MPTP Neurotoxicity: Actions, Mechanisms, and Animal Modeling of Parkinson’s Disease

  • Livia Pasquali
  • Elena Caldarazzo-Ienco
  • Francesco Fornai
Reference work entry
First Online:

Abstract

The study of neurotoxicity induced by MPTP led to drastically change the perspective on Parkinson’s Disease. In fact the selective neurotoxicity induced by MPTP rejuvenated PD research and generated a number of studies aimed at elucidating the mechanisms of action of MPTP. Remarkably, these molecular mechanisms turned out to be critical also for the survival of DA neurons in idiopathic PD. In this chapter we report the main concepts developed over the last three decades to understand key molecular steps which are pivotal in MPTP toxicity. This is the case of the role played by DAT and VMAT-2 in conditioning the sensitivity to MPTP neurotoxicity. Similarly, the mitochondria as targets of MPTP toxicity appear similarly affected by selective mutation of genes leading to PD. Again, the fate of mitochondria and the ability to clear these organelles when being dysfunctional is key in the modulation of MPTP toxicity. This also applies for misfolded proteins such as alpha synuclein. Again, multiple brain areas as well as peripheral sites are increasingly recognized to be affected both during MPTP toxicity and sporadic PD patients. Nowadays it seems that MPTP per se did not lead to discovery of the environmental compound which causes PD, nonetheless the study of MPTP did disclose several molecular and cellular pathways which are critical in the genesis of PD. This latter point fairly corresponds to what we enthusiastically expected from MPTP when it was identified as a causal agent of what it remains, a toxic form of environmental parkinsonism.

Keywords

Animal models MPP+ Parkinsonism 

List of Abbreviations

AMPA

Alpha-amino-3-hydroxy-5-methylisoxazole-4-propionic acid

ATG

Autophagy

ATP

Adenosine triphosphate

BBB

Blood–brain barrier

COX

Cyclooxygenase

DA

Dopamine

DAT

DA transporter

DSP-4

N-(−2-chloroethyl)-N-ethyl-2-bromobenzylamine

EAA

Excitatory amino acids

ENS

Enteric nervous system

GI

Gastrointestinal

GSH

Glutathione

i.c.v.

Intracerebroventricular

IP3

Inositol(1,4,5)trisphosphate

JNK

c-Jun N-terminal kinase

KO

Knockout

LC

Locus coeruleus

MAO-B

Monoamine oxidase type B

METH

Methamphetamine

MK-801

Dizocilpine

Mn-SOD

Manganese superoxide dismutase

MPDP+

1-Methyl-4-phenyl-2,3-dihydropyridine

MPP+

1-Methyl-4-phenylpyridinium

MPPP

1-Methyl-4-phenyl-4-propionoxy-piperidine

MPT

Mitochondrial permeability transition

MPTP

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

NAD

Nicotinamide adenine dinucleotide

NE

Norepinephrine

NET

NE transporter

NMDA

N-methyl-d-aspartate

NO

Nitric oxide

PD

Parkinson’s diseases

ROS

Reactive oxygen species

SC

Spinal cord

SNpc

Substantia nigra pars compacta

SOD

Superoxide dismutase

TH

Tyrosine hydroxylase

UP

Ubiquitin–proteasome

VMAT-2

Vesicular monoamine transporter type 2

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Copyright information

© Springer Science+Business Media New York 2014

Authors and Affiliations

  • Livia Pasquali
    • 1
  • Elena Caldarazzo-Ienco
    • 1
  • Francesco Fornai
    • 2
    • 3
  1. 1.Clinical NeurologyUniversity of PisaPisaItaly
  2. 2.Human AnatomyUniversity of PisaPisaItaly
  3. 3.NeuromedI.R.C.C.SPozzilliItaly

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