Skip to main content
SpringerLink
Log in

Withania somnifera Alleviates Parkinsonian Phenotypes by Inhibiting Apoptotic Pathways in Dopaminergic Neurons

  • Original Paper
  • Published:
Neurochemical Research Aims and scope Submit manuscript

Abstract

Maneb (MB) and paraquat (PQ) are environmental toxins that have been experimentally used to induce selective damage of dopaminergic neurons leading to the development of Parkinson’s disease (PD). Although the mechanism of this selective neuronal toxicity in not fully understood, oxidative stress has been linked to the pathogenesis of PD. The present study investigates the mechanisms of neuroprotection elicited by Withania somnifera (Ws), a herb traditionally recognized by the Indian system of medicine, Ayurveda. An ethanolic root extract of Ws was co-treated with the MB–PQ induced mouse model of PD and was shown to significantly rescue canonical indicators of PD including compromised locomotor activity, reduced dopamine in the substantia nigra and various aspects of oxidative damage. In particular, Ws reduced the expression of iNOS, a measure of oxidative stress. Ws also significantly improved the MB + PQ mediated induction of a pro-apoptotic state by reducing Bax and inducing Bcl-2 protein expression, respectively. Finally, Ws reduced expression of the pro-inflammatory marker of astrocyte activation, GFAP. Altogether, the present study suggests that Ws treatment provides nigrostriatal dopaminergic neuroprotection against MB–PQ induced Parkinsonism by the modulation of oxidative stress and apoptotic machinery possibly accounting for the behavioural effects.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2
Fig. 3
Fig. 4
Fig. 5
Fig. 6
Fig. 7
Fig. 8

Similar content being viewed by others

References

  1. Blum D, Torch S, Lambeng N, Nissou M, Benabid L, Sadoul R, Verna JM (2001) Molecular pathways involved in the neurotoxicity of 6-OHDA, dopamine and MPTP: contribution to the apoptotic theory in Parkinson’s disease. Prog Neurobiol 65:135–172

    Article  CAS  PubMed  Google Scholar 

  2. Simunovic F, Yi M, Wang Y, Macey L, Brown LT, Krichevsky AM, Andersen SL, Stephens RM, Benes FM, Sonntag KC (2009) Gene expression profiling of substantia nigra dopamine neurons, further insights into Parkinson’s disease pathology. Brain 132:1795–1809

    Article  PubMed Central  PubMed  Google Scholar 

  3. Bernheimer H, Birkmayer W, Hornykiewicz O, Jellinger K, Seitelberger F (1973) Brain dopamine and the syndromes of Parkinson and Huntington. Clinical, morphological and neurochemical correlations. J Neurol Sci 20:415–455

    Article  CAS  PubMed  Google Scholar 

  4. Yadav S, Dixit A, Agrawal S, Singh A, Srivastava G, Singh AK, Srivastava PK, Prakash O, Singh MP (2012) Rodent models and contemporary molecular techniques: notable feats yet incomplete explanations of Parkinson’s disease pathogenesis. Mol Neurobiol 829:1–8

    Google Scholar 

  5. Prakash J, Yadav SK, Chouhan S, Singh SP (2013) Neuroprotective role of Withania somnifera root extract in Maneb–Paraquat induced mouse model of parkinsonism. Neurochem Res 38:972–980

    Article  CAS  PubMed  Google Scholar 

  6. Rajasankara S, Manivasagam T, Sankar V, Prakash S, Muthusamy R, Krishnamurti A, Surendran S (2009) Withania somnifera root extract improves catecholamines and physiological abnormalities seen in a Parkinson’s disease model mouse. J Ethnopharmacol 125:369–373

    Article  Google Scholar 

  7. Somayajulu-Niţu M, Sandhu JK, Cohen J, Sikorska M, Sridhar TS, Matei A, Borowy-Borowski H, Pandey S (2009) Paraquat induces oxidative stress, neuronal loss in substantia nigra region and parkinsonism in adult rats: neuroprotection and amelioration of symptoms by water soluble formulation of coenzyme Q10. BMC Neurosci 10:1–12

