and anti-cancer properties [29].According to studies,quercetin may protect against hyperphosphorylation of tau protein and oxidative stress caused by Okadaic acid [29].Additionally, oral quercetin therapy significantly improves behavioral deficits, striatal dopamine deficiency, and TH neuronal cell loss in MitoPark transgenic mice with progressive dopaminergic neurodegeneration [30].

According to the studies cited,

may be a beneficial and abundant source for limiting PD progression.Thus,

is recommended for further experimental and clinical investigation in PD.

1.Lang AE, Lozano AM.Parkinson's disease (First of two parts).

1998;339(15):1044–1053.https://doi.org/10.1056/NEJM199810083391506

2.Lang AE, Lozano AM.Parkinson's disease (Second of two parts).

1998;339(16):1130–1143.https://doi.org/10.1056/NEJM199810153391607

3.Erb ML, Moore DJ.LRRK2 and the endolysosomal system in Parkinson's Disease.

2020;10(4):1271–1291.https://doi.org/10.3233/JPD-202138

4.Di Fonzo A, Rohé CF, Ferreira J, et al.A frequent LRRK2 gene mutation associated with autosomal dominant Parkinson's disease.

2005;365(9457):412–415.https://doi.org/10.1016/S0140-6736(05)17829-5

5.Zimprich A, Biskup S, Leitner P, et al.Mutations in LRRK2 cause autosomal-dominant parkinsonism with pleomorphic pathology.

2004:44(4):601–607.https://doi.org/10.1016/j.neuron.2004.11.005

6.Paisán-Ruíz C, Jain S, Evans EW,et al.Cloning of the gene containing mutations that cause PARK8-linked Parkinson's disease.

.2004;44(4):595–600.https://doi.org/10.1016/j.neuron.2004.10.023

7.Ross OA, Toft M, Whittle AJ, et al.Lrrk2 and Lewy body disease.

2006;59(2):388–393.https://doi.org/10.1002/ana.20731

8.Henderson MX, Sengupta M, Trojanowski JQ, Lee VMY.Alzheimer's disease tau is a prominent pathology in LRRK2 Parkinson's disease.

2019;7(1):183.https://doi.org/10.1186/s40478-019-0836-x

9.Rajput A, Dickson DW, Robinson CA, et al.Parkinsonism, Lrrk2 G2019S, and tau neuropathology.

2006;67(8):1506–1508.https://doi.org/10.1212/01.wnl.0000240220.33950.0c

10.Nalls MA, Pankratz N, Lill CM, et al.Large-scale meta-analysis of genome-wide association data identifies six new risk loci for Parkinson's disease.

2014;46(9):989–993.https://doi.org/10.1038/ng.3043

11.Gilks WP, Abou-Sleiman PM, Gandhi S, et al.A common LRRK2 mutation in idiopathic Parkinson's disease.

2005;365(9457):415–416.https://doi.org/10.1016/S0140-6736(05)17830-1

12.Lesage S, Janin S, Lohmann E, et al.LRRK2 exon 41 mutations in sporadic Parkinson disease in Europeans.

2007;64(3):425–430.https://doi.org/10.1001/archneur.64.3.425

13.Shu L, Zhang Y, Sun QY, Pan HX, Tang BS.A comprehensive analysis of population differences in LRRK2 variant distribution in Parkinson's disease.

2019;11:13.https://doi.org/10.3389/fnagi.2019.00013

14.Kesh S, Kannan RR, Sivaji K, Balakrishnan A.Hesperidin downregulates kinases lrrk2 and gsk3β in a 6-OHDA induced Parkinson's disease model.

.2021;740:135426.https://doi.org/10.1016/j.neulet.2020.135426

15.Golpich M, Amini E, Hemmati F, et al.Glycogen synthase kinase-3 beta (GSK-3β) signaling: implications for Parkinson's disease.

2015;97:16–26.https://doi.org/10.1016/j.phrs.2015.03.010

16.Li CC, An HQ, Wang JH, Jiang ZY, Zhang TQ, Huo Q.Comparison of efficacy and safety of complementary and alternative therapies for Parkinson's disease: a Bayesian network meta-analysis protocol.

(

).2020;99(38):e22265.https://doi.org/10.1097/MD.0000000000022265

17.Hussain G, Zhang LB, Rasul A, et al.Role of plant-derived flavonoids and their mechanism in attenuation of Alzheimer's and Parkinson's diseases: an update of recent data.

.2018;23(4):814.https://doi.org/10.3390/molecules23040814

18.Trautmann-Sponsel RD, Dienel A.Safety of

extract in mildly to moderately depressed outpatients: a review based on data from three randomized, placebo-controlled trials.

2004;82(2):303–307.https://doi.org/10.1016/j.jad.2003.12.017

19.Hou WN, Shakya P, Franklin G.A perspective on

genetic transformation.

2016;7:879.https://doi.org/10.3389/fpls.2016.00879

20.Sarikurkcu C, Locatelli M, Tartaglia A, et al.Enzyme and biological activities of the water extracts from the plants

,

and

that are used as folk remedies in Turkey.

.2020;25(5):1202.https://doi.org/10.3390/molecules25051202

21.Lecrubier Y, Clerc G, Didi R, Kieser M.Efficacy of St.John's wort extract WS 5570 in major depression: a double-blind,placebo-controlled trial.

2002;159(8):1361–1366.https://doi.org/10.1176/appi.ajp.159.8.1361

22.Butterweck V.Mechanism of action of St John's wort in depression: what is known?

2003;17(8):539–562.https://doi.org/10.2165/00023210-200317080-00001

23.Agostinis P, Vantieghem A, Merlevede W, de Witte PA.Hypericin in cancer treatment: more light on the way.

2002;34(3):221–241.https://doi.org/10.1016/S1357-2725(01)00126-1

24.Schinazi RF, Chu CK, Babu JR, et al.Anthraquinones as a new class of antiviral agents against human immunodeficiency virus.

1990;13(5):265–272.https://doi.org/10.1016/0166-3542(90)90071-E

25.Silva BA, Dias AC, Ferreres F, Malva JO, Oliveira CR.Neuroprotective effect of

extracts on beta-amyloid-induced neurotoxicity.

2004;6(2):119–130.https://doi.org/10.1007/BF03033214

26.Yadollah-Damavandi S, Chavoshi-Nejad M, Jangholi E, et al.Topical

improves tissue regeneration in full-thickness excisional wounds in diabetic rat model.

.2015;2015:245328.https://doi.org/10.1155/2015/245328

27.Silva BA, Ferreres F, Malva JO, Dias ACP.Phytochemical and antioxidant characterization of

alcoholic extracts.

.2005;90(1–2):157–167.https://doi.org/10.1016/j.foodchem.2004.03.049

28.Kwon SH, Lee SR, Park YJ, et al.Suppression of 6-hydroxydopamine-induced oxidative stress by hyperoside via activation of Nrf2/HO-1 signaling in dopaminergic neurons.

2019;20(23):5832.https://doi.org/10.3390/ijms20235832

29.Jiang W, Luo T, Li S, et al.Quercetin protects against okadaic acid-induced injury via MAPK and PI3K/Akt/GSK3β Signaling pathways in HT22 hippocampal neurons.

2016;11(4):e0152371.https://doi.org/10.1371/journal.pone.0152371

30.Ay M, Luo J, Langley M, et al.Molecular mechanisms underlying protective effects of quercetin against mitochondrial dysfunction and progressive dopaminergic neurodegeneration in cell culture and MitoPark transgenic mouse models of Parkinson's Disease.

2017;141(5):766–782.https://doi.org/10.1111/jnc.14033