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Effectiveness of Fragment C Domain of Tetanus Toxin and Pramipexole in an Animal Model of Parkinson’s Disease

  • Felipe Patricio
  • Irving Parra
  • Isabel Martínez
  • Francisca Pérez-Severiano
  • Sergio Montes
  • José Aguilera
  • Ilhuicamina Daniel Limón
  • Yousef Tizabi
  • Liliana Mendieta
Original Article

Abstract

Reports indicate that striatal dopaminergic damage induced by 6-hydoxydopamine (6-OHDA) can be blocked by C-terminal domain of tetanus toxin (Hc-TeTx), suggesting possible therapeutic potential of Hc-TeTx in Parkinson’s disease (PD). Pramipexole (PPX), a D2/D3 dopaminergic agonist, is currently used in PD treatment. The purpose of this study was to gain some understanding of the actions of each drug, including potential antioxidant and anti-inflammatory effects and importantly, to determine whether the combination of the two drugs would be superior to each alone. Adult male Wistar rats were administered 6-OHDA into the dorso­lateral striatum, and the effects of Hc-TeTx fragment (20 μg/kg i.m. every 24 h) for 3 days; PPX (1 mg/kg p.o., every 12 h) for 30 days and their combination on various motor and neurochemical parameters were evaluated. Behavioral tests were carried out at 15 and 30 days post-treatments. At day 31, the animals were sacrificed and the levels of tyrosine hydroxylase (TH), reflecting dopaminergic activity in both striatum and substantia nigra, were evaluated. In addition, indices of astrogliosis, microgliosis, as well as oxidative stress in the striatum were determined. Both Hc-TeTx and PPX ameliorated the motor and neurochemical deficits induced by 6-OHDA lesion; however, the combination of the two drugs was not superior to each alone. Hence, at concentrations used in this study, no significant advantage in combining Hc-TeTx with PPX was noted. Although the results suggest similar neurochemical effects of the two compounds, further evaluation of different concentrations of Hc-TeTx and PPX as potential intervention in PD is warranted.

Keywords

Tetanus toxin 6-Hydroxydopamine Astrogliosis Microgliosis Oxidative stress Superoxide dismutase Parkinson’s disease 

Abbreviations

6-OHDA

6-Hydoxydopamine

DA

Dopamine

DAB

Diaminobenzidine

DCF

2′,7′-Dichlorofluorescein

GFAP

Glial fibrillary acidic protein

Hc-TeTx

C-terminal domain of heavy-chain tetanus toxin

Iba-1

Ioninized calcium binding adaptor molecule 1

LPX

Lipid peroxidation

METH

Methamphetamine

MPP+

1-Methyl-4-phenylpyridinium (MPP+)

MPTP

1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine

NBT

Nitroblue tetrazolium

PD

Parkinson disease

PPX

Pramipexole

SNpc

Substantia nigra pars compacta

ROS

Reactive oxygen species

SOD

Superoxide dismutase

TH

Tyrosine hydroxylase

Notes

Acknowledgements

We thank Ana Candalija for her help in synthesizing Hc-TeTx fragment and Aldredo López from INNN-MVS for his technical assistance.

Funding

This work was supported by grants from PRODEP-SEP (N-PTC-472) and by VIEP-BUAP (2016-2017); F. Patricio was supported by a scholarship from CONACYT-Mexico (581481).

Compliance with Ethical Standards

All animal procedures were carried out in accordance with the Mexican Council for Care and Use of Laboratory Animals and the Norma Oficial Mexicana NOM-062-ZOO-1999

Conflict of Interest

The authors declare that they have no conflicts of interest.

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© Springer Science+Business Media, LLC, part of Springer Nature 2019

Authors and Affiliations

  • Felipe Patricio
    • 1
  • Irving Parra
    • 2
  • Isabel Martínez
    • 2
  • Francisca Pérez-Severiano
    • 3
  • Sergio Montes
    • 3
  • José Aguilera
    • 4
  • Ilhuicamina Daniel Limón
    • 1
  • Yousef Tizabi
    • 5
  • Liliana Mendieta
    • 2
  1. 1.Laboratorio de Neurofarmacología, Facultad de Ciencias QuímicasBenemérita Universidad Autónoma de PueblaPueblaMexico
  2. 2.Laboratorio de Neuroquímica, Facultad de Ciencias QuímicasBenemérita Universidad Autónoma de PueblaPueblaMexico
  3. 3.Departamento de Neuroquímica, Instituto Nacional de Neurología y Neurocirugía, Manuel Velasco SuárezMexico CityMexico
  4. 4.Institut de Neurociències and Departament de Bioquímica i de Biologia Molecular, Facultat de Medicina, and Centro de Investigación Biomédica en Red sobre Enfermedades Neurodegenerativas (CIBERNED)Universitat Autònoma de Barcelona (UAB)BarcelonaSpain
  5. 5.Department of PharmacologyHoward University College of MedicineWashingtonUSA

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