The therapeutic potential of neurotrophic factors in the treatment of Parkinson's disease

Abstract

Partial symptomatic relief from Parkinson's disease with levodopa has proven to be one of the rare success stories in the development of drugs to combat neurodegenerative diseases. However, no therapeutic agent has yet conclusively been shown to slow, halt, or reverse the underlying progression of neuronal loss in Parkinson's disease or any other human neurodegenerative disorder. This article reviews recent developments in the biology of neurotrophic growth factors, especially members of the nerve growth factor-related neurotrophin family, which may point to their potential as therapeutic agents for the treatment of Parkinson's disease. Parkinson's disease, characterized by the progressive loss of dopaminergic neurons of the substantia nigra, is one of the most well-characterized neurodegenerative disorders from both an anatomical and biochemical standpoint, but as yet the etiology of this disease remains poorly understood. Epidemiological, neurochemical, and pathological studies have provided a wealth of data that have spawned many theories of the underlying cause of Parkinson's disease, including environmental and genetic origins. Future elucidation of the disease process in Parkinson's disease may yield obvious therapeutic strategies, but even in the absence of such knowledge there are several general approaches that can be taken as strategies for the treatment of a "focal" neurodegenerative disease. These include: (a) mimetics, activation of the postsynaptic target(s) of the missing neurons through mimetics of the missing neurotransmitter, e.g., use of a dopamine precursor or dopamine receptor agonist in Parkinson's disease; (b) transplants, replenishment of the missing neurons via transplantation of neurons or nonneuronal cells secreting the appropriate neurotransmitter, e.g., fetal nigral grafts in Parkinson's disease; (c) neurotrophic factors or neuroprotectants, intervention with neurotrophic factors/neuroprotective agents which slow, halt, or reverse the progression of neuronal degeneration, e.g., a dopamine neurotrophic factor in Parkinson's disease. The scope of the present article is limited to a review of recent progress in the biology of neurotrophic factors that relates to their potential clinical use in treating the loss of dopamine neurons in Parkinson's disease.