    Article  Google Scholar 

  8. Srivastava G, Dixit A, Yadav S, Patel DK, Prakash O, Singh MP (2012) Resveratrol potentiates cytochrome P4502d22-mediated neuroprotection in maneb- and paraquat-induced Parkinsonism in the mouse. Free Radic Biol Med 52:1294–1306

    Article  CAS  PubMed  Google Scholar 

  9. Pezzoli G, Cereda E (2013) Exposure to pesticides or solvents and risk of Parkinson disease. Neurology 80:2035–2041

    Article  CAS  PubMed  Google Scholar 

  10. Singhal NK, Chauhan AK, Jain SK, Shanker R, Singh C, Singh MP (2013) Silymarin and melatonin-mediated changes in the expression of selected genes in pesticides-induced Parkinsonism. Mol Cell Biochem 384:47–58

    Article  CAS  PubMed  Google Scholar 

  11. Xu D, Duan H, Zhang Z, Cui W, Wang L, Sun Y, Lang M, Hoi PM, Han Y, Wang Y, Lee SM (2013) The novel TetramethylpyrazineBis-nitrone (TN-2) protects against MPTP/MPP+-induced neurotoxicity via inhibition of mitochondrial-dependent apoptosis. J Neuroimmune Pharmacol 9:245–258

    Article  Google Scholar 

  12. Alam N, Hossain M, Khalil MI, Moniruzzaman M, Sulaiman SA, Gan SH (2012) Recent advances in elucidating the biological properties of Withania somnifera and its potential role in health benefit. Phytochemistry 11:97–112

    Article  CAS  Google Scholar 

  13. Orru A, Marchese G, Casu G, Casu MA, Kasture S, Cottiglia F, Acquas E, Mascia MP, Anzani N, Ruiu S (2013) Withania somnifera root extract prolongs analgesia and suppresses hyperalgesia in mice treated with morphine. Phytomedicine 21:745–752

    Article  PubMed  Google Scholar 

  14. Kuboyama T, Tohda C, Zhao J, Nakamura N, Hattori M, Komatsu K (2002) Axon or dendrite predominant outgrowth induced by constituents from Ashwagandha. Neuroreport 13:1715–1720

    Article  CAS  PubMed  Google Scholar 

  15. Tohda C, Joyashiki E (2009) Sominone enhances neurite outgrowth and spatial memory mediated by the neurotrophic factor receptor RET. Br J Pharmacol 157:1427–1440

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  16. Dhuley JN (1997) Effect of some Indian herbs on macrophage functions in ochratoxin A treated mice. J Ethnopharmacol 58:15–20

    Article  CAS  PubMed  Google Scholar 

  17. Chaurasia SS, Panda S, Kar A (2000) Withania somnifera root extract in the regulation of lead-induced oxidative damage in male mouse. Pharmacol Res 44:663–666

    Article  Google Scholar 

  18. Singh S, Singh K, Patel DK, Singh C, Nath C, Singh VK, Singh RK, Singh MP (2009) The expression of CYP2D22 an ortholog of human CYP2D6 in mouse striatum and its modulation in 1-methyl 4-phenyl-1,2,3,6-tetrahydropyridine induced Parkinson’s disease phenotype and nicotine mediated neuroprotection. Rejuvenation Res 12:185–197

    Article  CAS  PubMed  Google Scholar 

  19. Chaurasiya ND, Uniyal GC, Lal P, Misra L, Sangwan NL, Tuli R, Sangwan RS (2008) Analysis of withanolides in root and leaf of Withania somnifera by HPLC with photodiode array and evaporative light scattering detection. Phytochem Anal 19:148–154

    Article  PubMed  Google Scholar 

  20. Tiwari MN, Singh AK, Ahmad I, Upadhyay G, Singh D, Patel DK, Singh C, Prakash O, Singh MP (2010) Effects of cypermethrin on monoamine transporters, xenobiotic metabolizing enzymes and lipid peroxidation in the rat nigrostriatal system. Free Radic Res 44:1416–1424

    Article  CAS  PubMed  Google Scholar 

  21. Martin PY, Bianchi M, Roger F, Niksic L, Féraille E (2002) Arginine vasopressin modulates expression of neuronal NOS in rat renal medulla. Am J Physiol Renal Physiol 283:559–568

