Loss of striatal DA innervation increases striatal trophic activity directed at DA neurons in culture.

Male rats received intraventricular infusions of the dopamine (DA) neurotoxin 6-hydroxydopamine (6-OHDA; 0, 75, 150, and 250 micrograms) in order to determine if DA neuron loss was associated with an increase in striatal trophic activity. After 4 weeks, the animals were sacrificed and perfused with normal saline, and the brains were removed, immediately frozen, and processed. Intraventricular infusions of 6-OHDA were associated with a dose-dependent reduction in striatal DA content and tyrosine hydroxylase-immunoreactive (THir) cell counts in the substantia nigra while striatal DA activity ([HVA]/[DA]) was increased. Extracts of the striatum from these animals increased the survival of E15 primary, dissociated rostral mesencphalic cultures growing at low cell density. This growth effect was positively correlated with the dose of 6-OHDA infused. THir cell counts present in high-cell-density mesencephalic cultures following 72 h of extract incubation were similarly correlated to 6-OHDA dose but inversely correlated with striatal DA content and THir cell counts in the substantia nigra. Trophic activity in the cerebellar extracts from these animals was significantly lower than that present in striatal extracts and was not influenced by 6-OHDA lesions. These data suggest that loss of DA innervation in the striatum is associated with an increase in striatal trophic activity directed at DA neurons. A compensatory response to the loss of DA neurons involving increased striatal trophic activity may result in increased DA terminal sprouting of remaining viable DA neurons that, in turn would serve to help reinstate normal DA tone.

Cerebrospinal fluid from patients with Parkinson's disease alters the survival of dopamine neurons in mesencephalic culture.

We have previously demonstrated that extracts of striatal tissue from patients with Parkinson's disease (PD) increase the survival of dopamine neurons in mesencephalic cultures relative to striatal extracts from control patients. In the present study, ventricular cerebrospinal fluid (vCSF) from patients with PD, Alzheimer's disease (AD), and age-matched controls was similarly assessed. vCSF samples were separated into > 10-kDa and < 10-kDa fractions. Cultures incubated with the > 10-kDa fractions from PD and AD patients contained 73 and 13%, respectively, more tyrosine hydroxylase immunoreactive neurons than cultures incubated with vCSF from age-matched controls. This trophic activity was positively correlated with the trophic activity present in striatal extracts from the same patients. The < 10-kDa vCSF fractions from all patient groups inhibited culture growth. These data suggest that the trophic environment in the striatum is altered in PD and can be successfully monitored in CSF.