Protective and symptomatic strategies for therapy of Parkinson's disease

Fabio Blandini, J. Timothy Greenamyre

Research output: Contribution to journalArticle

Abstract

Parkinson's disease (PD) is a neurodegenerative disorder characterized by loss of the capacity to execute voluntary movements appropriately. PD develops as a consequence of the degeneration of dopamine-containing neurons in the substantia nigra pars compacta (SNc). SNc is a component of the basal ganglia nuclei, the network that controls the neural signaling underlying voluntary movements. The nigral cell loss triggers a cascade Of functional modifications in the basal ganglia circuit, the most important of which is hyperactivity of another component of the circuit, the subthalamic nucleus (STN). Subthalamic hyperactivity represents a major neural substrate of PD motor symptoms. The etiopathogenesis of PD is probably multifactorial. Various mechanisms - including mitochondrial defects, oxidative stress, glutamate toxicity and genetic factors - are likely to contribute to the degenerative process. Current therapy for PD is essentially symptomatic. L- dopa, the direct precursor of dopamine, is still the gold standard'. However, long-term therapy with L-dopa is associated with significant side effects. Therefore, there is a need for new therapeutic strategies aimed at relieving motor symptoms and slowing the progression of neuronal degeneration. The excitatory amino acid glutamate plays a central role in the functional modifications that affect the basal ganglia in PD. In particular, it mediates the enhanced excitatory drive of the STN to the output nuclei of the basal ganglia, which leads to the expression of PD symptoms. Furthermore, since the STN projects to the SNc, the excessive glutamatergic stimulation on residual nigral neurons may sustain the degenerative process, generating a self- maintaining vicious circle. From these considerations, it ensues that the use of drugs capable of antagonizing the effects of glutamate may provide new symptomatic and neuroprotective strategies for therapy of PD.

Original languageEnglish
Pages (from-to)473-483
Number of pages11
JournalDrugs of Today
Volume35
Issue number6
Publication statusPublished - Jun 1999

ASJC Scopus subject areas

  • Molecular Medicine
  • Pharmacology (medical)
  • Pharmacology

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