    Google Scholar 

  22. Bradford MM (1976) A rapid and sensitive method for the quantitation of microgram quantities of protein utilizing the principle of protein-dye binding. Anal Biochem 72:248–254

    Article  CAS  PubMed  Google Scholar 

  23. Gupta SP, Patel S, Yadav S, Singh AK, Singh S, Singh MP (2010) Involvement of nitric oxide in maneb and paraquat-induced Parkinson’s disease phenotype in mouse: is there any link with lipid peroxidation. Neurochem Res 35:1206–1213

    Article  CAS  PubMed  Google Scholar 

  24. Kasture S, Pontis S, Pinna A, Schintu N, Spina L, Longoni R, Simola N, Ballero M, Morelli M (2009) Assessment of symptomatic and neuroprotective efficacy of Mucuna pruriens seed extract in rodent model of Parkinson’s disease. Neurotox Res 15:111–122

    Article  PubMed  Google Scholar 

  25. Yadav SK, Prakash J, Chouhan S, Westfall S, Verma M, Singh TD, Singh SP (2014) Comparison of the neuroprotective potential of Mucuna pruriens seed extract with estrogen in 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-induced PD mice model. Neurochem Int 65:1–13

    Article  CAS  PubMed  Google Scholar 

  26. Mochizuki H, Hayakawa H, Migit M, Shibata M, Tanaka R, Suzuki A, Shimo NY, Urabe T, Yamada M, Tamayos K, Shimada T, Miura M, Mizuno Y (2001) An AAV-derived Apaf-1 dominant negative inhibitor prevents MPTP toxicity as antiapoptotic gene therapy for Parkinson’s disease. Proc Natl Acad Sci USA 98:10918–10923

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  27. Agrawal R, Tyagi E, Saxena G, Nath C (2009) Cholinergic influence on memory stages A study on scopolamine amnesic mice. Indian J Pharmacol 41:192–196

    Article  PubMed Central  PubMed  Google Scholar 

  28. Widodo N, Kaur K, Shrestha BG, Takagi Y, Ishii T, Wadhwa R, Kaul SC (2007) Selective killing of cancer cells by leaf extract of Ashwagandha Identification of a tumor inhibitory factor and the first molecular insights to its effect. Clin Cancer Res 13:2298–2306

    Article  CAS  PubMed  Google Scholar 

  29. Liou HH, Tsai MC, Chen CJ, Jeng JS, Chang YC, Chen SY, Chen RC (1997) Environmental risk factors and Parkinson’s disease, a case-control study in Taiwan. Neurology 48:1583–1591

    Article  CAS  PubMed  Google Scholar 

  30. Willis AW (2013) Parkinson disease in the elderly adult. Mo Med 110:406–410

    PubMed  Google Scholar 

  31. Anglade P, Vyas S, Javoy-Agid F, Herrero MT, Michel PP, Marquez J, Mouatt-Prigent A, Ruberg M, Hirsch EC, Agid Y (1997) Apoptosis and autophagy in nigral neurons of patients with Parkinson’s disease. Histol Histopathol 12:25–31

    CAS  PubMed  Google Scholar 

  32. Kingsbury AE, Mardsen CD, Foster OJ (1998) DNA fragmentation in human substantia nigra: apoptosis or perimortem effect? Mov Disord 13:877–884

    Article  CAS  PubMed  Google Scholar 

  33. Levy OA, Malagelada C, Greene LA (2009) Cell death pathways in Parkinson’s disease: proximal triggers, distal effectors, and final steps. Apoptosis 14:478–500

    Article  PubMed Central  PubMed  Google Scholar 

  34. Schwarting RK, Bonatz AE, Carey RJ, Huston JP (1991) Relationships between indices of behavioral asymmetries and neurochemical changes following mesencephalic 6-hydroxydopamine injections. Brain Res 554:46–55

    Article  CAS  PubMed  Google Scholar 

  35. Konar A, Shah N, Singh R, Saxena N, Kaul SC, Wadhwa R, Thakur MK (2011) Protective role of Ashwagandha leaf extract and its component withanone on scopolamine-induced changes in the brain and brain-derived cells. PLoS One 6:1–11

