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The Journal of Neuroscience, December 1, 2000, 20(23):8604-8609
Estrogen Is Essential for Maintaining Nigrostriatal Dopamine Neurons in Primates: Implications for Parkinson's Disease and Memory
Csaba Leranth1, 5, Robert H. Roth2, 3, John D. Elsworth2, 3, Frederick Naftolin1, Tamas L. Horvath1, 5, and D. Eugene Redmond Jr2, 4 Departments of 1 Obstetrics and Gynecology, 2 Psychiatry, 3 Pharmacology, and 4 Neurosurgery and 5 Section of Neurobiology, Yale University, School of Medicine, New Haven, Connecticut 06520-8063
There are sexual differences in several parameters of the nigrostriatal dopamine neurons, as well as in the progression of diseases associated with this system, e.g., Parkinson's disease and dementia. These differences, as well as direct experimental data in rodents, suggest that gonadal hormones play a role in modulating this system. To determine whether circulating estrogen might have long-term effects by altering the number of dopamine neurons, the density of dopamine neurons was calculated in the compact zone of the substantia nigra of male and intact female short- (10 d) and longer-term (30 d) ovariectomized and short- and longer-term ovariectomized but estrogen-replaced nonhuman primates (African green monkeys). Furthermore, the number of tyrosine hydroxylase-expressing neurons, the total number of all types of neurons, and the volume of the compact zone of the substantia nigra were calculated in 30 d ovariectomized and in 30 d ovariectomized and estrogen-replaced monkeys. Unbiased stereological analyses demonstrated that a 30 d estrogen deprivation results in an apparently permanent loss of >30% of the total number of substantia nigra dopamine cells. Furthermore, the density calculations showed that brief estrogen replacement restores the density of tyrosine hydroxylase-immunoreactive cells after a 10 d, but not after a 30 d, ovariectomy. Moreover, the density of dopamine cells is higher in females than in males. These observations show the essential role of estrogen in maintaining the integrity of the nigral dopamine system, suggest a new treatment strategy for patients with Parkinson's disease and with certain forms of memory-impairing disorders, and provide another rationale for estrogen replacement therapy for postmenopausal women.
Key words: substantia nigra; African green monkey; ovariectomy; estrogen replacement; apoptosis; Parkinson's disease
Copyright © 2000 Society for Neuroscience 0270-6474/00/20238604-06$05.00/0
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