    Article  Google Scholar 

  36. Jinsmaa Y, Florang VR, Rees JN, Anderson DG, Strac S, Doorn JA (2009) Products of oxidative stress inhibit aldehyde oxidation and reduction pathways in dopamine catabolism yielding elevated levels of a reactive intermediate. Chem Res Toxicol 22:835–841

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  37. Marchitti SA, Deitrich RA, Vasiliou V (2007) Neurotoxicity and metabolism of the catecholamine-derived 3,4-dihydroxyphenylacetaldehyde and 3,4-dihydroxyphenylglycolaldehyde: the role of aldehyde dehydrogenase. Pharmacol Rev 59:125–150

    Article  CAS  PubMed  Google Scholar 

  38. Hinterberger H (1971) The biochemistry of catecholamines in relation to Parkinson’s disease. Aust N Z J Med Suppl 1:8–14

    Article  Google Scholar 

  39. Piggott MA, Marshall EF, Thomas N, Lloyd S, Court JA, Jaros E, Costa D, Perry RH, Perry EK (1999) Dopaminergic activities in the human striatum rostrocaudal gradients of uptake sites and of D1 and D2 but not of D3 receptor binding or dopamine. Neuroscience 90:433–445

    Article  CAS  PubMed  Google Scholar 

  40. Yang L, Matthews RT, Schulz JB, Klockgether T, Liao AW, Martinou JC, Penney JB Jr, Hyman BT, Beal MF (1998) 1-Methyl-4-phenyl-1,2,3,6-tetrahydropyride neurotoxicity is attenuated in mice over expressing Bcl-2. J Neurosci 18:8145–8152

    CAS  PubMed  Google Scholar 

  41. Bus JS, Gibson JE (1984) Paraquat: model for oxidant-initiated toxicity. Environ Health Perspect 55:37–46

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  42. Cohen GM, d’Arcy Doherty M (1987) Free radical mediated cell toxicity by redox cycling chemicals. Br J Cancer Suppl 8:46–52

    CAS  PubMed Central  PubMed  Google Scholar 

  43. Rappold PM, Tieu K (2010) Astrocytes and therapeutics for Parkinson’s disease. Neurotherapeutics 7:413–423

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  44. Mena MA, García de Yébenes J (2008) Glial cells as players in parkinsonism: the “good” the “bad” and the “mysterious” glia. Neuroscientist 14:544–560

    Article  CAS  PubMed  Google Scholar 

  45. Heneka MT, Rodríguez JJ, Verkhratsky A (2010) Neuroglia in neurodegeneration. Brain Res Rev 63:189–211

    Article  CAS  PubMed  Google Scholar 

  46. Jukkola P, Guerrero T, Gray V, Gu C (2013) Astrocytes differentially respond to inflammatory autoimmune insults and imbalances of neural activity. Acta Neuropathol Commun 23:1–10

    Google Scholar 

Download references

Acknowledgments

Authors are thankful to the Head, Department of Biochemistry and Zoology, BHU for providing the basic departmental and cryostat facility, respectively. We sincerely thank Indian Council of Medical Research, New Delhi for providing fellowship to Jay Prakash and Sachchida Nand Rai, Council of Scientific and Industrial Research, New Delhi for providing fellowship to Satyndra Kumar Yadav, Department of Science and Technology, New Delhi, for providing fellowship to Shikha Chouhan.

Conflict of interest

Authors declare that there is no conflict of interest.

Author information

Authors and Affiliations

  1. Department of Biochemistry, Faculty of Science, Banaras Hindu University, Varanasi, 221005, Uttar Pradesh, India

    Jay Prakash, Shikha Chouhan, Satyndra Kumar Yadav, Susan Westfall, Sachchida Nand Rai & Surya Pratap Singh

Authors
  1. Jay Prakash
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Shikha Chouhan
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Satyndra Kumar Yadav
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Susan Westfall
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Sachchida Nand Rai
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Surya Pratap Singh
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Surya Pratap Singh.

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Prakash, J., Chouhan, S., Yadav, S.K. et al. Withania somnifera Alleviates Parkinsonian Phenotypes by Inhibiting Apoptotic Pathways in Dopaminergic Neurons. Neurochem Res 39, 2527–2536 (2014). https://doi.org/10.1007/s11064-014-1443-7

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s11064-014-1443-7

Keywords

Search

Navigation